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Sepsis-associated encephalopathy (SAE) increases not only morbidity and mortality but has been associated with long-lasting mental impairment after hospital discharge in septic patients. Recently, studies have shown that these mental impairments are caused by infection-induced neuroinflammation. However, the role of T cells in the pathogenesis of SAE and mental impairments remains unclear. Thus, in this study, we aimed to clarify how immune cells, especially T cells, influence the development and recovery of these disorders. In the cecal slurry (CS)-induced septic mouse model, we performed three different kinds of behavioral tests, open-field test, marble burying test, and forced swimming test, and observed anxiety-like behavior in septic mice. Additionally, increased interleukin (IL)-1ß and IL-6 expression levels, and infiltration of neutrophils and T cells were examined in the brain of septic mice, 10 days after sepsis onset. Twenty days after sepsis onset, the septic mice could recover the number of astrocytes. At day 30, expression levels of IL-1ß and tumor necrosis factor (TNF)-α returned to normal levels in the cerebral cortex of septic mice. Interestingly, resolution of neuroinflammation and alleviation of depression were delayed in septic mice treated with FTY720, which inhibits sphingosine-1-phosphate (S1P)-dependent lymphocyte egress from lymph nodes. On analyzing the brain T cells with or without FTY720 in septic mice, the FTY720 untreated mice presented increased regulatory T cells (Treg) and Th2 cells in the brain, whereas the FTY720 treated mice demonstrated increased Th17 in the brain at day 30. Furthermore, in FTY720 treated septic mice, the number of astrocytes in the cerebral cortex remained reduced at day 30. These results suggest that infiltrated Treg and Th2 cells contribute to the attenuation SAE and alleviate SAE-induce mental disorder by resolving neuroinflammation in the chronic phase of sepsis.
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Transtornos Mentais , Encefalopatia Associada a Sepse , Sepse , Animais , Encéfalo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Sepse/complicações , Linfócitos T Reguladores , Células Th2RESUMO
BACKGROUND: Intensive care unit-acquired weakness (ICU-AW) is a syndrome characterized by a long-term muscle weakness often observed in sepsis-surviving patients during the chronic phase. Although ICU-AW is independently associated with increased mortality, effective therapies have yet to be established. Programmed death-1 (PD-1) inhibitors have attracted attention as potential treatments for reversing immune exhaustion in sepsis; however, its impact on ICU-AW remains to be elucidated. Here, we study how PD-1 deficiency affects sepsis-induced skeletal muscle dysfunction in a preclinical sepsis model. METHODS: Chronic sepsis model was developed by treating wild-type (WT) and PD-1 knockout (KO) mice with caecal slurry, followed by resuscitation with antibiotics and saline. Mice were euthanized on days 15-17. Body weights, muscle weights, and limb muscle strengths were measured. Interleukin 13 (IL-13) and PD-1 expressions were examined by flow cytometry. Messenger RNA (mRNA) expressions of slow-twitch muscles were measured by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). In an in vitro study, C2C12 myotubes were treated with lipopolysaccharide (LPS) and recombinant IL-13 followed by gene expression measurements. RESULTS: WT septic mice exhibited decreased muscle weight (quadriceps, P < 0.01; gastrocnemius, P < 0.05; and tibialis anterior, P < 0.01) and long-term muscle weakness (P < 0.0001), whereas PD-1 KO septic mice did not exhibit any reduction in muscle weights and strengths. Slow-twitch specific mRNAs, including myoglobin (Mb), troponin I type 1 (Tnni1), and myosin heavy chain 7 (Myh7) were decreased in WT skeletal muscle (Mb, P < 0.0001; Tnni1, P < 0.05; and Myh7, P < 0.05) after sepsis induction, but mRNA expressions of Tnni1 and Myh7 were increased in PD-1 KO septic mice (Mb, not significant; Tnni1, P < 0.0001; and Myh7, P < 0.05). Treatment of C2C12 myotube cells with LPS decreased the expression of slow-twitch mRNAs, which was restored by IL-13 (Mb, P < 0.0001; Tnni1, P < 0.001; and Myh7, P < 0.05). IL-13 production was significantly higher in ILC2s compared to T cells in skeletal muscle (P < 0.05). IL-13-producing ILC2s in skeletal muscle were examined and found to increase in PD-1 KO septic mice, compared with WT septic mice (P < 0.05). ILC2-derived IL-13 was increased by PD-1 KO septic mice and thought to protect the muscles from experimental ICU-AW. CONCLUSIONS: Long-term muscle weakness in experimental ICU-AW was ameliorated in PD-1 KO mice. ILC2-derived IL-13 production in skeletal muscles was increased in PD-1 KO mice, thereby suggesting that IL-13 alleviates muscle weakness during sepsis. This study demonstrates the effects of PD-1 blockade in preserving muscle strength during sepsis through an increase in ILC2-derived IL-13 and may be an attractive therapeutic target for sepsis-induced ICU-AW.
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Although proteinuria is highly prevalent in obese individuals, the association between proteinuria and low body weight is equivocal. In this study we determine whether low body weight is more strongly associated with proteinuria compared with normal weight. The association between body mass index (BMI) and proteinuria was examined in a cross-sectional study of 62,582 asymptomatic individuals aged 20-70 years without known kidney diseases recruited, based on the results of medical checkups in 1999. We also examined the incidence of recurrent or nonrecurrent proteinuria in an 8-year longitudinal analysis of 12,493 individuals without proteinuria at baseline. The prevalence of proteinuria showed a J-shaped relationship with BMI. Multivariate regression analysis showed that BMI of 27.0 kg/m(2) and above or 18.9 kg/m(2) and less was significantly associated with proteinuria relative to BMI 21.0-22.9 kg/m(2), even after adjusting for relevant cardiometabolic risk factors. In the longitudinal study, similar J-shaped relationships between the incident rates of proteinuria and baseline BMI groups were observed at post-baseline checkups. Baseline BMI 27.0 kg/m(2) and above was associated with significantly greater risk for recurrent and nonrecurrent proteinuria, whereas BMI 18.9 kg/m(2) and less was only associated with nonrecurrent proteinuria. Thus, obesity and low body weight may be associated with different types of proteinuria independent of cardiometabolic risk factors.
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Povo Asiático , Peso Corporal/etnologia , Proteinúria/etnologia , Adulto , Idoso , Doenças Assintomáticas , Distribuição de Qui-Quadrado , Estudos Transversais , Feminino , Humanos , Incidência , Japão/epidemiologia , Modelos Lineares , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Prevalência , Proteinúria/diagnóstico , Recidiva , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Adulto JovemRESUMO
Overactivated microglia play a key role in sepsis-associated encephalopathy (SAE), although the involvement of T cells is unclear. γδT cells in the brain and meninges regulate normal fear responses via interleukin (IL)-17 in healthy mice. In our sepsis model, the mice showed exacerbated anxious behavior at 10 days post-induction (dpi). At 8 dpi, IL-17 mRNA was significantly upregulated in the brains of septic mice compared with those of control mice. Simultaneously, the number of γδT cells increased in the brains of septic mice in a severity-dependent manner. Additionally, IL-17-producing γδT cells, expressing both the C-X-C motif receptor (CXCR) 6 and the C-C motif receptor (CCR) 6, increased in mice brains, dependent on the severity of sepsis. The frequency of γδT cells in the meninges fluctuated similarly to that in the brain, peaking at 8 dpi of sepsis. Behavioral tests were performed on septic mice after the continuous administration of anti-γδTCR (α-γδTCR) or anti-IL-17A (α-IL-17A) antibodies to deplete the γδT cells and IL-17A, respectively. Compared with IgG-treated septic mice, α-γδTCR- and α-IL-17A-treated septic mice showed suppressed microglial activation and improvements in anxious behavior. These results suggested that CCR6+CXCR6+ IL-17-producing γδT cells in the brain and meninges promote the exacerbation of SAE and sepsis-induced psychological disorders in mice.
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The Great East Japan Earthquake that occurred on March 11, 2011, was one of the largest natural disasters in modern times. Publication in medical journals is important aspects of the academic promotion process, and is thus important for all scientists. However, little is known about whether and how substantial natural disasters affect gender disparities in academic productivity in disaster-affected areas. We hypothesized that the Great East Japan Earthquake widened the existing disparities in scientific publishing between male and female researchers. To test this hypothesis, this retrospective observational study using existing databases was conducted. We extracted from the MEDLINE database all types of biomedical articles published from March 11, 2007, to March 11, 2015, by three medical universities in a disaster-affected area of Japan. Differences in the proportion of female first authorship during the 4 years before and after the Great East Japan Earthquake were compared. A total of 5,873 papers were analyzed. The proportion of female first authors significantly declined after the Great East Japan Earthquake (20.5% vs. 14.1%; odds ratio 0.64; 95% confidence interval 0.56-0.73). A similar trend was identified across all prespecified subgroups, including clinical department; original article; public medical university; and prestigious journal with impact factor >6. Reference data from two medical universities minimally affected by the Great East Japan Earthquake showed the opposite trend. These results collectively suggest that large natural disasters can reinforce existing gender disparities in first authorship in biomedicine.
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Terremotos , Feminino , Masculino , Humanos , Universidades , Autoria , JapãoRESUMO
Aim: To identify whether the coronavirus disease 2019 (COVID-19) pandemic affects the operational efficiency of emergency medical services (EMS) and the survival rate of out-of-hospital cardiac arrest (OHCA) in prehospital settings. Methods: We conducted a population-based cohort study in Kobe, Japan, between March 1, 2020, and September 31, 2022. In study 1, the operational efficiency of EMS, such as the total out-of-service time for ambulances, the daily occupancy rate of EMS, and response time, was compared between the pandemic and nonpandemic periods. In study 2, the impacts of the changes in EMS operational efficiency were investigated among patients with OHCA, with 1-month survival as the primary outcome and return of spontaneous circulation, 24-h survival, 1-week survival, and favorable neurological outcomes as the secondary outcomes. Logistic regression analysis was conducted to identify the factors associated with survival among patients with OHCA. Results: The total out-of-service time, occupancy rate, and response time significantly increased during the pandemic period (p < 0.001). The response time during the pandemic period increased significantly per pandemic wave. Regarding OHCA outcomes, 1-month survival rates during the pandemic period significantly decreased compared with those during the nonpandemic period (pandemic 3.7% vs. nonpandemic 5.7%; p < 0.01). Similarly, 24-h survival (9.9% vs. 12.8%), and favorable neurological outcomes significantly decreased during the pandemic period. In the logistic regression analysis, response time was associated with lower OHCA survival in all outcomes (p < 0.05). Conclusion: The COVID-19 pandemic has been associated with reduced operational efficiency of EMS and decreased OHCA survival rates. Further research is required to improve the efficiency of EMS and OHCA survival rates.
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BACKGROUND/AIM: In pathology, the digitization of tissue slide images and the development of image analysis by deep learning have dramatically increased the amount of information obtainable from tissue slides. This advancement is anticipated to not only aid in pathological diagnosis, but also to enhance patient management. Deep learning-based image cytometry (DL-IC) is a technique that plays a pivotal role in this process, enabling cell identification and counting with precision. Accurate cell determination is essential when using this technique. Herein, we aimed to evaluate the performance of our DL-IC in cell identification. MATERIALS AND METHODS: Cu-Cyto, a DL-IC with a bit-pattern kernel-filtering algorithm designed to help avoid multi-counted cell determination, was developed and evaluated for performance using tumor tissue slide images with immunohistochemical staining (IHC). RESULTS: The performances of three versions of Cu-Cyto were evaluated according to their learning stages. In the early stage of learning, the F1 score for immunostained CD8+ T cells (0.343) was higher than the scores for non-immunostained cells [adenocarcinoma cells (0.040) and lymphocytes (0.002)]. As training and validation progressed, the F1 scores for all cells improved. In the latest stage of learning, the F1 scores for adenocarcinoma cells, lymphocytes, and CD8+ T cells were 0.589, 0.889, and 0.911, respectively. CONCLUSION: Cu-Cyto demonstrated good performance in cell determination. IHC can boost learning efficiencies in the early stages of learning. Its performance is expected to improve even further with continuous learning, and the DL-IC can contribute to the implementation of precision oncology.
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Adenocarcinoma , Aprendizado Profundo , Humanos , Linfócitos T CD8-Positivos , Medicina de Precisão , Algoritmos , Processamento de Imagem Assistida por Computador/métodosRESUMO
Burn injury is the leading cause of death and disability worldwide and places a tremendous economic burden on society. Systemic inflammatory responses induced by thermal burn injury can cause muscle wasting, a severe involuntary loss of skeletal muscle that adversely affects the survival and functional outcomes of these patients. Currently, no pharmacological interventions are available for the treatment of thermal burn-induced skeletal muscle wasting. Elevated levels of inflammatory cytokines, such as interleukin-6 (IL-6), are important hallmarks of severe burn injury. The levels of signal transducer and activator of transcription 3 (STAT3)-a downstream component of IL-6 inflammatory signaling-are elevated with muscle wasting in various pro-catabolic conditions, and STAT3 has been implicated in the regulation of skeletal muscle atrophy. Here, we tested the effects of the STAT3-specific signaling inhibitor C188-9 on thermal burn injury-induced skeletal muscle wasting in vivo and on C2C12 myotube atrophy in vitro after the administration of plasma from burn model mice. In mice, thermal burn injury severity dependently increased IL-6 in the plasma and tibialis anterior muscles and activated the STAT3 (increased ratio of phospho-STAT3/STAT3) and ubiquitin-proteasome proteolytic pathways (increased Atrogin-1/MAFbx and MuRF1). These effects resulted in skeletal muscle atrophy and reduced grip strength. In murine C2C12 myotubes, plasma from burn mice activated the same inflammatory and proteolytic pathways, leading to myotube atrophy. In mice with burn injury, the intraperitoneal injection of C188-9 (50 mg/kg) reduced activation of the STAT3 and ubiquitin-proteasome proteolytic pathways, reversed skeletal muscle atrophy, and increased grip strength. Similarly, pretreatment of murine C2C12 myotubes with C188-9 (10 µM) reduced activation of the same inflammatory and proteolytic pathways, and ameliorated myotube atrophy induced by plasma taken from burn model mice. Collectively, these results indicate that pharmacological inhibition of STAT3 signaling may be a novel therapeutic strategy for thermal burn-induced skeletal muscle wasting.
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Obesity, a known risk factor for various types of cancer, reduces the number and function of cytotoxic immune cells in the tumor immune microenvironment (TIME). However, the impact of obesity on CD4+ T cells remains unclear. Therefore, this study aimed to clarify the impact of obesity on CD4+ T cells in the TIME. A tumor-bearing obese mouse model was established by feeding with 45% high-fat diet (HFD), followed by inoculation with a colon cancer cell line MC38. Tumor growth was significantly accelerated compared to that in mice fed a control diet. Tumor CD4+ T cells showed a significant reduction in number and an increased expression of programmed death-1 (PD-1), and decreased CD107a expression and cytokine such as IFN-γ and TNF-α production, indicating dysfunction. We further established CD4+ T cell-depleted HFD-fed model mice, which showed reduced tumor infiltration, increased PD-1 expression in CD8+ T cells, and obesity-induced acceleration of tumor growth in a CD4+ T cell-dependent manner. These findings suggest that the reduced number and dysfunction of CD4+ T cells due to obesity led to a decreased anti-tumor response of both CD4+ and CD8+ T cells to ultimately accelerate the progression of colorectal cancer. Our findings may elucidate the pathogenesis for poor outcomes of colorectal cancer associated with obesity.
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Linfócitos T CD4-Positivos , Neoplasias Colorretais , Camundongos , Animais , Receptor de Morte Celular Programada 1/metabolismo , Obesidade/patologia , Linfócitos T CD8-Positivos , Processos Neoplásicos , Neoplasias Colorretais/complicações , Microambiente TumoralRESUMO
BACKGROUND: Anaesthetics generally have an immunosuppressive effect, which may be related to prognosis. We conducted to clarify the relationship between peri-operative immunosuppression and anaesthetic agents in patients undergoing lung cancer surgery, resulting in better selection of intraoperative anaesthesia. METHODS: Prospective randomized controlled study was performed in single-University hospital. Patients with lung cancer who were scheduled to undergo lung cancer resection between June 2018 and July 2019. Patients were randomly divided to three groups: desflurane (group D), sevoflurane (group S), and propofol (group P) groups. Peripheral blood mononuclear cells were separated from the blood samples. CD4+ and CD8+ T cells, programmed death 1 (PD-1) on CD4+ and CD8+ T cells, and regulatory T cells were measured by flow cytometry. The Wilcoxon signed rank sum test was used to compare pre- and post-operative values for each anaesthesia. RESULTS: Eighty-two patients were enrolled; samples from 64 individuals (20 in group D, 22 in group S, and 22 in group P) were analysed after exclusion. The number of CD8+ T cells was significantly lower after the operation than before the operation in the group P (P<0.05). The proportion of regulatory T cells was significantly increased after surgery, compared with before surgery in the group S (P<0.05). There was no difference in PD-1 on CD4+ and CD8+ T cells after lung surgery among the three groups. CONCLUSIONS: Propofol decreased the number of CD8+ T cells, while sevoflurane increased the proportion of regulatory T cells in patients after lung surgery; however, propofol, sevoflurane, and desflurane did not increase the proportion of PD-1 on CD4+ and CD8+ T cells after lung surgery. Sevoflurane and propofol may cause immunosuppression via different mechanisms after lung cancer surgery. TRIAL REGISTRATION: UMIN-CTR: UMIN000031911.
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A single-center retrospective cohort study examined the association between molar malocclusion status at ICU admission and loss of activities of daily living (ADL) at hospital discharge among acutely ill patients. Patients were assigned to the bilateral occlusion group or malocclusion group (N = 227 and 93, respectively). The following data were collected from electronic medical records: age, sex, Clinical Frailty Scale (CFS) on admission, Acute Physiology and Chronic Health Evaluation (APACHE) â ¡ score, confirmed diagnosis (neurological disorders or others), CFS at hospital discharge, and occlusion condition. Patients who were frail at admission (CFS > 5) were excluded from analysis, and ADL loss was defined as CFS > 5 at hospital discharge. Multivariate analysis showed malocclusion was independently associated with ADL loss [OR, 2.03; 95% CI, 1.13-3.64; p = 0.02]. For those aged 65 and older, malocclusion was significantly associated with both ADL loss [OR, 3.25; 95% CI, 1.44-7.32; p < 0.01] and the incidence of delirium [OR, 2.61; 95% CI, 1.14-5.95; p = 0.02]. Malocclusion on ICU admission was associated with ADL loss in critically ill patients, and was associated with ADL loss and the incidence of delirium in the elderly. Poor oral health was a poor prognostic factor among critically ill patients.
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Neonatal sepsis is characterized by systemic bacterial invasion followed by a massive inflammatory response. At present, no therapeutic strategy has been found that significantly reduces the mortality of neonatal sepsis. We aimed to investigate the protective role of an initial low-dose septic challenge for the prevention of subsequent lethal sepsis in a mouse model. A stock cecal slurry (CS) solution was prepared from adult ceca. The LD83 (1.5 mg CS/g) was used for all animals. An initial challenge of normal saline (NS) or 0.5 mg CS/g (non-lethal dose) was administered at four days of age, then 1.5 mg CS/g was administered intraperitoneally at seven days of age (72 h post-initial challenge), and survival was monitored. Initial exposure to NS (n = 10) resulted in 90% mortality following exposure to the LD83 CS dose in contrast to an initial exposure to CS (n = 16), which significantly decreased mortality to 6% (p < 0.0001), reduced blood bacterial counts, attenuated inflammatory responses, and suppressed lipid mediators. Initial exposure to a non-lethal CS dose prior to exposure to a lethal CS dose significantly reduces sepsis mortality, a protective effect that might be mediated by modulating abnormal systemic inflammatory responses.
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Despite the recent development of chemotherapeutic agents, the prognosis of colorectal cancer (CRC) patients with peritoneal dissemination (PD) remains poor. The tumor immune microenvironment (TIME) has drawn attention as a key contributing factor of tumor progression. Of TIME components, myeloidderived suppressor cells (MDSCs) are considered to play a responsible role in the immunosuppressive characteristics of the TIME. MDSCs are classified into two major subsets: Monocytic MDSCs (MMDSCs) and polymorphonuclear MDSCs (PMNMDSCs). Therefore, we hypothesize that MDSCs would play important roles in the PDrelevant TIME and PD progression. To address this hypothesis, we established PD mouse models. As the PD nodules consisted scarcely of immune cells, we focused on the peritoneal cavity, but not PD nodule, to evaluate the PDrelevant TIME. As a result, intraperitoneal PMNMDSCs were found to be substantially increased in association with PD progression. Based on these results, we phenotypically and functionally verified the usefulness of CD244 for identifying PMNMDSCs. In addition, the concentrations of interleukin (IL)6 and granulocytecolony stimulating factor (GCSF) were significantly increased in the peritoneal cavity, both of which were produced by the tumors and thought to contribute to the increases in the PMNMDSCs. In vivo depletion of the PMNMDSCs by antiLy6G monoclonal antibody (mAb) significantly inhibited the PD progression and reverted CD4+ and CD8+ T cells in the peritoneal cavity and the peripheral blood. Collectively, these results suggest that the targeted therapy for PMNMDSCs would provide not only new therapeutic value but also a novel strategy to synergize with Tcellbased immunotherapy for CRCderived PD.
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Neoplasias do Colo/patologia , Células Supressoras Mieloides/patologia , Neoplasias Peritoneais/secundário , Peritônio/patologia , Microambiente Tumoral , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Células Supressoras Mieloides/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismoRESUMO
BACKGROUND/AIM: Cancer stem cells (CSCs) contribute to resistance against neoadjuvant chemotherapy (NAC) in esophageal squamous cell carcinoma (ESCC). We conducted a retrospective observational study for the relationship between the expression levels of CSC markers in biopsy specimens prior to 5-fluorouracil plus cisplatin (FP)-NAC and the pathological responses. PATIENTS AND METHODS: We included 171 patients with ESCC who underwent the FP-NAC followed by radical resection. Biopsy specimens prior to the FP-NAC were obtained and immunochemically stained for CD44, CD133, and CD24. RESULTS: The biopsy specimens of the non-responders had the CD44high/CD24low expression at high levels, which was found as an independent predictor of not only FP-NAC resistance but also poor overall survival by multivariate analyses. CONCLUSION: CD44high/CD24low expression in the biopsy specimens prior to FP-NAC may be a predictor of FP-NAC resistance and poor prognosis of ESCC patients.
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Antígenos CD/metabolismo , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Fluoruracila/uso terapêutico , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/cirurgia , Esofagectomia , Feminino , Humanos , Masculino , Terapia Neoadjuvante , Células-Tronco Neoplásicas/metabolismo , Estudos RetrospectivosRESUMO
(1) Background: Cancer vaccines are administered to induce cytotoxic CD8+ T cells (CTLs) specific for tumor antigens. Invariant natural killer T (iNKT) cells, the specific T cells activated by α-galactosylceramide (α-GalCer), play important roles in this process as they are involved in both innate and adaptive immunity. We developed a new cancer vaccine strategy in which dendritic cells (DCs) were loaded with an exogenous ovalbumin (OVA) protein by electroporation (EP) and pulsed with α-GalCer. (2) Methods: We generated bone marrow-derived DCs from C57BL/6 mice, loaded full-length ovalbumin proteins to the DCs by EP, and pulsed them with α-GalCer (OVA-EP-galDCs). The OVA-EP-galDCs were intravenously administered to C57BL/6 mice as a vaccine. We then investigated subsequent immune responses, such as the induction of iNKT cells, NK cells, intrinsic DCs, and OVA-specific CD8+ T cells, including tissue-resident memory T (TRM) cells. (3) Results: The OVA-EP-galDC vaccine efficiently rejected subcutaneous tumors in a manner primarily dependent on CD8+ T cells. In addition to the OVA-specific CD8+ T cells both in early and late phases, we observed the induction of antigen-specific TRM cells in the skin. (4) Conclusions: The OVA-EP-galDC vaccine efficiently induced antigen-specific antitumor immunity, which was sustained over time, as shown by the TRM cells.
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Aging is a grave problem in sepsis, and T cell exhaustion is the main cause of sepsis-induced immunosuppression. Sepsis- and aging-induced T cell exhaustion is related to secondary infection with a poor long-term outcome in the elderly. However, the trend, impact, and mechanism of T cell exhaustion are still unclear. Interleukin (IL)-15 improves survival rate of septic mice via its antiapoptotic effect on T cells; however, it is still unclear how IL-15 reverses prolonged T cell exhaustion in aged septic mice. The purpose of this study was to clarify the trend of sepsis-induced T cell exhaustion and whether IL-15 prevents aging-induced persistent T cell exhaustion in septic mice. Preserved cecal slurry was injected intraperitoneally into young (6-week-old) and aged mice (18-24-month-old) 4 times, to induce clinically relevant repeated sepsis. IL-15 (1.5âµg) or phosphate-buffered saline was injected subcutaneously 3 times, body weight was serially measured, and peripheral blood cells from their cheek were serially collected for 50 days. Sepsis-induced T cell exhaustion was significantly severe in aged mice than in young mice and was accompanied with decreased naive CD4 and CD8 T cells (Pâ<â0.01) and increased expression of program death 1 on T cell (Pâ<â0.01) and regulatory T cell population (Pâ<â0.01). IL-15 significantly improved sepsis-induced T exhaustion, with significantly increased numbers of natural killer cells and macrophages, and significantly enhanced phagocytosis activity in aged septic mice (Pâ<â0.05). It decreased the long-term mortality associated with sepsis survivors by improving T cell exhaustion over an extended duration and also ameliorated aging-induced persistent T cell exhaustion in septic mice.
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Envelhecimento/fisiologia , Interleucina-15/uso terapêutico , Sepse/tratamento farmacológico , Sepse/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Feminino , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismoRESUMO
Circulating lipopolysaccharide (LPS) concentrations are often elevated in patients with sepsis or various endogenous diseases related to bacterial translocation from the gut. Systemic inflammatory responses induced by endotoxemia induce severe involuntary loss of skeletal muscle, termed muscle wasting, which adversely affects the survival and functional outcomes of these patients. Currently, no drugs are available for the treatment of endotoxemia-induced skeletal muscle wasting. Here, we tested the effects of TAK-242, a Toll-like receptor 4 (TLR4)-specific signalling inhibitor, on myotube atrophy in vitro and muscle wasting in vivo induced by endotoxin. LPS treatment of murine C2C12 myotubes induced an inflammatory response (increased nuclear factor-κB activity and interleukin-6 and tumour necrosis factor-α expression) and activated the ubiquitin-proteasome and autophagy proteolytic pathways (increased atrogin-1/MAFbx, MuRF1, and LC-II expression), resulting in myotube atrophy. In mice, LPS injection increased the same inflammatory and proteolytic pathways in skeletal muscle and induced atrophy, resulting in reduced grip strength. Notably, pretreatment of cells or mice with TAK-242 reduced or reversed all the detrimental effects of LPS in vitro and in vivo. Collectively, our results indicate that pharmacological inhibition of TLR4 signalling may be a novel therapeutic intervention for endotoxemia-induced muscle wasting.
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Endotoxemia/complicações , Fibras Musculares Esqueléticas/citologia , Atrofia Muscular/prevenção & controle , Sulfonamidas/administração & dosagem , Animais , Linhagem Celular , Modelos Animais de Doenças , Endotoxemia/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Home cooking has been suggested as a key to healthy dietary intakes. However, little is known about the association between cooking behaviour and nutrient intake among young-to-middle-aged women. We aimed to investigate the association between home cooking frequency and nutrient intake adequacy among married Japanese women. Self-administered questionnaires were used to assess the weekly frequency of cooking dinner at home and habitual nutrient intake during the preceding month. We evaluated nutrient intake adequacy by comparing the self-reported intake with two indices of the dietary reference intakes for Japanese (2015): the estimated average requirement (EAR) of fourteen nutrients, and the 'tentative dietary goal for preventing lifestyle-related diseases' (DG) of seven nutrients. A total of 143 participants (25-44 years old) completed the questionnaires, with 32·9 % of participants reporting a weekly home cooking frequency of seven times/week. Women with a higher home cooking frequency (seven times/week) were more likely to have children (P = 0·001) than those with a lower home cooking frequency (0-6 times/week). Of the nutrients evaluated, there was no significant difference between the two groups in meeting EAR and DG. Our findings suggest that daily home cooking may not be necessary to achieve adequate nutrient intake, specifically among married, young-to-middle-aged Japanese women.
Assuntos
Culinária , Ingestão de Energia , Refeições , Nutrientes , Adulto , Estudos Transversais , Feminino , Humanos , Japão , Estilo de Vida , Casamento , Avaliação Nutricional , Necessidades Nutricionais , Recomendações Nutricionais , Inquéritos e QuestionáriosRESUMO
Expanding elderly populations are a major social challenge in advanced countries worldwide and have led to a rapid increase in the number of elderly patients in intensive care units (ICUs). Innovative advances in medical technology have enabled lifesaving of patients in ICUs, but there remain various problems to improve their long-term prognoses. Post-intensive care syndrome (PICS) refers to physical, cognition, and mental impairments that occur during ICU stay, after ICU discharge or hospital discharge, as well as the long-term prognosis of ICU patients. Its concept also applies to pediatric patients (PICS-p) and the mental status of their family (PICS-F). Intensive care unit-acquired weakness, a syndrome characterized by acute symmetrical limb muscle weakness after ICU admission, belongs to physical impairments in three domains of PICS. Prevention of PICS requires performance of the ABCDEFGH bundle, which incorporates the prevention of delirium, early rehabilitation, family intervention, and follow-up from the time of ICU admission to the time of discharge. Diary, nutrition, nursing care, and environmental management for healing are also important in the prevention of PICS. This review outlines the pathophysiology, prevention, and future directions of PICS.