Serous ovarian cancer is the most frequent type of epithelial ovarian cancer. Despite the use of surgery and platinum‐based chemotherapy, many patients suffer from recurrence within 6 months, termed ...platinum resistance. Currently, the lack of relevant molecular biomarkers for the prediction of the early recurrence of serous ovarian cancers is linked to the poor prognosis. To identify an effective biomarker for early recurrence, we analyzed the genome‐wide DNA methylation status characteristic of early recurrence after treatment. The patients in The Cancer Genome Atlas (TCGA) dataset who showed a complete response after the first therapy were categorized into 2 groups: early recurrence serous ovarian cancer (ERS, recurrence ≤12 months, n = 51) and late recurrence serous ovarian cancer (LRS, recurrence >12 months, n = 158). Among the 12 differently methylated probes identified between the 2 groups, we found that ZNF671 was the most significantly methylated gene in the early recurrence group. A validation cohort of 78 serous ovarian cancers showed that patients with ZNF671 DNA methylation had a worse prognosis (P < .05). The multivariate analysis revealed that the methylation status of ZNF671 was an independent factor for predicting the recurrence of serous ovarian cancer patients both in the TCGA dataset and our cohort (P = .049 and P = .021, respectively). Functional analysis revealed that the depletion of ZNF671 expression conferred a more migratory and invasive phenotype to the ovarian cancer cells. Our data indicate that ZNF671 functions as a tumor suppressor in ovarian cancer and that the DNA methylation status of ZNF671 might be an effective biomarker for the recurrence of serous ovarian cancer after platinum‐based adjuvant chemotherapy.
The lack of relevant molecular biomarkers for the early recurrence of serous ovarian cancers is linked to the poor prognosis of this disease. This study identified ZNF671 as a prognostic and predictive biomarker for the early recurrence of serous ovarian cancer.
Epigenetic dysregulation in glioma Kondo, Yutaka; Katsushima, Keisuke; Ohka, Fumiharu ...
Cancer science,
April 2014, Volume:
105, Issue:
4
Journal Article
Peer reviewed
Open access
Given that treatment options for patients with glioblastoma are limited, much effort has been made to clarify the underlying mechanisms of gliomagenesis. Recent genome‐wide genomic and epigenomic ...analyses have revealed that mutations in epigenetic modifiers occur frequently in gliomas and that dysregulation of epigenetic mechanisms is closely associated with glioma formation. Given that epigenetic changes are reversible, understanding the epigenetic abnormalities that arise in gliomagenesis might be key to developing more effective treatment strategies for glioma. In this review, we focus on the recent advancements in epigenetic research with respect to gliomas, consider how epigenetic mechanisms dynamically regulate tumor cells, including the cancer stem cell population, and discuss perspectives and challenges for glioma treatment in the near future.
In this review, we focus on the recent advancements in epigenetic research with respect to gliomas, consider how epigenetic mechanisms dynamically regulate tumor cells, including the cancer stem cell population, and discuss perspectives and challenges for glioma treatment in the near future.
Emissions of black carbon (BC) particles from anthropogenic and natural sources contribute to climate change and human health impacts. Therefore, they need to be accurately quantified to develop an ...effective mitigation strategy. Although the spread of the emission flux estimates for China have recently narrowed under the constraints of atmospheric observations, consensus has not been reached regarding the dominant emission sector. Here, we quantified the contribution of the residential sector, as 64% (44-82%) in 2019, using the response of the observed atmospheric concentration in the outflowing air during Feb-Mar 2020, with the prevalence of the COVID-19 pandemic and restricted human activities over China. In detail, the BC emission fluxes, estimated after removing effects from meteorological variability, dropped only slightly (- 18%) during Feb-Mar 2020 from the levels in the previous year for selected air masses of Chinese origin, suggesting the contributions from the transport and industry sectors (36%) were smaller than the rest from the residential sector (64%). Carbon monoxide (CO) behaved differently, with larger emission reductions (- 35%) in the period Feb-Mar 2020, suggesting dominance of non-residential (i.e., transport and industry) sectors, which contributed 70% (48-100%) emission during 2019. The estimated BC/CO emission ratio for these sectors will help to further constrain bottom-up emission inventories. We comprehensively provide a clear scientific evidence supporting mitigation policies targeting reduction in residential BC emissions from China by demonstrating the economic feasibility using marginal abatement cost curves.
Abstract Purpose Sepsis remains an unresolved clinical problem with high in-hospital mortality. Despite intensive research over decades, no treatments for sepsis have become available. Here we ...explore the role of ATP in the pathophysiology of sepsis. ATP is not only a universal energy carrier but it also acts as an extracellular signaling molecule that regulates immune function. ATP stimulates a large family of purinergic receptors found on the cell surface of virtually all mammalian cells. In severe sepsis and septic shock, ATP is released in large amounts into the extracellular space where it acts as a “danger” signal. In this review, we focus on the roles of ATP as a key regulator of immune cell function and as a disruptive signal that contributes to immune dysfunction in sepsis. Methods We summarized the current understanding of the pathophysiology of sepsis, with special emphasis on the emerging role of systemic ATP as a disruptive force that promotes morbidity and mortality in sepsis. Findings Over the past two decades, the discovery that regulated ATP release and purinergic signaling represent a novel regulatory mechanism in immune cell physiology has opened up new possibilities in the treatment of sepsis. Immune cells respond to stimulation with the release of cellular ATP, which regulates cell functions in autocrine and paracrine fashions. In sepsis, large amounts of systemic ATP produced by tissue damage and inflammation disrupt these regulatory purinergic signaling mechanisms, leading to immune dysfunction that promotes the pathophysiologic processes involved in sepsis. Implications The knowledge of these ATP-dependent signaling processes is likely to reveal exciting new avenues in the treatment of the unresolved clinical problem of sepsis.
The degradation of trace gases and pollutants in the troposphere is dominated by their reaction with hydroxyl radicals (OH). The importance of OH rests on its high reactivity, its ubiquitous ...photochemical production in the sunlit atmosphere, and most importantly on its regeneration in the oxidation chain of the trace gases. In the current understanding, the recycling of OH proceeds through HO₂ reacting with NO, thereby forming ozone. A recent field campaign in the Pearl River Delta, China, quantified tropospheric OH and HO₂ concentrations and turnover rates by direct measurements. We report that concentrations of OH were three to five times greater than expected, and we propose the existence of a pathway for the regeneration of OH independent of NO, which amplifies the degradation of pollutants without producing ozone.
The 2016 International Guidelines for the Management of Sepsis and Septic Shock recommend antibiotic therapy for 7-10 days for most patients with sepsis. However, evidence on critically ill patients ...is limited. Thus, we conducted the first systematic review and meta-analysis comparing the effectiveness and adverse events of shorter- (≤1 week) with longer-course antibiotics in adults with critical infections including sepsis.
We searched the MEDLINE, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi databases for randomised controlled trials (RCTs) and observational studies (OSs) from inception to 31 March 2021.
We included 6 of 3,766 identified articles, incorporating data from 4 RCTs and 2 OSs (1,721 patients) in meta-analyses. Three RCTs and one OS focussed on ventilator-associated pneumonia, and one RCT and one OS investigated intra-abdominal infections. The severity score levels were similar to that of sepsis, but no study comprehensively focussing on sepsis was found. There were no significant differences in mortality at a maximum follow-up of 30 days (RR 1.08, 95%CI 0.80-1.46); 28-day mortality, clinical cure, the occurrence of new events, and the emergence of resistant organisms between the groups in the RCTs. The OSs findings were consistent. The quality of evidence was assessed as very low to moderate using the GRADE approach, with no uniform description of severity scores, sepsis, or adverse events.
Shorter, fixed-duration antibiotic therapy for clinically heterogeneous sepsis or severe infections was not associated with poorer outcomes, but the overall quality of evidence was poor.
Recent studies have implicated epigenetics in the pathophysiology of diabetes. Furthermore, DNA methylation, which irreversibly deactivates gene transcription, of the insulin promoter, particularly ...the cAMP response element, is increased in diabetes patients. However, the underlying mechanism remains unclear. We aimed to investigate insulin promoter DNA methylation in an over-nutrition state. INS-1 cells, the rat pancreatic beta cell line, were cultured under normal-culture-glucose (11.2 mmol/l) or experimental-high-glucose (22.4 mmol/l) conditions for 14 days, with or without 0.4 mmol/l palmitate. DNA methylation of the rat insulin 1 gene (Ins1) promoter was investigated using bisulfite sequencing and pyrosequencing analysis. Experimental-high-glucose conditions significantly suppressed insulin mRNA and increased DNA methylation at all five CpG sites within the Ins1 promoter, including the cAMP response element, in a time-dependent and glucose concentration-dependent manner. DNA methylation under experimental-high-glucose conditions was unique to the Ins1 promoter; however, palmitate did not affect DNA methylation. Artificial methylation of Ins1 promoter significantly suppressed promoter-driven luciferase activity, and a DNA methylation inhibitor significantly improved insulin mRNA suppression by experimental-high-glucose conditions. Experimental-high-glucose conditions significantly increased DNA methyltransferase activity and decreased ten-eleven-translocation methylcytosine dioxygenase activity. Oxidative stress and endoplasmic reticulum stress did not affect DNA methylation of the Ins1 promoter. High glucose but not palmitate increased ectopic triacylglycerol accumulation parallel to DNA methylation. Metformin upregulated insulin gene expression and suppressed DNA methylation and ectopic triacylglycerol accumulation. Finally, DNA methylation of the Ins1 promoter increased in isolated islets from Zucker diabetic fatty rats. This study helps to clarify the effect of an over-nutrition state on DNA methylation of the Ins1 promoter in pancreatic beta cells. It provides new insights into the irreversible pathophysiology of diabetes.
In this study, we aimed to develop and validate a machine learning-based mortality prediction model for hospitalized heat-related illness patients. After 2393 hospitalized patients were extracted ...from a multicentered heat-related illness registry in Japan, subjects were divided into the training set for development (n = 1516, data from 2014, 2017-2019) and the test set (n = 877, data from 2020) for validation. Twenty-four variables including characteristics of patients, vital signs, and laboratory test data at hospital arrival were trained as predictor features for machine learning. The outcome was death during hospital stay. In validation, the developed machine learning models (logistic regression, support vector machine, random forest, XGBoost) demonstrated favorable performance for outcome prediction with significantly increased values of the area under the precision-recall curve (AUPR) of 0.415 95% confidence interval (CI) 0.336-0.494, 0.395 CI 0.318-0.472, 0.426 CI 0.346-0.506, and 0.528 CI 0.442-0.614, respectively, compared to that of the conventional acute physiology and chronic health evaluation (APACHE)-II score of 0.287 CI 0.222-0.351 as a reference standard. The area under the receiver operating characteristic curve (AUROC) values were also high over 0.92 in all models, although there were no statistical differences compared to APACHE-II. This is the first demonstration of the potential of machine learning-based mortality prediction models for heat-related illnesses.
Background
No prediction scores for the mortality of both inpatients and outpatients who developed nonvariceal upper gastrointestinal bleeding (UGIB) without endoscopic findings have been ...established. We aimed to derive and validate a novel prediction score for in-hospital mortality.
Methods
We conducted a three-stage, multicenter retrospective study. In the derivation stage, patients with nonvariceal UGIB at six institutions were enrolled to derive the prediction score by logistic regression analysis. External validation of the score was performed to analyze discrimination by patients at six other institutions. Then the performance of this score was compared with that of four existing scores.
Results
We enrolled 1380 and 825 patients in the derivation and validation cohorts, respectively. A prediction score (CHAMPS-R Score) comprising seven variables (Charlson Comorbidity Index ≥ 2, in-hospital onset, albumin < 2.5 g/dL, altered mental status, Eastern Cooperative Oncology Group performance status ≥ 2, steroids, and rebleeding) with equal-weight scores was established, with high discriminative ability in both derivation and validation cohorts (
c
statistic, 0.91 and 0.80, respectively). When rebeeding was excluded from the score (an onset model; CHAMPS Score), this score also achieved high discriminative ability (
c
statistic, 0.90 and 0.81, respectively). The prediction scores had significantly higher discriminative ability than the Glasgow Blatchford Score, AIMS65, ABC Score, and clinical Rockall Score in both cohorts (all,
p
< 0.05).
Conclusions
We derived and externally validated prediction scores for in-hospital mortality in patients with nonvariceal UGIB. The CHAMPS Score might be optimal for managing such patients. Its mobile application is freely available (
https://apps.apple.com/app/id1565716902
for iOS and
https://play.google.com/store/apps/details?id=hatta.CHAMPS
for Android).
Background: The aim of the present study was to determine whether instructors could accurately assess chest compression quality visually, considering the association between chest compression depth ...and rate. Methods and Results: In this prospective, observational study, the quality of chest compressions performed by a simulated actor in a video was visually assessed by certified instructors. The film consisted of 14 case scenarios, each including a combination of depth (2 patterns: adequate, 5–6 cm; and inadequate, <5 cm) and rate (7 categories: compressions 90–150 times/min in increments of 10 times/min). The participants evaluated whether the compression depth was adequate, deep, or inadequate; and whether the compression rate was appropriate, fast, or slow. Of 198 instructors, 56% of participants misidentified adequate depth as deep at a chest compression rate of 120/min (the tendency toward this response increased as chest compression rate increased), and 64.1% of participants incorrectly determined 130/min to be appropriate. On generalized linear mixed-effects model analysis, perceived chest compression depth and rate were significant factors for a correct response (P<0.01, both). A significant interaction between chest compression depth and rate was observed (P<0.01). Conclusions: In the visual assessment of chest compression quality, recognition of chest compression depth was closely associated with compression rate. Misidentification of adequate chest compression depth as deep increased as the compression rate increased.
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