Advancements in Research on Duck Tembusu Virus Infections.

Duck Tembusu Virus (DTMUV) is a pathogen of the Flaviviridae family that causes infections in poultry, leading to significant economic losses in the duck farming industry in recent years. Ducks infected with this virus exhibit clinical symptoms such as decreased egg production and neurological disorders, along with serious consequences such as ovarian hemorrhage, organ enlargement, and necrosis. Variations in morbidity and mortality rates exist across different age groups of ducks. It is worth noting that DTMUV is not limited to ducks alone; it can also spread to other poultry such as chickens and geese, and antibodies related to DTMUV have even been found in duck farm workers, suggesting a potential risk of zoonotic transmission. This article provides a detailed overview of DTMUV research, delving into its genomic characteristics, vaccines, and the interplay with host immune responses. These in-depth research findings contribute to a more comprehensive understanding of the virus's transmission mechanism and pathogenic process, offering crucial scientific support for epidemic prevention and control.

Implementation of Health IT for Cancer Screening in US Primary Care: Scoping Review.

BACKGROUND: A substantial percentage of the US population is not up to date on guideline-recommended cancer screenings. Identifying interventions that effectively improve screening rates would enhance the delivery of such screening. Interventions involving health IT (HIT) show promise, but much remains unknown about how HIT is optimized to support cancer screening in primary care. OBJECTIVE: This scoping review aims to identify (1) HIT-based interventions that effectively support guideline concordance in breast, cervical, and colorectal cancer screening provision and follow-up in the primary care setting and (2) barriers or facilitators to the implementation of effective HIT in this setting. METHODS: Following scoping review guidelines, we searched MEDLINE, CINAHL Plus, Web of Science, and IEEE Xplore databases for US-based studies from 2015 to 2021 that featured HIT targeting breast, colorectal, and cervical cancer screening in primary care. Studies were dual screened using a review criteria checklist. Data extraction was guided by the following implementation science frameworks: the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework; the Expert Recommendations for Implementing Change taxonomy; and implementation strategy reporting domains. It was also guided by the Integrated Technology Implementation Model that incorporates theories of both implementation science and technology adoption. Reporting was guided by PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews). RESULTS: A total of 101 studies met the inclusion criteria. Most studies (85/101, 84.2%) involved electronic health record-based HIT interventions. The most common HIT function was clinical decision support, primarily used for panel management or at the point of care. Most studies related to HIT targeting colorectal cancer screening (83/101, 82.2%), followed by studies related to breast cancer screening (28/101, 27.7%), and cervical cancer screening (19/101, 18.8%). Improvements in cancer screening were associated with HIT-based interventions in most studies (36/54, 67% of colorectal cancer-relevant studies; 9/14, 64% of breast cancer-relevant studies; and 7/10, 70% of cervical cancer-relevant studies). Most studies (79/101, 78.2%) reported on the reach of certain interventions, while 17.8% (18/101) of the included studies reported on the adoption or maintenance. Reported barriers and facilitators to HIT adoption primarily related to inner context factors of primary care settings (eg, staffing and organizational policies that support or hinder HIT adoption). Implementation strategies for HIT adoption were reported in 23.8% (24/101) of the included studies. CONCLUSIONS: There are substantial evidence gaps regarding the effectiveness of HIT-based interventions, especially those targeting guideline-concordant breast and colorectal cancer screening in primary care. Even less is known about how to enhance the adoption of technologies that have been proven effective in supporting breast, colorectal, or cervical cancer screening. Research is needed to ensure that the potential benefits of effective HIT-based interventions equitably reach diverse primary care populations.

Applying Machine Learning Techniques to Implementation Science.

Machine learning (ML) approaches could expand the usefulness and application of implementation science methods in clinical medicine and public health settings. The aim of this viewpoint is to introduce a roadmap for applying ML techniques to address implementation science questions, such as predicting what will work best, for whom, under what circumstances, and with what predicted level of support, and what and when adaptation or deimplementation are needed. We describe how ML approaches could be used and discuss challenges that implementation scientists and methodologists will need to consider when using ML throughout the stages of implementation.

Large-scale Prospective Validation Study of a Multiplex RNA Urine Test for Noninvasive Detection of Upper Tract Urothelial Carcinoma.

BACKGROUND: Current approaches for diagnosis and monitoring of upper tract urothelial carcinoma (UTUC) are often invasive, costly, and not efficient for early-stage and low-grade tumors. OBJECTIVE: To validate a noninvasive urine-based RNA test for accurate UTUC diagnosis. DESIGN, SETTING, AND PARTICIPANTS: Urine samples were prospectively collected from 61 patients with UTUC and 99 controls without urothelial carcinomas, in five clinical centers between October 2022 and August 2023 prior to any invasive test (cystoscope or ureteroscope) or treatment. All samples were analyzed with a urine-based RNA test composed of eight genes (CA9, CCL18, ERBB2, IGF2, MMP12, PPP1R14D, SGK2, and SWINGN). The test results were presented with a risk score for each participant, which was applied to categorize patients into low- or high-risk groups. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The diagnosis of UTUC was based mainly on preoperative radiological examination criteria and confirmed by postoperative pathological results. The recursive feature elimination and support vector machine algorithms, χ2, and Student t test were used. RESULTS AND LIMITATIONS: The eight-gene urine test accurately detected UTUC patients and controls with an area under the curve (AUC) of 0.901 in a single-center testing cohort (n = 93) and an AUC of 0.926 in a multicenter clinical validation cohort (n = 66). In the merged validation cohort, the eight-gene urine test achieved high sensitivity of 90.16%, specificity of 88.89%, and overall accuracy of 89.38%. Remarkably, excellent performance was achieved in 11 low-grade UTUC patients with accuracy of 100%. However, this study collected the urine of UTUC patients only at a single preoperative time point and did not perform continuous tests during the pathological process of UTUC in the surveillance population. CONCLUSIONS: Our results demonstrated that the eight-gene urine test can differentiate accurately between UTUC and other urological diseases with high sensitivity and specificity. In clinical practice, it may be used for identifying UTUC patients effectively, leading to reduced reliance on ureteroscopy and blind surgery. PATIENT SUMMARY: In this study, we investigated a multiplex RNA urine test for noninvasive upper tract urothelial carcinoma (UTUC) diagnosis before treatment. We found that the risk scores derived from the multiplex RNA urine test differed significantly between UTUC patients and corresponding controls.

Duck Tembusu virus infection activates the MKK3/6-p38 MAPK signaling pathway to promote virus replication.

Duck Tembusu virus (DTMUV) infection poses a serious threat to ducks, chickens, and geese, causing a range of detrimental effects, including reduced egg production, growth retardation, and even death. These consequences lead to substantial economic losses for the Chinese poultry industry. Although it is established that various viral infections can trigger activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway, the precise role and mechanisms underlying p38 MAPK activation in DTMUV infection remain poorly understood. To address this knowledge gap, we conducted a study to investigate whether the replication of DTMUV necessitates the activation of p38 MAPK. We found that DTMUV infection stimulates activation of the MKK3/6-p38 MAPK pathway, and the activation of p38 MAPK increases with viral titer. Subsequently, the use of the small molecule inhibitor SB203580 significantly reduced DTMUV replication by inhibiting p38 MAPK activity. Furthermore, downregulation of p38 MAPK protein expression by siRNA also inhibited DTMUV replication, whereas transient transfection of p38 MAPK protein promoted DTMUV replication. Interestingly, we found that the DTMUV capsid protein activates p38 MAPK, and there is interaction between DTMUV capsid and p38 MAPK. Finally, we found that DTMUV infection induces elevated mRNA expression of IFN-α, IFN-ß, IFN-γ, IL-1ß, IL-6, and IL-12, which is associated with p38 MAPK activity. These results indicated that virus hijacking of p38 activation is a crucial event for DTMUV replication, and that pharmacological blockade of p38 activation represents a potential anti-DTMUV strategy.

Alzheimer's Disease Stage Transitions Among United States Veterans.

BACKGROUND: Alzheimer's disease (AD) and related dementias are progressive neurological disorders with stage-specific clinical features and challenges. An important knowledge gap is the "window of time" within which patients transition from mild cognitive impairment or mild AD to moderate or severe AD. Better characterization/establishment of transition times would help clinicians initiating treatments, including anti-amyloid therapy. OBJECTIVE: To describe cognitive test score-based AD stage transitions in Veterans with AD in the US Veterans Affairs Healthcare System (VAHS). METHODS: This retrospective analysis (2010-2019) identified Veterans with AD from the VAHS Electronic Health Record (EHR) notes. AD stage was based on Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), or Saint Louis University Mental Status (SLUMS) Examination scores in the EHR. RESULTS: We identified 296,519 Veterans with cognitive test-based AD staging. Over the 10-year study, the proportion of veterans with MMSE scores declined from 24.9% to 9.5% while those with SLUMS rose from 9.0% to 17.8%; and MoCA rose from 5.0% to 25.4%. The average forward transition times between each stage were approximately 2-4 years, whether assessed by MMSE, MoCA, or SLUMS. CONCLUSION: The average transition time for cognitive test-based assessments of initial cognitive decline, early-stage AD, and moderate/severe AD in the VAHS is 2-4 years. In view of the short window for introducing disease-modifying therapy and the significant benefits of early treatment of AD, our data suggest a critical need for treatment guidelines in the management of AD.

[Relationship between Iron Metabolic Parameters and Platelet Counts in Blood Donors].

OBJECTIVE: To investigate the correlation of iron metabolic parameters with platelet counts in blood donors. METHODS: A total of 400 blood donors who met requirements of apheresis platelet donation were collected, and their hematological parameters were analyzed. The donors were divided into low ferritin group and normal group, the differences of hematological parameters between the two groups were compared, and the correlation of iron metabolic parameters and routine hematology parameters with platelet counts were analyzed. RESULTS: Whether male or female, low ferritin group had higher platelet counts than normal group (P < 0.01). Among the iron metabolic parameters, the platelet counts was negatively correlated with serum ferritin (SF), serum iron (SI), and transferrin saturation (TSAT) (r =-0.162, r =-0.153, r =-0.256), and positively correlated with total iron binding capacity (TIBC) and unsaturated iron binding capacity (UIBC) (r =0.219, r =0.294) in female blood donors. Platelet counts was also negatively correlated with SF, SI and TSAT (r =-0.188, r =-0.148, r =-0.224) and positively correlated with UIBC (r =0.220) in male blood donors. Among the routine hematology parameters, platelet counts was negatively correlated with mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and reticulocyte hemoglobin equivalent (Ret-He) in female blood donors (r =-0.236, r =-0.267, r =-0.213, r =-0.284). Platelet counts was also negatively correlated with MCH, MCHC and Ret-He in male blood donors (r =-0.184, r =-0.221, r =-0.209). CONCLUSION: In blood donors with low C-reactive protein level, the lower the iron store capacity, the lower the iron utilization, and the platelet counts tends to rise.

Monitoring the Implementation of Tobacco Cessation Support Tools: Using Novel Electronic Health Record Activity Metrics.

BACKGROUND: Clinical decision support (CDS) tools in electronic health records (EHRs) are often used as core strategies to support quality improvement programs in the clinical setting. Monitoring the impact (intended and unintended) of these tools is crucial for program evaluation and adaptation. Existing approaches for monitoring typically rely on health care providers' self-reports or direct observation of clinical workflows, which require substantial data collection efforts and are prone to reporting bias. OBJECTIVE: This study aims to develop a novel monitoring method leveraging EHR activity data and demonstrate its use in monitoring the CDS tools implemented by a tobacco cessation program sponsored by the National Cancer Institute's Cancer Center Cessation Initiative (C3I). METHODS: We developed EHR-based metrics to monitor the implementation of two CDS tools: (1) a screening alert reminding clinic staff to complete the smoking assessment and (2) a support alert prompting health care providers to discuss support and treatment options, including referral to a cessation clinic. Using EHR activity data, we measured the completion (encounter-level alert completion rate) and burden (the number of times an alert was fired before completion and time spent handling the alert) of the CDS tools. We report metrics tracked for 12 months post implementation, comparing 7 cancer clinics (2 clinics implemented the screening alert and 5 implemented both alerts) within a C3I center, and identify areas to improve alert design and adoption. RESULTS: The screening alert fired in 5121 encounters during the 12 months post implementation. The encounter-level alert completion rate (clinic staff acknowledged completion of screening in EHR: 0.55; clinic staff completed EHR documentation of screening results: 0.32) remained stable over time but varied considerably across clinics. The support alert fired in 1074 encounters during the 12 months. Providers acted upon (ie, not postponed) the support alert in 87.3% (n=938) of encounters, identified a patient ready to quit in 12% (n=129) of encounters, and ordered a referral to the cessation clinic in 2% (n=22) of encounters. With respect to alert burden, on average, both alerts fired over 2 times (screening alert: 2.7; support alert: 2.1) before completion; time spent postponing the screening alert was similar to completing (52 vs 53 seconds) the alert, and time spent postponing the support alert was more than completing (67 vs 50 seconds) the alert per encounter. These findings inform four areas where the alert design and use can be improved: (1) improving alert adoption and completion through local adaptation, (2) improving support alert efficacy by additional strategies including training in provider-patient communication, (3) improving the accuracy of tracking for alert completion, and (4) balancing alert efficacy with the burden. CONCLUSIONS: EHR activity metrics were able to monitor the success and burden of tobacco cessation alerts, allowing for a more nuanced understanding of potential trade-offs associated with alert implementation. These metrics can be used to guide implementation adaptation and are scalable across diverse settings.

Sympathetic ß2-adrenergic receptor blockade overcomes docetaxel resistance in prostate cancer.

PURPOSE: Due to the limited effective therapies, resistance to docetaxel is ordinarily fatal and remains a critical clinical challenge.ß2-adrenergic receptor(ß2-AR)can promote the metastasis and invasion of prostate cancer, but the role in chemotherapy-resistant prostate cancer remains unclear. METHODS: By downloading the GEO database in NCBI, the expression of ß2-AR in different prostate tissues was analyzed. We constructed docetaxel-resistant prostate cancer cell lines by the method of dose-escalation. LC3B-labeled stable cells and shAtg5 knockdown stable cells were constructed by lentivirus infection. The molecular mechanism of ß2-AR affecting docetaxel sensitivity through apoptosis and autophage were investigated by flow cytometry, mitochondrial membrane potential and western blot. Then we detected the interaction between autophagy and apoptotic by performing immunoprecipitation assay. RESULTS: We show that restraining the activity of ß2-AR sensitized the cell response and reduced the resistance to docetaxel. The mechanism involves the regulation of ß2-AR in the cellular response to docetaxel through apoptosis and autophagy via caspase signaling and Atg5/AMPK/mTOR pathway as well as the effect of ß2-AR on the crosstalk between apoptosis and autophagy via p38 MAPK and JNK/c-Jun/FOXO3a signaling pathways. CONCLUSION: Our data demonstrate that ß2-AR inhibitor-induced autophagy and apoptosis contribute to the effectiveness responses to docetaxel in castration-resistant prostate cancer, and in combination with pharmacological agents of ß2-AR and autophagy inhibitors may provide a potential therapeutic strategy to enhance the limited capacity of docetaxel to control castration-resistant prostate cancer.

An analysis of risk factors associated with recurrent wheezing in the pediatric population.

BACKGROUND: Recurrent wheezing is a common clinical problem in early childhood, which is associated with significant morbidity. There is no international consensus on the management and prevention of recurrent wheezing; therefore, identifying the risk factors associated with recurrent wheezing is crucial to prevent episodes of wheezing in young children. METHODS: In this retrospective study, we collected the data of 24,737 patients who were admitted to our hospital between 27th April 2012 and 11th September 2019. After screening for patients with wheezing, we identified 8572 patients with a primary diagnosis of pneumonia with wheezing. Patients' clinical data were collected from the hospital medical records. Patients were stratified for age in the groups of < 6 months, 6-12 months, and > 12 months. RESULTS: Among the 8569 pediatric pneumonia patients with wheezing, there were 343 patients with recurrent wheezing. Most enrolled patients were under 6 months of age (45.17%) and had a normal birth weight (86.95%). Winter was the most common onset season for the first episode of wheezing, while spring was the most common season for the second episode of wheezing for those with recurrent wheezing. The univariate and multivariate logistic regression analysis for the risk factor associated with recurrent wheezing showed that male gender, past history of respiratory and cardiovascular diseases, low birth weight, development of severe pneumonia, and PICU admission were significantly associated with recurrent wheezing. CONCLUSION: Male gender, past history of respiratory and cardiovascular diseases, low birth weight, severe pneumonia, and PICU admission are independent risk factors of recurrent wheezing in the pediatric population.

Effect of a Machine Learning Recommender System and Viral Peer Marketing Intervention on Smoking Cessation: A Randomized Clinical Trial.

Importance: Novel data science and marketing methods of smoking-cessation intervention have not been adequately evaluated. Objective: To compare machine learning recommender (ML recommender) computer tailoring of motivational text messages vs a standard motivational text-based intervention (standard messaging) and a viral peer-recruitment tool kit (viral tool kit) for recruiting friends and family vs no tool kit in a smoking-cessation intervention. Design, Setting, and Participants: This 2 ×2 factorial randomized clinical trial with partial allocation, conducted between July 2017 and September 2019 within an online tobacco intervention, recruited current smokers aged 18 years and older who spoke English from the US via the internet and peer referral. Data were analyzed from March through May 2022. Interventions: Participants registering for the online intervention were randomly assigned to the ML recommender or standard messaging groups followed by partially random allocation to access to viral tool kit or no viral tool kit groups. The ML recommender provided ongoing refinement of message selection based on user feedback and comparison with a growing database of other users, while the standard system selected messages based on participant baseline readiness to quit. Main Outcomes and Measures: Our primary outcome was self-reported 7-day point prevalence smoking cessation at 6 months. Results: Of 1487 participants who smoked (444 aged 19-34 years [29.9%], 508 aged 35-54 years [34.1%], 535 aged ≥55 years [36.0%]; 1101 [74.0%] females; 189 Black [12.7%] and 1101 White [78.5%]; 106 Hispanic [7.1%]), 741 individuals were randomly assigned to the ML recommender group and 746 individuals to the standard messaging group; viral tool kit access was provided to 745 participants, and 742 participants received no such access. There was no significant difference in 6-month smoking cessation between ML recommender (146 of 412 participants [35.4%] with outcome data) and standard messaging (156 of 389 participants [40.1%] with outcome data) groups (adjusted odds ratio, 0.81; 95% CI, 0.61-1.08). Smoking cessation was significantly higher in viral tool kit (177 of 395 participants [44.8%] with outcome data) vs no viral tool kit (125 of 406 participants [30.8%] with outcome data) groups (adjusted odds ratio, 1.48; 95% CI, 1.11-1.98). Conclusions and Relevance: In this study, machine learning-based selection did not improve performance compared with standard message selection, while viral marketing did improve cessation outcomes. These results suggest that in addition to increasing dissemination, viral recruitment may have important implications for improving effectiveness of smoking-cessation interventions. Trial Registration: ClinicalTrials.gov Identifier: NCT03224520.

Detection of the freshness of rice by chemiluminescence.

Reactive oxygen species (ROS) are usually produced in rice under aerobic environmental conditions, resulting in peroxidative changes in polyunsaturated fatty acids, and affecting the deterioration of rice during storage. In addition, as an important enzyme that participates in removing ROS, peroxidase is also present in rice, and takes part in protecting rice from attack by ROS. Moreover, loss of peroxidase activity may give rise to rice deterioration during storage. Therefore, measuring peroxidase activity makes it possible to ascertain the freshness of rice. In addition, peroxidase can also catalyze the luminol-hydrogen peroxide system. Based on this, in this work we established a new chemiluminescence (CL) method that was used to detect the freshness of stored rice. Under optimal experimental conditions, we showed that the freshness of rice can be measured using this CL method. This study is the first to detect the freshness of rice using a CL method, opening up a novel direction for the application of CL.

TAK1 blockade as a therapy for retinal neovascularization.

Retinal neovascularization, or pathological angiogenesis in the retina, is a leading cause of blindness in developed countries. Transforming growth factor-ß-activated kinase 1 (TAK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK) activated by TGF-ß1 and other proinflammatory cytokines. TAK1 is also a key mediator of proinflammatory signals and plays an important role in maintaining vascular integrity upon proinflammatory cytokine stimulation such as TNFα. However, its role in pathological angiogenesis, particularly in retinal neovascularization, remains unclear. Here, we investigate the regulatory role of TAK1 in human endothelial cells responding to inflammatory stimuli and in a rat model of oxygen-induced retinopathy (OIR) featured retinal neovascularization. Using TAK1 knockout human endothelial cells that subjected to inflammatory stimuli, transcriptome analysis revealed that TAK1 is required for activation of NFκB signaling and mediates its downstream gene expression related to endothelial activation and angiogenesis. Moreover, pharmacological inhibition of TAK1 by 5Z-7-oxozeaenol attenuated angiogenic activities of endothelial cells. Transcriptome analysis also revealed enrichment of TAK1-mediated NFκB signaling pathway in the retina of OIR rats and retinal neovascular membrane from patients with proliferative diabetic retinopathy. Intravitreal injection of 5Z-7-oxozeaenol significantly reduced hypoxia-induced inflammation and microglial activation, thus attenuating aberrant retinal angiogenesis in OIR rats. Our data suggest that inhibition of TAK1 may have therapeutic potential for the treatment of retinal neovascular pathologies.

Plasma Extracellular Vesicle Long RNA in Diagnosis and Prediction in Small Cell Lung Cancer.

(1) Introduction: The aim of this study was to identify the plasma extracellular vesicle (EV)-specific transcriptional profile in small-cell lung cancer (SCLC) and to explore the application value of plasma EV long RNA (exLR) in SCLC treatment prediction and diagnosis. (2) Methods: Plasma samples were collected from 57 SCLC treatment-naive patients, 104 non-small-cell lung cancer (NSCLC) patients and 59 healthy participants. The SCLC patients were divided into chemo-sensitive and chemo-refractory groups based on the therapeutic effects. The exLR profiles of the plasma samples were analyzed by high-throughput sequencing. Bioinformatics approaches were used to investigate the differentially expressed exLRs and their biofunctions. Finally, a t-signature was constructed using logistic regression for SCLC treatment prediction and diagnosis. (3) Results: We obtained 220 plasma exLRs profiles in all the participants. Totals of 5787 and 1207 differentially expressed exLRs were identified between SCLC/healthy controls, between the chemo-sensitive/chemo-refractory groups, respectively. Furthermore, we constructed a t-signature that comprised ten exLRs, including EPCAM, CCNE2, CDC6, KRT8, LAMB1, CALB2, STMN1, UCHL1, HOXB7 and CDCA7, for SCLC treatment prediction and diagnosis. The exLR t-score effectively distinguished the chemo-sensitive from the chemo-refractory group (p = 9.268 × 10-9) with an area under the receiver operating characteristic curve (AUC) of 0.9091 (95% CI: 0.837 to 0.9811) and distinguished SCLC from healthy controls (AUC: 0.9643; 95% CI: 0.9256-1) and NSCLC (AUC: 0.721; 95% CI: 0.6384-0.8036). (4) Conclusions: This study firstly characterized the plasma exLR profiles of SCLC patients and verified the feasibility and value of identifying biomarkers based on exLR profiles in SCLC diagnosis and treatment prediction.

Flavonoid Extract from Propolis Provides Cardioprotection following Myocardial Infarction by Activating PPAR-γ.

We have previously reported that flavonoid extract from propolis (FP) can improve cardiac function in rats following myocardial infarction (MI). However, the mechanisms responsible for the cardioprotective effects of FP have not been fully elucidated. In the current study, we explored whether FP can reduce inflammatory cytokines and attenuate sympathetic nerve system activity and antiendoplasmic reticulum (ER) stress and whether the cardioprotective effects are related to peroxisome proliferator-activated receptor gamma (PPAR-γ) activation. Sprague Dawley rats were randomly divided into six groups: Sham group received the surgical procedure but no artery was ligated; MI group received ligation of the left anterior descending (LAD) branch of the coronary artery; MI + FP group received FP (12.5 mg/kg/d, intragastrically) seven days prior to LAD ligation; FP group (Sham group + 12.5 mg/kg/d, intragastrically); MI + FP + GW9662 group received FP prior to LAD ligation with the addition of a specific PPAR-γ inhibitor (GW9662), 1 mg/kg/d, orally); and MI + GW9662 group received the PPAR-γ inhibitor and LAD ligation. The results demonstrated that the following inflammatory markers were significantly elevated following MI as compared with expression in sham animals: IL-1ß, TNF-α, CRP; markers of sympathetic activation: plasma norepinephrine, epinephrine and GAP43, nerve growth factor, thyroid hormone; and ER stress response markers GRP78 and CHOP. Notably, the above changes were attenuated by FP, and GW9662 was able to alleviate the effect of FP. In conclusion, FP induces a cardioprotective effect following myocardial infarction by activating PPAR-γ, leading to less inflammation, cardiac sympathetic activity, and ER stress.

Autophagy Induced by Muscarinic Acetylcholine Receptor 1 Mediates Migration and Invasion Targeting Atg5 via AMPK/mTOR Pathway in Prostate Cancer.

Increasing numbers of researchers discovered the expression of muscarinic acetylcholine receptor 1 in human cancers, while its function in human prostate cancer is still unclear. Our present study focused on CHRM1 to clarify its role in mediating autophagy in prostate cancer. We used immunohistochemistry, western blotting, and immunofluorescence experiments to observe the expression of muscarinic acetylcholine receptor 1 both in nude mice with subcutaneous tumors and in prostate cancer cells. The autophagy was observed through transmission electron microscopy, western blotting, quantitative real-time PCR, and immunofluorescence. After that, we used lentivirus to establish CHRM1 and Atg5 knockdown models. Then, the migration and invasion abilities after knocking down muscarinic acetylcholine receptor 1 and Atg5 were detected by transwell assays. In addition, the AMPK/mTOR pathway-related targets were detected by western blotting. We found that muscarinic acetylcholine receptor 1 was abundantly expressed both in vitro and in vivo in prostate cancer. The overexpression of muscarinic acetylcholine receptor 1 positively regulated migration and invasion in tumor cells as well as the activation of autophagy. Muscarinic acetylcholine receptor 1 was highly correlated with Atg5 and activated the AMPK/mTOR signaling pathway. Downregulation of Atg5 inhibited cell autophagy in prostate cancer cells and the migration and invasion of prostate cancer cells. Meanwhile, abnormal expressions of AMPK/mTOR pathway-related proteins were found. In conclusion, the present findings indicated that muscarinic acetylcholine receptor 1 is highly expressed in prostate cancer cells and promotes cell invasion and migration of prostate cancer. Autophagy is activated in prostate cancer cells and the activation of muscarinic acetylcholine receptor 1 positively regulates autophagy in prostate cancer cells. Moreover, muscarinic acetylcholine receptor 1 induces autophagy-mediated cell migration and invasion by targeting Atg5 in prostate cancer cells via AMPK/mTOR pathway, which uncovered that regulating muscarinic acetylcholine receptor 1, identified in this study, can be a promising solution for treating prostate cancer.

Osteoclastogenesis inhibitory phenolic derivatives produced by the Beibu Gulf coral-associated fungus Acremonium sclerotigenum GXIMD 02501.

Three new chlorinated orsellinic aldehyde derivatives, orsaldechlorins A - C (1-3) and a naturally new brominated orsellinic acid (7), along with ten known biosynthetically related phenolic (4-6, 8-13) and cyclohexanone (14) derivatives, were identified from the Beibu Gulf coral-derived fungus Acremonium sclerotigenum GXIMD 02501. Their structures were determined by spectroscopic data interpretation and comparison with those reported in the literature. Several of them showed inhibition of lipopolysaccharide (LPS)-induced NF-κB activation in RAW 264.7 macrophages at 20 µM. Moreover, the two new potent inhibitors (1 and 2) suppressed RANKL-induced osteoclast differentiation without cytotoxicity in bone marrow macrophages cells (BMMs). Our findings reveal that the phenolic compounds could be potential candidates for the prevention and treatment of osteolytic bone diseases.

An Integrative Multi-Omics Analysis Reveals MicroRNA-143 as a Potential Therapeutic to Attenuate Retinal Angiogenesis.

Retinal neovascularization is a severe complication of proliferative diabetic retinopathy (PDR). MicroRNAs (miRNAs) are master regulators of gene expression that play an important role in retinal neovascularization. In this study, we show that miR-143-3p is significantly downregulated in the retina of a rat model of oxygen-induced retinopathy (OIR) by miRNA-sequencing. Intravitreal injection of synthetic miR-143 mimics significantly ameliorate retinal neovascularization in OIR rats. miR-143 is identified to be highly expressed in the neural retina particularly in the ganglion cell layer and retinal vasculature. In miR-143 treated cells, the functional evaluation showed a decrease in cell migration and delayed endothelial vessel-like tube remodeling. The multiomics analysis suggests that miR-143 negatively impacts endothelial cell activity through regulating cell-matrix adhesion and mediating hypoxia-inducible factor-1 signaling. We predict hub genes regulated by miR-143 that may be involved in mediating endothelial cell function by cytoHubba. We also demonstrate that the retinal neovascular membranes in patients with PDR principally consist of endothelial cells by CIBERSORTx. We then identify 2 hub genes, thrombospondin 1 and plasminogen activator inhibitor, direct targets of miR-143, that significantly altered in the PDR patients. These findings suggest that miR-143 appears to be essential for limiting endothelial cell-matrix adhesion, thus suppressing retinal neovascularization.

Clinical validation of a 90-gene expression test for tumor tissue of origin diagnosis: a large-scale multicenter study of 1417 patients.

BACKGROUND: Once malignancy tumors were diagnosed, the determination of tissue origin and tumor type is critical for clinical management. Although the significant advance in imaging techniques and histopathological approaches, the diagnosis remains challenging in patients with metastatic and poorly differentiated or undifferentiated tumors. Gene expression profiling has been demonstrated the ability to classify multiple tumor types. The present study aims to assess the performance of a 90-gene expression test for tumor classification (i.e. the determination of tumor tissue of origin) in real clinical settings. METHODS: Formalin-fixed paraffin-embedded samples and associated clinicopathologic information were collected from three cancer centers between January 2016 and January 2021. A total of 1417 specimens that met quality control criteria (RNA quality, tumor cell content ≥ 60% and so on) were analyzed by the 90-gene expression test to identify the tumor tissue of origin. The performance was evaluated by comparing the test results with histopathological diagnosis. RESULTS: The 1417 samples represent 21 main tumor types classified by common tissue origins and anatomic sites. Overall, the 90-gene expression test reached an accuracy of 94.4% (1338/1417, 95% CI: 0.93 to 0.96). Among different tumor types, sensitivities were ranged from 74.2% (head&neck tumor) to 100% (adrenal carcinoma, mesothelioma, and prostate cancer). Sensitivities for the most prevalent cancers of lung, breast, colorectum, and gastroesophagus are 95.0%, 98.4%, 93.9%, and 90.6%, respectively. Moreover, specificities for all 21 tumor types are greater than 99%. CONCLUSIONS: These findings showed robust performance of the 90-gene expression test for identifying the tumor tissue of origin and support the use of molecular testing as an adjunct to tumor classification, especially to those poorly differentiated or undifferentiated tumors in clinical practice.

Understanding Patients' Intention to Use Digital Health Apps That Support Postdischarge Symptom Monitoring by Providers Among Patients With Acute Coronary Syndrome: Survey Study.

BACKGROUND: After hospital discharge, patients with acute coronary syndrome (ACS) often experience symptoms that prompt them to seek acute medical attention. Early evaluation of postdischarge symptoms by health care providers may reduce unnecessary acute care utilization. However, hospital-initiated follow-up encounters are insufficient for timely detection and assessment of symptoms. While digital health tools can help address this issue, little is known about the intention to use such tools in ACS patients. OBJECTIVE: This study aimed to assess ACS patients' intention to use digital health apps that support postdischarge symptom monitoring by health care providers and identify patient-perceived facilitators and barriers to app use. METHODS: Using email invitations or phone calls, we recruited ACS patients discharged from a central Massachusetts health care system between December 2020 and April 2021, to participate in the study. Surveys were delivered online or via phone to individual participants. Demographics and access to technology were assessed. The intention to use a symptom monitoring app was assessed using 5-point Likert-type (from strongly agree to strongly disagree) items, such as "If this app were available to me, I would use it." Responses were compared across demographic subgroups and survey delivery methods. Two open-ended questions assessed perceived facilitators and barriers to app use, with responses analyzed using qualitative content analysis. RESULTS: Among 100 respondents (response rate 8.1%), 45 (45%) completed the survey by phone. The respondents were on average 68 years old (SD 13 years), with 90% (90/100) White, 39% (39/100) women, and 88% (88/100) having access to the internet or a mobile phone. Most participants (65/100, 65%) agreed or strongly agreed that they would use the app, among which 53 (82%) would use the app as often as possible. The percentage of participants with the intention to use the app was 75% among those aged 65-74 years and dropped to 44% among those older than 75 years. The intention to use was higher in online survey respondents (vs phone survey respondents; odds ratio 3.07, 95% CI 1.20-7.88) after adjusting for age and access to technology. The analysis of open-ended questions identified the following 4 main facilitators (motivations): (1) easily reaching providers, (2) accessing or providing information, (3) quickly reaching providers, and (4) consulting providers for symptoms, and the following 4 main barriers: (1) privacy/security concerns, (2) uncomfortable using technology, (3) user-unfriendly app interface, and (4) preference for in-person/phone care. CONCLUSIONS: There was a strong intention to use a symptom monitoring app postdischarge among ACS patients. However, this intent decreased in patients older than 75 years. The survey identified barriers related to technology use, privacy/security, and the care delivery mode. Further research is warranted to determine if such intent translates into app use, and better symptom management and health care quality.