RATIONALE:Cardiac fibrosis plays a critical role in the pathogenesis of heart failure (HF). Excessive accumulation of extracellular matrix (ECM) resulting from cardiac fibrosis impairs cardiac ...contractile function and increases arrhythmogenicity. Current treatment options for cardiac fibrosis, however, are limited and there is a clear need to identify novel mediators of cardiac fibrosis to facilitate the development of better therapeutics. Exploiting co-expression gene network analysis on RNA sequencing data from failing human heart, we identified thioredoxin domain containing 5 (TXNDC5), a cardiac fibroblast (CF)-enriched endoplasmic reticulum (ER) protein, as a potential novel mediator of cardiac fibrosis and we completed experiments to test this hypothesis directly.
OBJECTIVE:To determine the functional role of TXNDC5 in the pathogenesis of cardiac fibrosis.
METHODS AND RESULTS:RNASeq and Western blot analyses revealed that TXNDC5 mRNA and protein were highly upregulated in failing human left ventricles (LV) and in hypertrophied/failing mouse LV. In addition, cardiac TXNDC5 mRNA expression levels were positively correlated with those of transcripts encoding transforming growth factor β1 (TGFβ1) and ECM proteins in vivo. TXNDC5 mRNA and protein were increased in human CF (hCF) under TGFβ1 stimulation in vitro. Knockdown of TXNDC5 attenuated TGFβ1-induced hCF activation and ECM protein upregulation independent of SMAD3, whereas increasing expression of TXNDC5 triggered hCF activation and proliferation and increased ECM protein production. Further experiments showed that TXNDC5, a protein disulfide isomerase, facilitated ECM protein folding and that depletion of TXNDC5 led to ECM protein misfolding and degradation in CF. In addition, TXNDC5 promotes hCF activation and proliferation by enhancing JNK activity via increased reactive oxygen species, derived from NAD(P)H oxidase 4. TGFβ1-induced TXNDC5 upregulation in hCF was dependent on ER stress and activating transcription factor 6-mediated transcriptional control. Targeted disruption of Txndc5 in mice (Txndc5) revealed protective effects against isoproterenol (ISO)-induced cardiac hypertrophy, reduced fibrosis (by ~70%) and markedly improved LV function; post-ISO LV ejection fraction was 59.1±1.5 vs 40.1±2.5 (P<0.001) in Txndc5 vs wild-type mice, respectively.
CONCLUSIONS:The ER protein TXNDC5 promotes cardiac fibrosis by facilitating ECM protein folding and CF activation via redox-sensitive JNK signaling. Loss of TXNDC5 protects against β agonist-induced cardiac fibrosis and contractile dysfunction. Targeting TXNDC5, therefore, could be a powerful new therapeutic approach to mitigate excessive cardiac fibrosis, thereby improving cardiac function and outcomes in HF patients.
Nurses’ distress in response to the professional experience of the neonatal loss and stillbirth care is poorly addressed in nursing practice; therefore, the purpose of this study is to explore ...nurses’ experiences of labour of a stillborn baby. A qualitative approach with ten Registered Nurses from hospital birth units in northern Taiwan was used to investigate the stillbirth care experiences of nurses. Research data analysed by interpretative phenomenological analysis (IPA) were collected from eight digital recorded sessions of group dialogues, nurses' responses and feedbacks. Three main themes extracted from data include unfolding the suffering, engrossing in stillborn parents and demonstrating compassionate actions for the stillborn baby. Unfolding the suffering includes shame, guilt and disenfranchised grief. Engrossing in stillborn parents includes perceiving the mother’s suppress sadness and empathising with the father’s anger. Finally, demonstrating compassionate actions includes fulfilling the parents’ needs to say goodbye to their stillborn baby and saying a personal goodbye to the dead baby. The finding of this study shows that the reflective group provided the space for nurses to unfold their suffering, share their emotion, and develop practical wisdom in caring for stillborn baby and the parents. The experience of nurse group conducting the reflecting dialogues could be a expository strategy to promote the nurse to provide the compassionate care actions.
To our knowledge, there have been no systematic reviews of health economic evaluations of proton therapy specific to lung cancer.
We conducted this systematic review according to the predefined ...protocol PROSPERO CRD42022365869. We summarized the results of the included studies via structured narrative synthesis.
We identified four studies (all used passively scattered proton therapy) from 787 searches. Two cost analyses reported that proton therapy was more costly than photon therapy for early- or locally advanced-stage non-small cell lung cancer, one cost-utility analysis reported that proton therapy was dominated by nonproton therapy in early-stage non-small cell lung cancer, and one cost-utility analysis reported that proton therapy was not cost-effective (vs. photon) in locally advanced non-small cell lung cancer.
Passively scattered proton therapy was more costly and not cost-effective than photon therapy for early- and locally advanced-stage non-small cell lung cancer. Further health economic evaluations regarding modern proton therapy (such as scanning beam) for common radiotherapy indications of lung cancer are eagerly awaited.
A multifunctional ion‐sensitive floating gate Fin field‐effect transistor (ISFGFinFET) for hydrogen and sodium detection is demonstrated. The ISFGFinFET comprises a FGFET and a sensing film, both of ...which are used to detect and improve sensitivity. The sensitivity of the ISFGFinFET can be adjusted by modulating the coupling effect of the FG. A nanoseaweed structure is fabricated via glancing angle deposition (GLAD) technology to obtain a large sensing area to enhance the sensitivity for hydrogen ion detection. A sensitivity of 266 mV per pH can be obtained using a surface area of 3.28 mm2. In terms of sodium ion detection, a calix4arene sensing film to monitor sodium ions, obtaining a Na+ sensitivity of 432.7 mV per pNa, is used. In addition, the ISFGFinFET demonstrates the functionality of multiple ions detection simultaneously. The sensor arrays composed of 3 × 3 pixels are demonstrated, each of which comprise of an FGFET sensor and a transistor. Furthermore, 16 × 16 arrays with a decoder and other peripheral circuits are constructed and simulated. The performance of the proposed ISFGFinFET is competitive with that of other state‐of‐the‐art ion sensors.
The necessity for high sensitivity for ion detection has been improved in recent years. In this work, to adjust and increase the sensitivity, a floating gate (FG) structure is introduced into the Fin field‐effect transistor (FinFET) device while the nanoseaweed Al2O3 structure is fabricated for the ion reacting layer via glancing angle deposition. Furthermore, combining different materials, the ion‐sensitive FGFinFET can realize multiple ion detection.
Hepatocellular carcinoma (HCC) is associated with high rates of metastasis and recurrence, and is one of the most common causes of cancer-associated death worldwide. This study examined the protein ...changes within circulating exosomes in patients with HCC against those in healthy people using isobaric tags for a relative or absolute quantitation (iTRAQ)-based quantitative proteomics analysis. The protein levels of von Willebrand factor (VWF), cathelicidin antimicrobial peptide (CAMP), and proteasome subunit beta type-2 (PSMB2) were altered in HCC. The increased levels of VWF and PSMB2 but decreased CAMP levels in the serum of patients with HCC were validated by enzyme-linked immunosorbent assays. The level of CAMP (the only cathelicidin found in humans) also decreased in the circulating exosomes and buffy coat of the HCC patients. The serum with reduced levels of CAMP protein in the HCC patients increased the cell proliferation of Huh-7 cells; this effect was reduced following the addition of CAMP protein. The depletion of CAMP proteins in the serum of healthy people enhances the cell proliferation of Huh-7 cells. In addition, supplementation with synthetic CAMP reduces cell proliferation in a dose-dependent manner and significantly delays G1-S transition in Huh-7 cells. This implies that CAMP may act as a tumor suppressor in HCC.
Purpose
To evaluate the efficacy of logotherapy on meaning in life, depression, hopelessness, and suicide ideation in patients with depression.
Design and Methods
A quasi‐experimental approach was ...used and 86 participants were recruited from a psychiatric department in Taiwan. The experimental group received logotherapy for 12 weeks. The control group received depression education as usual.
Findings
The results revealed significant differences between and within the groups for meaning in life, depression, hopelessness, and suicide ideation.
Practice Implications
Logotherapy was an effective method for increasing meaning in life, reducing the degree of depression, hopelessness, and suicidal ideation for patients with depression.
To establish the composition of bacteria in mice following cecum ligation and puncture (CLP) through metagenomic analysis and investigate the role of TLRs on the composition of bacteria.
Total DNA ...extraction was done from the ascites, blood, and fecal samples from C57BL/6 mice sacrificed at 0, 4, 8, and 16 h, as well as from Tlr2-/-, Tlr4-/-, Tlr5-/-, and NF-κB-/-mice sacrificed at 16 h following CLP. Amplification of the V3-V4 regions of the bacterial 16S rRNA genes by PCR and the Illumina MiSeq sequencer was used for deep sequencing. Hierarchical clustering of the isolates was performed with Ward's method using Euclidean distances. The relative abundance according to operational taxonomic unit (OTU) number or taxa was used to compare the richness among subgroups in the experiments.
There were 18 taxa that had significantly different abundances among the different samples of the C57BL/6 mice at 16 h following CLP. Various dynamic changes in the infectious bacteria inside the peritoneal cavity after CLP were found. While knockout of Tlr5 and NF-κB impaired the ability of bacterial clearance inside the peritoneal cavity for some kinds of bacteria found in the C57BL/6 mice, the knockout of Tlr4 enhanced clearance for other kinds of bacteria, and they presented excessive abundance in the peritoneal cavity despite their scarce abundance in the stool.
NF-κB and TLRs are involved in bacterial clearance and in the expression pattern of the bacterial abundance inside the peritoneal cavity during polymicrobial infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: Allopurinol, a first-line drug used for treating gout, is increasingly prescribed worldwide to patients with asymptomatic hyperuricemia and comorbid renal or cardiovascular diseases. ...Nevertheless, allopurinol use has been associated with fatal hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The overall risks of allopurinol use remain unclear. OBJECTIVE: To investigate the incidence of, risk factors for, and mortality associated with allopurinol hypersensitivity in new users of allopurinol. DESIGN, SETTING, AND PARTICIPANTS: A retrospective nationwide population study was conducted using data from the Taiwan National Health Insurance Research Database, which includes detailed medical records of more than 23 million insured enrollees. Data were collected from January 1, 2005, through December 31, 2011, using the Anatomical Therapeutic Chemical classification system and International Classification of Diseases, Ninth Revision, Clinical Modification codes. Among 1 613 719 patients receiving allopurinol prescriptions, 495 863 were identified as new users. MAIN OUTCOMES AND MEASURES: Allopurinol hypersensitivity was identified within 3 months since the first prescription. The period for measuring related hospitalizations was 1 month since the episode, and the period for measuring renal complications or mortality was 2 months since the episode. Poisson regression test and multivariable logistic regression analysis were performed, and P < .01 was considered statistically significant. RESULTS: Among the more than 23 million insured enrollees, the annual incidence rates were 4.68 per 1000 new users for allopurinol hypersensitivity, 2.02 per 1000 new users for related hospitalization, and 0.39 per 1000 new users for related mortality. The annual incidence of allopurinol hypersensitivity rose statistically significantly during the study period (P < .001). Risk factors for allopurinol hypersensitivity included female sex, age 60 years or older, initial allopurinol dosage exceeding 100 mg/d, renal or cardiovascular comorbidities, and use for treating asymptomatic hyperuricemia. Patients with asymptomatic hyperuricemia and renal or cardiovascular diseases had statistically significantly increased risk of allopurinol hypersensitivity (odds ratio OR, 1.61; 95% CI, 1.33-1.94; P < .001 for renal diseases and OR, 1.52; 95% CI, 1.19-1.93; P < .001 for cardiovascular diseases). They also had statistically significantly increased risk of mortality (OR, 5.59; 95% CI, 2.61-11.94; P < .001 for renal diseases and OR, 3.57; 95% CI, 2.31-5.51; P < .001 for cardiovascular diseases). CONCLUSIONS AND RELEVANCE: The use of allopurinol in patients with asymptomatic hyperuricemia accompanied by renal or cardiovascular diseases statistically significantly increased the risk of hypersensitivity reactions. Physicians should be cautious when prescribing allopurinol to high-risk populations and should consider the potential risks of fatal adverse reactions.
Insulin resistance (IR) is a pathophysiological construct that derives a series of metabolic disturbances that promote cardiometabolic dysfunction. This study evaluated mediating and modifying ...effects of homeostatic model assessment-based IR (HOMA-IR) on the association between sugar-sweetened beverage (SSB) consumption and a constellation of adolescent cardiometabolic abnormalities.
Comprehensive data on sociodemographics, diet, physical activity, and anthropometric and biochemical parameters for 1454 adolescents were obtained from a large-scale representative study for adolescent metabolic syndrome (MetS) conducted in Taiwan. The original (HOMA1-IR) and updated nonlinear (HOMA2-IR) HOMA-IR indicators were used as IR biomarkers. Principal component (PC) analysis was employed to create reduced groups of variables and risk scores for retained PCs.
Higher SSB intake was associated with higher levels of HOMA1-IR and HOMA2-IR, and the two IR biomarkers were positively correlated with metabolic dysfunction clustering. Compared with SSB nondrinkers, adolescents who consumed >500 mL/day of hand-shaken high-fructose corn syrup beverages (HHB) had a 0.22 increase in the number of abnormal MetS components, and HOMA-IR mediation explained 33.9-37.9% of the effect. IR biomarkers accounted for 26.5-31.0% of the relationship between >500 mL/day of SSB consumption and bodyweight-enhanced PC scores. The effects of HOMA-IR indicators on all bodyweight-related factors were consistently intensified among >350 mL/day HHB drinkers (all P
< 0.05).
Fructose-rich SSB intake correlates with a constellation of cardiometabolic abnormalities in adolescents, and this association may be partly mediated by HOMA-IR levels. The adverse effects of HOMA-IR on bodyweight-associated cardiometabolic risk factors depend on the type of SSB consumption, with enhanced risks observed in the intake of high amounts of HFCS-containing SSBs.
Background
The optimal radiotherapy dose for locally advanced esophageal squamous cell carcinoma in endemic areas treated with neoadjuvant concurrent chemoradiotherapy is unclear.
Methods
Eligible ...patients diagnosed between 2010 and 2019 were identified via the Taiwan Cancer Registry. We used propensity score (PS) weighting to balance observable potential confounders. The hazard ratio (HR) of death was compared between high dose (50–50.4 Gy) and low dose (40–41.4 Gy) radiotherapy. We also evaluated other outcomes and performed supplementary analyses via an alternative approach.
Results
Our study population consisted of 644 patients. The PS weight-adjusted HR of death was 0.92 (95% confidence interval: 0.7–1.19, p = 0.51). There were no statistically significant differences for other outcomes or supplementary analyses.
Conclusions
In this population-based study from an endemic area, we found no significant difference in overall survival between high vs. low radiotherapy doses.
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