| 431. |
- Tang, W. H. Wilson, et al.
(författare)
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Trimethylamine N-Oxide and Related Gut Microbe-Derived Metabolites and Incident Heart Failure Development in Community-Based Populations
- 2024
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Ingår i: CIRCULATION-HEART FAILURE. - 1941-3289 .- 1941-3297. ; 17:8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Growing evidence indicates that trimethylamine N-oxide, a gut microbial metabolite of dietary choline and carnitine, promotes both cardiovascular disease and chronic kidney disease risk. It remains unclear how circulating concentrations of trimethylamine N-oxide and its related dietary and gut microbe-derived metabolites (choline, betaine, carnitine, gamma-butyrobetaine, and crotonobetaine) affect incident heart failure (HF). METHODS:We evaluated 11 768 participants from the Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis with serial measures of metabolites. Cox proportional hazard models were used to examine the associations between metabolites and incident HF, adjusted for cardiovascular disease risk factors. RESULTS:In all, 2102 cases of HF occurred over a median follow-up of 15.9 years. After adjusting for traditional risk factors, higher concentrations of trimethylamine N-oxide (hazard ratio, 1.15 [95% CI, 1.09-1.20]; P<0.001), choline (hazard ratio, 1.44 [95% CI, 1.26-1.64]; P<0.001), and crotonobetaine (hazard ratio, 1.24 [95% CI, 1.16-1.32]; P<0.001) were associated with increased risk for incident HF. After further adjustment for renal function (potential confounder or mediator), these associations did not reach Bonferroni-corrected statistical significance (P=0.01, 0.049, and 0.006, respectively). Betaine and carnitine were nominally associated with a higher incidence of HF (P<0.05). In exploratory analyses, results were similar for subtypes of HF based on left ventricular ejection fraction, and associations appeared generally stronger among Black and Hispanic/Latino versus White adults, although there were no interactions for any metabolites with race. CONCLUSIONS:In this pooled analysis of 2 well-phenotyped, diverse, community-based cohorts, circulating concentrations of gut microbe-derived metabolites such as trimethylamine N-oxide, choline, and crotonobetaine were independently associated with a higher risk of developing HF.
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| 432. |
- Toh, Shen Yon, et al.
(författare)
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Therapeutic application of extracellular vesicular EGFR isoform D as a co-drug to target squamous cell cancers with tyrosine kinase inhibitors
- 2024
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Ingår i: Developmental Cell. - : Elsevier. - 1534-5807 .- 1878-1551. ; 59:16
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Tidskriftsartikel (refereegranskat)abstract
- Targeting wild-type epidermal growth factor receptor (EGFR) using tyrosine kinase inhibitors (TKIs) never achieved its purported success in cancers such as head and neck squamous cell carcinoma, which are largely EGFR-dependent. We had previously shown that exceptional responders to TKIs have a genetic aberration that results in overexpression of an EGFR splice variant, isoform D (IsoD). IsoD lacks an integral transmembrane and kinase domain and is secreted in extracellular vesicles (EVs) in TKI-sensitive patient-derived cultures. Remarkably, the exquisite sensitivity to TKIs could be transferred to TKI-resistant tumor cells, and IsoD protein in the EV is necessary and sufficient to transfer the phenotype in vitro and in vivo across multiple models and drugs. This drug response requires an intact endocytic mechanism, binding to full-length EGFR, and signaling through Src-phosphorylation within the endosomal compartment. We propose a therapeutic strategy using EVs containing EGFR IsoD as a co-drug to expand the use of TKI therapy to EGFR-driven cancers.
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| 433. |
- Wan, Guihong, et al.
(författare)
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Prediction of early-stage melanoma recurrence using clinical and histopathologic features
- 2022
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Ingår i: NPJ precision oncology. - : Springer Science and Business Media LLC. - 2397-768X. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Prognostic analysis for early-stage (stage I/II) melanomas is of paramount importance for customized surveillance and treatment plans. Since immune checkpoint inhibitors have recently been approved for stage IIB and IIC melanomas, prognostic tools to identify patients at high risk of recurrence have become even more critical. This study aims to assess the effectiveness of machine-learning algorithms in predicting melanoma recurrence using clinical and histopathologic features from Electronic Health Records (EHRs). We collected 1720 early-stage melanomas: 1172 from the Mass General Brigham healthcare system (MGB) and 548 from the Dana-Farber Cancer Institute (DFCI). We extracted 36 clinicopathologic features and used them to predict the recurrence risk with supervised machine-learning algorithms. Models were evaluated internally and externally: (1) five-fold cross-validation of the MGB cohort; (2) the MGB cohort for training and the DFCI cohort for testing independently. In the internal and external validations, respectively, we achieved a recurrence classification performance of AUC: 0.845 and 0.812, and a time-to-event prediction performance of time-dependent AUC: 0.853 and 0.820. Breslow tumor thickness and mitotic rate were identified as the most predictive features. Our results suggest that machine-learning algorithms can extract predictive signals from clinicopathologic features for early-stage melanoma recurrence prediction, which will enable the identification of patients that may benefit from adjuvant immunotherapy.
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| 434. |
- Wang, L. H., et al.
(författare)
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Correlation between the germline methylation status in ER beta promoter and the risk in prostate cancer: a prospective study
- 2016
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Ingår i: Familial Cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 15:2, s. 309-315
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Tidskriftsartikel (refereegranskat)abstract
- Familial aggregation of cancer may reflect an overall contribution of inherited genes or a shared mechanism for the manipulation of gene function. DNA methylation in the promoter regions is considered to be a mechanism through which tumor suppressor genes are inhibited, which will lead to tumorigenesis and tumor progression. To evaluate the association between the methylation status in the promoter of estrogen receptor (ER) beta, possibly a tumor suppressor gene specific for prostate cancer, and the risk in prostate cancer in a Chinese population, a case-control study that included 56 sporadic prostate cancer cases and 60 healthy controls was conducted. Genomic DNA was extracted from peripheral blood of all the subjects for analyzing the methylation status of the ER beta promoter by methylation-specific PCR, which was verified by bisulfite genomic sequencing PCR. A significant difference was observed in the methylation frequencies of the ER beta promoter between cancer patients (12/56, 21.4 %) and healthy controls (5/60, 8.3 %). Prostate cancer (PC-3 and DU-145) and prostatic epithelial (RWPE-1) cell lines were treated with various concentrations of the methyltransferase inhibitor 5-Aza-2'-dC. Expression of ER beta was detected at both transcriptional and translational levels. As a result, both mRNA and protein of ER beta were elevated following treatment with increasing concentrations of the demethylating agent. Taken together, our results support the conclusion that abnormal methylation of the ER beta promoter may increase genetic susceptibility to prostate cancer.
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| 435. |
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| 436. |
- Wu, Dong, et al.
(författare)
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Four-Wave Mixing-Based Wavelength Conversion and Parametric Amplification in Submicron Silicon Core Fibers
- 2021
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Ingår i: IEEE Journal of Selected Topics in Quantum Electronics. - : Institute of Electrical and Electronics Engineers (IEEE). - 1077-260X .- 1558-4542. ; 27:2
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Tidskriftsartikel (refereegranskat)abstract
- Silicon core fibers represent a versatile platform for all-fiber integrated nonlinear optical applications. This paper describes the state of the art in four-wave mixing-based parametric amplification, and wavelength conversion in silicon fibers that have been tapered to improve the material quality, and engineer the dispersion profile. Fibers with submicron core dimensions have been fabricated, and used to demonstrate high gain parametric amplification in the C-Band, and broadband wavelength conversion extending out to the S-, and L-bands. The potential to use these fibers for all-optical signal processing of 20 Gbit/s data signals has also been demonstrated, with a robust all-fiber coupling scheme presented to improve the efficiency, and practicality of these devices. These results highlight the potential of silicon core fibers for use in nonlinear signal processing within future telecommunication systems.
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| 437. |
- Xia, W., et al.
(författare)
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Optimal tradeoff between instantaneous and delayed neighbor information in consensus algorithms
- 2017
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Ingår i: Automatica. - : Elsevier. - 0005-1098 .- 1873-2836. ; 83, s. 116-123
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Tidskriftsartikel (refereegranskat)abstract
- We consider a distributed consensus problem over a network, where at each time instant every node receives two pieces of information from disjoint neighboring sets: a weighted average of current states of neighbors from a primary network, and a weighted average of one-hop delayed states of neighbors from a secondary network. The proposed algorithm makes each node update its state to a weighted average of these individual averages. We show that convergence to consensus is guaranteed with non-trivial weights. We also present an explicit formula for the weights allocated to each piece of the information for the optimal rate of convergence, when the secondary network is the complement of the primary network. Finally numerical examples are given to explore the case when the neighbor sets of the agents do not cover the whole network.
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| 438. |
- Xiu-Zhen, Z., et al.
(författare)
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Cross-cultural adaptation and validation of the First-Time Fathers Questionnaire in China
- 2021
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Ingår i: Midwifery. - : Elsevier BV. - 0266-6138. ; 93
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The study aimed to cross-culturally adapt and validate the First-Time Fathers Questionnaire (FTFQ) in the cultural context of China. Design: Prospective validation study. Setting: The study was conducted in four public hospitals in Hangzhou, a southeast coastal city of China. Participants: Four hundred and nineteen first-time fathers (mean age=30.45 years, SD=3.44, range 22-46) whose partners had given birth between July 20 and October 10, 2019. Methods: The instrument "First Time Fathers Questionnaire (FTFQ)" was translated and culturally adapted to the Chinese context according to the methodological criteria of the International Society for Pharmacoeconomic and Outcomes Research. The construct-related validity of the instrument was tested through EFA and CFA. Content validity was evaluated with an analysis of the expert judgment. Reliability was assessed based on the internal consistency. Results: Four domains were identified: "Worry", "Information", "Emotional Support", and "Acceptance", with 19 items and adequate internal reliability (0.86, 0.80, 0.86, and 0.72, respectively) and a total variance of 64.65%. The CFA model showed there is a good fit for the data: X2/df =1.20; RMSA = 0.03; CFI = 0.99; and NFI = 0.93. Additionally, each item achieved an I-CVI ≧0.83, and the S-CVI/Ave = 0.90. Key Conclusions: The Chinese version of the FTFQ is a valid and reliable instrument to assess first-time fathers' experience of childbirth in China. Implications for Practice: This study provides a validated questionnaire that is suitable for the Chinese cultural context. It contributes to the knowledge of first-time fathers' experience of childbirth and facilitate further actions to improve paternal satisfaction and behavior as labour companion. © 2020
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| 439. |
- Yang, H, et al.
(författare)
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MD-2 is required for disulfide HMGB1-dependent TLR4 signaling
- 2015
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 212:1, s. 5-14
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Tidskriftsartikel (refereegranskat)abstract
- Innate immune receptors for pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) orchestrate inflammatory responses to infection and injury. Secreted by activated immune cells or passively released by damaged cells, HMGB1 is subjected to redox modification that distinctly influences its extracellular functions. Previously, it was unknown how the TLR4 signalosome distinguished between HMGB1 isoforms. Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2–deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling. By screening HMGB1 peptide libraries, we identified a tetramer (FSSE, designated P5779) as a specific MD-2 antagonist preventing MD-2–HMGB1 interaction and TLR4 signaling. P5779 does not interfere with lipopolysaccharide-induced cytokine/chemokine production, thus preserving PAMP-mediated TLR4–MD-2 responses. Furthermore, P5779 can protect mice against hepatic ischemia/reperfusion injury, chemical toxicity, and sepsis. These findings reveal a novel mechanism by which innate systems selectively recognize specific HMGB1 isoforms. The results may direct toward strategies aimed at attenuating DAMP-mediated inflammation while preserving antimicrobial immune responsiveness.
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| 440. |
- Ye, XF, et al.
(författare)
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Genome-wide mutational signatures revealed distinct developmental paths for human B cell lymphomas
- 2021
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 218:2
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Tidskriftsartikel (refereegranskat)abstract
- Both somatic hypermutation (SHM) and class switch recombination (CSR) are initiated by activation-induced cytidine deaminase (AID). Dysregulation of these processes has been linked to B cell lymphomagenesis. Here we performed an in-depth analysis of diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) genomes. We characterized seven genomic mutational signatures, including two B cell tumor-specific signatures, one of which is novel and associated with aberrant SHM. We further identified two major mutational signatures (K1 and K2) of clustered mutations (kataegis) resulting from the activities of AID or error-prone DNA polymerase η, respectively. K1 was associated with the immunoglobulin (Ig) switch region mutations/translocations and the ABC subtype of DLBCL, whereas K2 was related to the Ig variable region mutations and the GCB subtype of DLBCL and FL. Similar patterns were also observed in chronic lymphocytic leukemia subtypes. Thus, alterations associated with aberrant CSR and SHM activities can be linked to distinct developmental paths for different subtypes of B cell lymphomas.
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