Emerging evidence suggests that gut microbiome composition alterations affect neurodegeneration through neuroinflammation in the pathogenesis of Parkinson's disease (PD). Here, we evaluate gut ...microbiota alterations and host cytokine responses in a population of Taiwanese patients with PD.
Fecal microbiota communities from 80 patients with PD and 77 age and gender-matched controls were assessed by sequencing the V3-V4 region of the 16S ribosomal RNA gene. Diet and comorbidities were controlled in the analyses. Plasma concentrations of IL-1β, IL-2, IL-4, IL-6, IL-13, IL-18, GM-CSF, IFNγ, and TNFα were measured by a multiplex immunoassay and relationships between microbiota, clinical characteristics, and cytokine levels were analyzed in the PD group. We further examined the cytokine changes associated with the altered gut microbiota seen in patients with PD in another independent cohort of 120 PD patients and 120 controls.
Microbiota from patients with PD was altered relative to controls and dominated by Verrucomicrobia, Mucispirillum, Porphyromonas, Lactobacillus, and Parabacteroides. In contrast, Prevotella was more abundant in controls. The abundances of Bacteroides were more increased in patients with non-tremor PD subtype than patients with tremor subtype. Bacteroides abundance was correlated with motor symptom severity defined by UPDRS part III motor scores (rho = 0.637 95% confidence interval 0.474 to 0.758, P < 0.01). Altered microbiota was correlated with plasma concentrations of IFNγ and TNFα. There was a correlation between Bacteroides and plasma level of TNFα (rho = 0.638 95% CI: 0.102-0.887, P = 0.02); and a correlation between Verrucomicrobia abundance and plasma concentrations of IFNγ (rho = 0.545 95% CI - 0.043-0.852, P = 0.05). The elevated plasma cytokine responses were confirmed in an additional independent 120 patients with PD and 120 controls (TNFα: PD vs. control 8.51 ± 4.63 pg/ml vs. 4.82 ± 2.23 pg/ml, P < 0.01; and IFNγ: PD vs. control: 38.45 ± 7.12 pg/ml vs. 32.79 ± 8.03 pg/ml, P = 0.03).
This study reveals altered gut microbiota in PD and its correlation with clinical phenotypes and severity in our population. The altered plasma cytokine profiles associated with gut microbiome composition alterations suggest aberrant immune responses may contribute to inflammatory processes in PD.
Competitive endogenous RNA (ceRNA) represents a novel mechanism of gene regulation that controls several biological and pathological processes. Recently, an increasing number of
in silico
methods ...have been developed to accelerate the identification of such regulatory events. However, there is still a need for a tool supporting the hypothesis that ceRNA regulatory events only occur at specific miRNA expression levels. To this end, we present an R package, ceRNAR, which allows identification and analysis of ceRNA-miRNA triplets via integration of miRNA and RNA expression data. The ceRNAR package integrates three main steps: (i) identification of ceRNA pairs based on a rank-based correlation between pairs that considers the impact of miRNA and a running sum correlation statistic, (ii) sample clustering based on gene-gene correlation by circular binary segmentation, and (iii) peak merging to identify the most relevant sample patterns. In addition, ceRNAR also provides downstream analyses of identified ceRNA-miRNA triplets, including network analysis, functional annotation, survival analysis, external validation, and integration of different tools. The performance of our proposed approach was validated through simulation studies of different scenarios. Compared with several published tools, ceRNAR was able to identify true ceRNA triplets with high sensitivity, low false-positive rates, and acceptable running time. In real data applications, the ceRNAs common to two lung cancer datasets were identified in both datasets. The bridging miRNA for one of these, the ceRNA for
MAP4K3
, was identified by ceRNAR as hsa-let-7c-5p. Since similar cancer subtypes do share some biological patterns, these results demonstrated that our proposed algorithm was able to identify potential ceRNA targets in real patients. In summary, ceRNAR offers a novel algorithm and a comprehensive pipeline to identify and analyze ceRNA regulation. The package is implemented in R and is available on GitHub (
https://github.com/ywhsiao/ceRNAR
).
Objectives
To analyze the effect of preoperative body composition on survival in patients with pancreatic cancer following pancreaticoduodenectomy (PD).
Methods
Between October 2005 and August 2018, ...116 patients (68 men, 48 women, mean age 66.2 ± 11.9 years) diagnosed with pancreatic adenocarcinoma following PD were retrospectively enrolled. The preoperative CT on vertebral level L3 was assessed for total abdominal muscle area (TAMA), visceral adipose tissue area (VAT), subcutaneous adipose tissue area (SAT), and mean skeletal muscle attenuation (SMD). The clinical data and pathological findings of tumors were collected. The impact of these factors on disease-free survival (DFS) and overall survival (OS) was evaluated by the Kaplan–Meier method and by univariable and multivariable Cox proportional hazards models.
Results
The 3-year DFS and OS rates were 8% and 25%, respectively. Of 116 patients, 20 (17.2%), 3 (2.6%), and 46 (39.7%) patients were classified as having sarcopenia, sarcopenic obesity, and myosteatosis, respectively. The VAT–TAMA ratio (1.2 ± 0.7 vs 0.9 ± 0.5,
p
= 0.01) and the visceral to subcutaneous adipose tissue area ratio (1.3 ± 0.7 vs 0.9 ± 0.5,
p
= 0.04) were higher in sarcopenic patients than in the nonsarcopenic group. Preoperative sarcopenia and sarcopenic obesity were associated with shorter OS (
p
= 0.012 and
p
= 0.041, respectively), but not shorter DFS. Myosteatosis was neither associated with DFS nor OS. On multivariable analysis, sarcopenia was the only significant prognostic factor for OS (
p
= 0.039).
Conclusions
Preoperative sarcopenia assessed by CT is a poor prognostic factor for OS in pancreatic cancer patients after PD.
Key Points
•
Sarcopenia and sarcopenic obesity can be evaluated by abdominal CT on L3 level.
•
Patients with diabetes mellitus (DM) had lower sex-standardized subcutaneous adipose tissue area index and skeletal muscle density and higher visceral to subcutaneous adipose tissue area ratio than did those without DM.
•
Preoperative sarcopenia, sarcopenic obesity, and new-onset diabetes mellitus may predict poor overall survival in pancreatic cancer patients following pancreaticoduodenectomy.
Many prediction tools for microRNA (miRNA) targets have been developed, but inconsistent predictions were observed across multiple algorithms, which can make further analysis difficult. Moreover, the ...nomenclature of human miRNAs changes rapidly. To address these issues, we developed a web-based system, miRSystem, for converting queried miRNAs to the latest annotation and predicting the function of miRNA by integrating miRNA target gene prediction and function/pathway analyses.
First, queried miRNA IDs were converted to the latest annotated version to prevent potential conflicts resulting from multiple aliases. Next, by combining seven algorithms and two validated databases, potential gene targets of miRNAs and their functions were predicted based on the consistency across independent algorithms and observed/expected ratios. Lastly, five pathway databases were included to characterize the enriched pathways of target genes through bootstrap approaches. Based on the enriched pathways of target genes, the functions of queried miRNAs could be predicted.
MiRSystem is a user-friendly tool for predicting the target genes and their associated pathways for many miRNAs simultaneously. The web server and the documentation are freely available at http://mirsystem.cgm.ntu.edu.tw/.
Abstract
Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we ...show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of
Txndc5
markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFβ1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFβ1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of
Txndc5
mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF.
Background
The clinicopathological features and prognosis of breast cancer in Asia are different from those in the Western countries. Tumor‐infiltrating immune cells can influence the outcome of ...patients with breast cancer, but they have not been systemically evaluated in Asian patients with breast cancer.
Methods
We compared the immune score, composition, and prognostic impact of infiltrating immune cells between Asian and Western patients with breast cancer by analyzing gene expression profiles from eight Gene Expression Omnibus data sets and The Cancer Genome Atlas data set. The Estimation of Stromal and Immune Cells in Malignant Tumours Using Expression Data (ESTIMATE) and Cell Type Identification by Estimating Relative Subsets of Known RNA Transcripts (CIBERSORT) algorithms were used to determine the immune score and composition of tumor‐infiltrating immune cells, respectively.
Findings
This study included 462 Asian patients and 2,186 Western patients. Tumors of Asian patients had significantly higher immune score, particularly in the luminal B and HER2‐enriched subtypes. High immune score was associated with favorable prognosis in both Asian and Western patients, and Asian race with a high ESTIMATE immune score provided additional power to predict longer disease‐free survival. Activated CD4 T cells and M2 macrophages were the most strongly associated with survival in both Asian and Western patients.
Interpretation
Our study highlights the difference in tumor immune microenvironments between Asian and Western patients. The higher ESTIMATE immune score, which represents more abundant tumor‐infiltrating immune cells, in tumors of Asian patients partly explains their favorable prognosis.
Implications for Practice
The tumor microenvironment serves as an interface that affects the human body's reaction to cancer cells. Evidence has revealed that tumor‐infiltrating immune cells were associated with patient prognosis. This study demonstrated the disparity of tumor microenvironments and their prognostic impact between Asian and Western patients with breast cancer. The differences in immune score partially explained the racial survival differences noted in recent studies. Integrated analysis of tumor cells, tumor microenvironment, and racial effect may significantly improve recurrence risk prediction for patients with stage I–III breast cancer. Because the effect of tumor microenvironment varies across different populations, a model of interaction between immune score and race/ethnicity is recommended in accessing the risk of patients with cancer.
Statistics indicate that the incidence of breast cancer in Asia has increased in the past three decades. This article evaluates tumor‐infiltrating immune cells of breast cancer, comparing a representative amount and the composition of infiltrating immune cells in breast cancer between Asian and Western patients.
Background
The choice between wedge resection and segmentectomy as a sublobar resection method for patients with cT1N0 lung cancer remains debatable. This study aimed to evaluate the clinical ...outcomes after wedge resection and segmentectomy for patients with cT1N0 lung adenocarcinoma.
Methods
The study enrolled 1002 consecutive patients with cT1N0 lung adenocarcinoma who underwent sublobar resection at the authors’ institution between 2011 and 2017. A propensity score-matching analysis was used to compared the clinical outcomes between the wedge resection and segmentectomy groups.
Results
Wedge resection was performed for 810 patients (80.8%), and segmentectomy was performed for 192 patients (19.2%). Wedge resection resulted in better perioperative outcomes than segmentectomy. The multivariate analysis showed that the significant risk factors for poor disease-free survival (DFS) were elevated preoperative serum carcinoembryonic antigen levels, total tumor diameter greater than 2 cm, and a consolidation-to-tumor (C/T) ratio higher than 50%. After propensity-matching, no differences in overall survival or DFS were noted between the two matched groups. However, subgroup analysis showed that segmentectomy was associated with better DFS than wedge resection (
p
= 0.039) for the patients with a tumor diameter greater than 2 cm and a C/T ratio higher than 50%.
Conclusion
Segmentectomy is the appropriate surgical method for sublobar resection in cT1N0 lung adenocarcinoma patients with a tumor diameter greater than 2 cm and a C/T ratio higher than 50%. Wedge resection may be a safe and feasible sublobar resection method for patients with a tumor diameter of 2 cm or smaller or a C/T ratio of 50% or lower.
Background and aims
Ketamine has become a new recreational drug of choice among young people in parts of Asia. Using national databases in Taiwan, this study aimed to (1) examine the yearly trend in ...the ketamine offence rate over time; (2) estimate the 3‐year risk of drug‐related re‐offence and its correlates among the first‐time offenders; and (3) estimate the 3‐year standardized mortality ratio (SMR) among the first‐time offenders.
Design, Setting and Participants
Retrospective cohort studies of offenders for recreational ketamine use in a penalty system initiated in 2009. Offenders for recreational ketamine use were identified from the Administrative Penalty System for Schedule III/IV Substances database from 2009 to 2017, and the re‐offence rate and mortality among first‐time offenders were assessed via record‐linkage within the database as well as with both the criminal drug offence database and the national mortality database. The cohort from 2009 to 2016 (n = 39 178) was used for the recidivism analysis and the cohort from 2009 to 2013 (n = 25 357) was used for the 3‐year SMR analysis.
Measurements
Recidivism was estimated using survival analysis of the event as re‐arrest for using ketamine, more serious illicit drugs (Schedules I/II), or any illicit drugs (ketamine or Schedules I/II). SMRs were estimated for overall and cause‐specific death within 3 years after the first offence for ketamine use.
Findings
The age‐standardized rates for both prevalent (1.38 per 1000) and first‐time offenders (0.65 per 1000) peaked in 2013 and then decreased steadily. The 3‐year risk of re‐offence was 33.85% 95% confidence interval (CI) = 33.23–34.47%) for ketamine use and 39.52% (95% CI = 39.00–40.04%) for any illicit drug use. These first‐time offenders had an SMR of 4.9 (95% CI = 4.3–5.4) for overall mortality, 2.1 (95% CI = 1.6–2.7) for natural deaths and 7.6 (95% CI = 6.7–8.6) for unnatural deaths.
Conclusions
Recreational ketamine use in Taiwan appears to lead not only to high risk for drug‐related re‐offence but also to excess mortality.
The molecular basis for the focal nature of atherosclerotic lesions is poorly understood. Here, we explored whether disturbed flow patterns activate an innate immune response to form the NLRP3 ...inflammasome scaffold in vascular endothelial cells via sterol regulatory element binding protein 2 (SREBP2).
Oscillatory flow activates SREBP2 and induces NLRP3 inflammasome in endothelial cells. The underlying mechanisms involve SREBP2 transactivating NADPH oxidase 2 and NLRP3. Consistently, SREBP2, NADPH oxidase 2, and NLRP3 levels were elevated in atheroprone areas of mouse aortas, suggesting that the SREBP2-activated NLRP3 inflammasome causes functionally disturbed endothelium with increased inflammation. Mimicking the effect of atheroprone flow, endothelial cell-specific overexpression of the activated form of SREBP2 synergized with hyperlipidemia to increase atherosclerosis in the atheroresistant areas of mouse aortas.
Atheroprone flow induces NLRP3 inflammasome in endothelium through SREBP2 activation. This increased innate immunity in endothelium synergizes with hyperlipidemia to cause topographical distribution of atherosclerotic lesions.
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