[Mechanism of bulleyaconitine A in inhibiting bone destruction of rheumatoid arthritis via Src/PI3K/Akt signaling pathway].

Based on the sarcoma receptor coactivator(Src)/phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway, the mechanism of action of bulleyaconitine A in the treatment of bone destruction of experimental rheumatoid arthritis(RA) was explored. Firstly, key targets of RA bone destruction were collected through GeneCards, PharmGKB, and OMIM databa-ses. Potential targets of bulleyaconitine A were collected using SwissTargetPrediction and PharmMapper databases. Next, intersection targets were obtained by the Venny 2.1.0 platform. Protein-protein interaction(PPI) network and topology analysis were managed by utilizing the STRING database and Cytoscape 3.8.0. Then, Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were conducted in the DAVID database. AutoDock Vina was applied to predict the molecular docking and binding ability of bulleyaconitine A with key targets. Finally, a receptor activator of nuclear factor-κB(RANKL)-induced osteoclast differentiation model was established in vitro. Quantitative real-time polymerase chain reaction(qRT-PCR) was used to detect the mRNA expression levels of related targets, and immunofluorescence and Western blot were adopted to detect the protein expression level of key targets. It displayed that there was a total of 29 drug-disease targets, and Src was the core target of bulleyaconitine A in anti-RA bone destruction. Furthermore, KEGG enrichment analysis revealed that bulleyaconitine A may exert an anti-RA bone destruction effect by regulating the Src/PI3K/Akt signaling pathway. The molecular docking results showed that bulleyaconitine A had better bin-ding ability with Src, phosphatidylinositol-4,5-diphosphate 3-kinase(PIK3CA), and Akt1. The result of the experiment indicated that bulleyaconitine A not only dose-dependently inhibited the mRNA expression levels of osteoclast differentiation-related genes cathepsin K(CTSK) and matrix metalloproteinase-9(MMP-9)(P<0.01), but also significantly reduced the expression of p-c-Src, PI3K, as well as p-Akt in vitro osteoclasts(P<0.01). In summary, bulleyaconitine A may inhibit RA bone destruction by regulating the Src/PI3K/Akt signaling pathway. This study provides experimental support for the treatment of RA bone destruction with bulleyaconitine A and lays a foundation for the clinical application of bulleyaconitine A.

[Mechanism of Yuxuebi Tablets in treating synovial inflammation in rheumatoid arthritis based on transcriptomics].

This study investigated the mechanism of Yuxuebi Tablets(YXB) in the treatment of synovial inflammation in rheumatoid arthritis(RA) based on transcriptomic analysis. Transcriptome sequencing technology was employed to analyze the gene expression profiles of joint tissues from normal rats, collagen-induced arthritis(CIA) rats(an RA model), and YXB-treated rats. Common diffe-rentially expressed genes(DEGs) were subjected to Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses. RA synovial inflammation-related target genes were retrieved from the OMIM and GeneCards databases. Venny 2.1 software was used to identify the intersection of YXB target genes and RA synovial inflammation-related target genes, and GO and KEGG enrichment analyses were performed on the intersecting target genes. Immunohistochemistry was used to assess the protein expression levels of the inflammatory factors interleukin-1ß(IL-1ß) and tumor necrosis factor-α(TNF-α) in rat joint tissues. Western blot analysis was employed to measure the expression levels of key proteins in the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway. A total of 2 058 DEGs were identified by intersecting the genes from the normal group vs model group and the model group vs YXB treatment group. A search in OMIM and GeneCards databases yielded 1 102 RA synovial inflammation-related target genes. After intersecting with the DEGs in the YXB treatment group, 204 intersecting target genes were identified, primarily involving biological processes such as immune response, signal transduction, and inflammatory response; cellular components including plasma membrane, extracellular space, and extracellular region; molecular functions like protein binding, identical protein binding, and receptor binding. These target genes were mainly enriched in signaling pathways such as PI3K/Akt, cytokine-cytokine receptor interaction, and Janus kinase/signal transducer and activator of transcription(JAK/STAT). Western blot results showed that YXB at low, medium, and high doses could significantly inhibit the expression levels of key proteins in the PI3K/Akt signaling pathway in rat joint tissues in a dose-dependent manner. Immunohistochemistry further confirmed these findings, showing that YXB not only suppressed the protein expression levels of the inflammatory factors IL-1ß and TNF-α in the joint synovial tissues of CIA rats, but also inhibited p-Akt protein expression. In conclusion, this study used transcriptomic analysis to uncover the key mechanisms of YXB in inhibiting synovial inflammation and alleviating the progression of RA, with a focus on its role in suppressing the PI3K/Akt signaling pathway.

Growth modulatory effects of fenretinide encompass keratinocyte terminal differentiation: A favorable outcome for oral squamous cell carcinoma chemoprevention.

Oral squamous cell carcinoma (OSCC) is world-wide health problem associated with high morbidity and mortality. From both the patient and socio-economic perspectives, prevention of progression of premalignant oral intraepithelial neoplasia (OIN) to OSCC is clearly the preferable outcome. Optimal OSCC chemopreventives possess a variety of attributes including high-tolerability, bioavailability, efficacy and preservation of an intact surface epithelium. Terminal differentiation, which directs oral keratinocytes leave the proliferative pool to form protective cornified envelopes, preserves the protective epithelial barrier while concurrently eliminating growth-aberrant keratinocytes. This study employed human premalignant oral keratinocytes and an OSCC cell line to evaluate the differentiation-inducing capacity of the synthetic retinoid, fenretinide (4HPR). Full thickness oral mucosal explants were evaluated for proof of concept differentiation studies. Results of this study characterize the ability of 4HPR to fulfill all requisite components for keratinocyte differentiation i.e. nuclear import via binding to CRABP-II (molecular modeling), binding to and subsequent activation of retinoic acid nuclear receptors (receptor activation assays), increased expression and translation of genes associated with keratinocyte differentiation (RT-PCR, immunoblotting) upregulation of a transglutaminase enzyme essential for cornified envelope formation (TGM3, functional assay) and augmentation of terminal differentiation in human oral epithelial explants (image-analyses quantified corneocyte desquamation). These data build upon the chemoprevention repertoire of 4HPR that includes function as a small molecule kinase inhibitor and inhibition of essential mechanisms necessary for basement membrane invasion. An upcoming clinical trial, which will assess whether a 4HPR-releasing mucoadhesive patch induces histologic, clinical and molecular regression in OIN lesions, will provide essential clinical insights.

[Coronasomnia: A Concept Analysis].

COVID-19 has been a global pandemic for three years. Symptoms experienced by patients with this disease include fever, cough, fatigue, muscle pain, and diarrhea as well as mental health issues. The terms "coronasomnia" and "COVID-somnia" emerged in 2021 to describe sleep disorders attributable to stress associated with the COVID-19 pandemic. In this study, the concept analysis method proposed by Walker & Avant (2019) was utilized to define the concept of coronasomnia (Walker & Avant, 2019), with three key attributes identified, including COVID-related anxiety or depression; insomnia that emerges after the pandemic; and experiencing difficulty falling asleep, interrupted sleep, or early morning awakenings accompanied by difficulty returning to sleep. Furthermore, the concept was elucidated in this study using typical, borderline, opposite, and relative cases. Lastly, evidence-based tools for validating the antecedents and consequences of coronasomnia were introduced. We hope the results of this concept analysis enhance nurses' understanding of coronasomnia and facilitate the implementation of clinical care and research in this area.

Predicting dice similarity coefficient of deformably registered contours using Siamese neural network.

Objective. Automatic deformable image registration (DIR) is a critical step in adaptive radiotherapy. Manually delineated organs-at-risk (OARs) contours on planning CT (pCT) scans are deformably registered onto daily cone-beam CT (CBCT) scans for delivered dose accumulation. However, evaluation of registered contours requires human assessment, which is time-consuming and subjects to high inter-observer variability. This work proposes a deep learning model that allows accurate prediction of Dice similarity coefficients (DSC) of registered contours in prostate radiotherapy.Approach. Our dataset comprises 20 prostate cancer patients with 37-39 daily CBCT scans each. The pCT scans and planning contours were deformably registered to each corresponding CBCT scan to generate virtual CT (vCT) scans and registered contours. The DSC score, which is a common contour-based validation metric for registration quality, between the registered and manual contours were computed. A Siamese neural network was trained on the vCT-CBCT image pairs to predict DSC. To assess the performance of the model, the root mean squared error (RMSE) between the actual and predicted DSC were computed.Main results. The model showed promising results for predicting DSC, giving RMSE of 0.070, 0.079 and 0.118 for rectum, prostate, and bladder respectively on the holdout test set. Clinically, a low RMSE implies that the predicted DSC can be reliably used to determine if further DIR assessment from physicians is required. Considering the event where a registered contour is classified as poor if its DSC is below 0.6 and good otherwise, the model achieves an accuracy of 92% for the rectum. A sensitivity of 0.97 suggests that the model can correctly identify 97% of poorly registered contours, allowing manual assessment of DIR to be triggered.Significance. We propose a neural network capable of accurately predicting DSC of deformably registered OAR contours, which can be used to evaluate eligibility for plan adaptation.

Mucopenetrating Janus Nanoparticles For Field-Coverage Oral Cancer Chemoprevention.

INTRODUCTION: Oral squamous cell carcinoma (OSCC), is associated with high morbidity and mortality. Preemptive interventions have been postulated to provide superior therapeutic options, but their implementation has been restricted by the availability of broadly applicable local delivery systems. METHODS: We address this challenge by engineering a delivery vehicle, Janus nanoparticles (JNP), that combine the dual mucoadhesive properties of a first cationic chitosan compartment with a second hydrophobic poly(lactide-co-glycolide) release compartment. JNP are designed to avoid rapid mucus clearance while ensuring stable loading and controlled release of the IL-6 receptor antagonist, tocilizumab (TCZ). RESULTS: The JNP featured defined and monodispersed sizes with an average diameter of 327 nm and a PDI of 0.245, high circularities above 0.90 and supported controlled release of TCZ and effective internalization by oral keratinocytes. TCZ released from JNP retained its biological activity and effectively reduced both, soluble and membrane-bound IL-6Rα (71% and 50%). In full-thickness oral mucosal explants, 76% of the JNP breached the stratum corneum and in 41% were observed in the basal cell layer indicating excellent mucopenetrating properties. When tested in an aggressive OSCC xenograft model, TCZ-loaded JNP showed high levels of xenograft inhibition and outperformed all control groups with respect to inhibition of tumor cell proliferation, reduction in tumor size and reduced expression of the proto-oncogene ERG. CONCLUSION: By combining critically required, yet orthogonal properties within the same nanoparticle design, the JNP in this study, demonstrate promise as precision delivery platforms for intraoral field-coverage chemoprevention, a vastly under-researched area of high clinical importance.

Silencing of V-ATPase-E gene causes midgut apoptosis of Diaphorina citri and affects its acquisition of Huanglongbing pathogen.

The Asian citrus psyllid, Diaphorina citri Kuwayama, is among the most important pests of citrus. It is the main vector of the Huanglongbing (HLB) pathogen Candidatus Liberibacter asiaticus (CLas), which causes severe losses in citrus crops. Control of D. citri is therefore of paramount importance to reduce the spread of HLB. In this regard, using RNA interference (RNAi) to silence target genes is a useful strategy to control psyllids. In this study, using RNAi, we examined the biological functions of the V-ATPase subunit E (V-ATP-E) gene of D. citri, including its effect on acquisition of CLas. The amino acid sequence of V-ATP-E from D. citri had high homology with proteins from other insects. V-ATP-E was expressed at all D. citri life stages analyzed, and the expression level in mature adults was higher than that of teneral adults. Silencing of V-ATP-E resulted in a significant increase in mortality, reduced body weight, and induced cell apoptosis of the D. citri midgut. The reduced expression of V-ATP-E was indicated to inhibit CLas passing through the midgut and into the hemolymph, leading to a majority of CLas being confined to the midgut. In addition, double-stranded RNA of D. citri V-ATP-E was safe to non-target parasitic wasps. These results suggest that V-ATP-E is an effective RNAi target that can be used in D. citri control to block CLas infection.

Amorphous Calcium Carbonate Cluster Nanospheres in Water-Deficient Organic Solvents.

As the key intermediate phase of crystalline calcium carbonate biominerals, amorphous calcium carbonate (ACC) remains mysterious in its structures because of its long-range disorder and instability. We herein report the synthesis of ACC nanospheres in a water-deficient organic solvent system. The obtained ACC nanospheres are very stable under dry conditions. Cryo-TEM reveals that each nanospheres consists of smaller nanosized clusters. We further demonstrate that these clusters can precipitate on other substrates to form an ultrathin ACC coating, which should be an ACC cluster monolayer. The results demonstrate that the presence of small ACC clusters as the subunits of larger aggregates is inherent to ACC synthesized in water-alcohol system but not induced by polymer additives.

Fenretinide combines perturbation of signaling kinases, cell-extracellular matrix interactions and matrix metalloproteinase activation to inhibit invasion in oral squamous cell carcinoma cells.

Basement membrane invasion defines malignant transformation of surface premalignancy. Treatment of oral squamous cell carcinoma (OSCC) cells with the synthetic vitamin A derivative, fenretinide (4HPR), induces numerous cancer-preventive effects including suppression of basement membrane invasion, elimination of anchorage-independent growth, disruption of actin cytoskeletal components and inhibition of the invasion-enabling focal adhesive kinase. The purpose of this study was to elucidate 4HPR's effects on additional invasion-relevant mechanisms including matrix metalloproteinase (MMP) activation and function, cell-extracellular matrix (ECM) attachments and interaction with a kinase that is essential for the epithelial-myoepithelial transformation i.e. c-Jun NH2-terminal kinase (JNK). Our data revealed that 4HPR binds with high affinity to the ATP-binding site of all three JNK isoforms with concurrent suppression of kinase function. Additional studies showed 4HPR treatment inhibited both OSCC cell-ECM adhesion and MMP activation and function. JNK downregulation and induced expression studies confirmed that the JNK3 isoform conveyed that largest impact on OSCC migration and invasion. Biodegradable polymeric implants formulated to preserve 4HPR's function and bioavailability were employed to assess 4HPR's chemopreventive impact on an OSCC tumor induction model. These studies revealed 4HPR local delivery significantly inhibited OSCC tumor size, mitotic indices and expression of the endothelial marker, erythroblast transformation-specific-related gene with concurrent increases in tumor apoptosis (cleaved caspase-3). Collectively, these data show that 4HPR suppresses invasion at multiple sites including 'outside-in' signaling, cell-ECM interactions and suppression of MMPs. These functions are also essential for physiologic function. Regulation is therefore essential and reinforces the pharmacologic advantage of local delivery chemopreventive formulations. .

Evaluation of inter- and intra-observer variations in prostate gland delineation using CT-alone versus CT/TPUS.

Background: This study aims to explore the role of four-dimensional (4D) transperineal ultrasound (TPUS) in the contouring of prostate gland with planning computed tomography (CT) images, in the absence of magnetic resonance imaging (MRI). Materials and methods: Five radiation oncologists (ROs) performed two rounds of prostate gland contouring (single-blinded) on CT-alone and CT/TPUS datasets obtained from 10 patients who underwent TPUS-guided external beam radiotherapy. Parameters include prostate volume, DICE similarity coefficient (DSC) and centroid position. Wilcoxon signed-rank test assessed the significance of inter-modality differences, and the intraclass correlation coefficient (ICC ) reflected inter- and intra-observer reliability of parameters. Results: Inter-modality analysis revealed high agreement (based on DSC and centroid position) of prostate gland contours between CT-alone and CT/TPUS. Statistical significant difference was observed in the superior-inferior direction of the prostate centroid position (p = 0.011). All modalities yielded excellent inter-observer reliability of delineated prostate volume with ICC > 0.9, mean DSC > 0.8 and centroid position: CT-alone (ICC = 1.000) and CT/TPUS (ICC = 0.999) left-right (L/R); CT-alone (ICC = 0.999) and CT/TPUS (ICC = 0.998) anterior-posterior (A/P); CT-alone (ICC = 0.999) and CT/TPUS (ICC = 1.000) superior-inferior (S/I). Similarly, all modalities yielded excellent intra-observer reliability of delineated prostate volume, ICC > 0.9 and mean DSC > 0.8. Lastly, intra-observer reliability was excellent on both imaging modalities for the prostate centroid position, ICC > 0.9. Conclusion: TPUS does not add significantly to the amount of anatomical information provided by CT images. However, TPUS can supplement planning CT to achieve a higher positional accuracy in the S/I direction if access to CT/MRI fusion is limited.

Cardiovascular toxicities of androgen deprivation therapy in Asian men with localized prostate cancer after curative radiotherapy: a registry-based observational study.

BACKGROUND: Androgen deprivation therapy (ADT) and radiotherapy (RT) are the mainstay treatment for localized prostate cancer and recurrence after surgery. Cardiovascular (CV) toxicity of ADT is increasingly recognized, and the risk relates to pre-existing risk factors and ADT modalities. Despite ethnic differences in the prevalence of CV risk factors and variations of CV mortality, data on ADT-related cardiotoxicities in the Asian population remain inconclusive. Our registry-based study investigated ADT-related major adverse cardiovascular events (MACE) after primary or salvage RT. METHODS: Our study combined two prospectively established registry databases from National Cancer Center Singapore and National Heart Center Singapore. The primary endpoint is time to first MACE after treatment. MACE is defined as myocardial infarction, stroke, unstable angina, or cardiovascular death. Two types of propensity score adjustments, including ADT propensity score as a covariate in the multivariable regression model and propensity score weighting, were applied to balance baseline features and CV risk factors between RT alone and RT + ADT groups. RESULTS: From 2000 to 2019, 1940 patients received either RT alone (n = 494) or RT + ADT (n = 1446) were included. After a median follow-up of 10 years (RT) and 7.2 years (RT+ ADT), the cumulative incidence of MACE at 1, 3 and 9 years was 1.2, 5 and 16.2% in RT group, and 1.1, 5.2 and 17.6% in RT + ADT group, respectively. There were no differences in the incidence of MACE between 2 groups (HR 1.01, 95% CI 0.78-1.30, p = 0.969). Pre-treatment CV risk factors were common (80%), and CV disease (15.9%) was the second leading cause of death after prostate cancer (21.1%). On univariate analysis, older age, Indians and Malays, pre-existing CV risk factors, and history of MACE were associated with higher MACE risk. After propensity score adjustments, there remained no significant differences in MACE risk between RT + ADT and RT group on multivariable analysis. CONCLUSIONS: In our registry-based study, ADT is not associated with increased risk of major cardiovascular events among Southeast Asian men with prostate cancer after curative radiotherapy.

Geraniin as a potential inhibitor of SARS-CoV-2 3CLpro.

Geraniin is a polyphenolic compound first isolated from Geranium thunbergii. The major protease (Mpro), namely 3 C-like protease (3CLpro), of coronaviruses is considered an attractive drug target as it is essential for the processing and maturation of viral polyproteins. Thus, our primary goal is to explore the efficiency of geraniin on 3CLpro of SARS-CoV-2 using the computational biology strategy. In this work, we studied the anti-coronavirus effect of geraniin in vitro and its potential inhibitory mode against the 3CLpro of SARS-CoV-2. We found that geraniin inhibited HCoV-OC43 coronavirus-infected cells during the attachment and penetration phases. Molecular docking and dynamics simulations exhibited that geraniin had a strong binding affinity and high stable binding to 3CLpro of SARS-CoV-2. Geraniin showed a strong inhibitory activity on coronavirus and may be a potential inhibitor of SARS-CoV-2 3CLpro.

Impact of Huanglongbing Pathogen Infection on the Amino Acid Composition in Both Citrus Plants and the Asian Citrus Psyllid.

The Asian citrus psyllid (ACP) Diaphorina citri is the main vector of the pathogen Candidatus Liberibacter asiaticus (CLas), which is the causal agent of citrus Huanglongbing disease. Feeding by both ACP nymphs and adults on host plants allows them to obtain nutrition. Therefore, the nutritional content within the plant phloem is of much importance for the development and reproduction of ACP. The infection by pathogenic microbiomes may affect the amino acid contents of their host plants and then indirectly affect the biology of sap-feeding insects. In this study, we investigated the amino acid contents and their proportions in both CLas-infected and CLas-free citrus plants, ACP adults, and also in honeydew produced by ACP nymphs. Results showed that infection by CLas had a large impact on the amino acid species and proportion in all the tested target plants, ACP adults, and in the honeydew of ACP nymphs. The content of total amino acids in CLas-infected citrus was much higher than that of CLas-free citrus. However, CLas infection significantly reduced the proportion of essential amino acids (EAAs) in these plants. When feeding on CLas-infected citrus plants, ACP adults absorbed less total amino acids than those adults feeding on healthy plants, but the proportion of EAAs was significantly higher when they fed on CLas-infected citrus plants. The proportion of EAAs also significantly increased in the honeydew secreted by ACP nymphs that fed on CLas-infected citrus plants. However, EAA detection in the honeydew of ACP nymphs indicated that the utilization rate of EAAs by CLas positive ACP nymphs was reduced. Our study has revealed that CLas infection significantly affects the contents, proportion, and utilization efficiency of different amino acids in citrus plants, ACP adults, and nymphs, leading to a developmental pattern of ACP that is more conducive to CLas transmission.

A Prospective Randomized Controlled Trial to Compare the Use of Conventional Dark-Ink Tattoo and Ultraviolet-Ink Tattoo for Patients Undergoing Breast Radiation Therapy.

PURPOSE: Permanent tattoo marks used in radiation therapy remain for the duration of treatment and essentially for the rest of the patient's life. This study compared the initial positioning setup errors and body image perception between patients with ultraviolet (UV) and conventional dark ink tattoos. METHODS AND MATERIALS: Thirty-four patients from February 2018 to March 2019, who underwent radiation therapy (RT) to the breast or chest wall for ductal carcinoma in situ or breast cancer were prospectively recruited and randomized (1:1) to receive either conventional dark ink or UV ink tattoos. Each patient received the assigned tattoos during computed tomography (CT) simulation and initial treatment setup shifts were compared. A 9-item body-image survey was administered to all patients at 3 time points: CT simulation, last week of RT, and 6 weeks post-RT. Feedback from CT and treatment staff in terms of setup time and challenges were collated. RESULTS: The median age of the patient cohort was 46 years old. No statistically significant difference was observed between the mean setup errors for the conventional dark ink group (0.11 cm inferior, 0.01 cm left, 0.11 cm posterior) and UV ink group (0.01 cm superior, 0.01 cm right, 0.06 cm posterior; P = NS). Similar responses were observed in the body-image survey between the 2 groups across all time points (P = NS). The majority of the patients (dark ink 82.3% vs UV ink 88.2%) did not feel less sexually attractive as a result of the tattoo at 6 weeks post-RT. At 6 weeks post-RT, patients in both groups were satisfied with the appearance of the tattoo and did not feel cautious about their choice of clothes (82.4% vs 88.2%; P = NS). In addition, 88.6% of staff (n = 35) felt minimum effect of UV ink on the overall setup time, and 94.3% found no difficulty localizing the UV ink tattoos during patient positioning. CONCLUSIONS: No difference in setup accuracy was found using UV ink tattoos, and it could be implemented clinically with minimal effect on the existing workflow. Patients expressed high satisfaction and self-confidence with the use of UV ink tattoos.

A comparative analysis between low-dose-rate brachytherapy and external beam radiation therapy for low- and intermediate-risk prostate cancer in Asian men.

OBJECTIVE: To report the long-term clinical outcomes of low-risk (LR) and intermediate-risk (IR) prostate cancer patients treated with low-dose-rate brachytherapy (LDR-BT) and external beam radiation therapy (EBRT). PATIENTS AND METHODS: Men with biopsy-proven low- and intermediate-risk prostate cancer received EBRT and LDR-BT in an Asian academic center from 2000 to 2019 were reviewed. Kaplan-Meier survival analysis was performed to compare biochemical failure-free survival (bFFS) and overall survival (OS) between LDR and EBRT in the low- and intermediate-risk cohorts. RESULTS: 642 patients (521 EBRT and 121 LDR-BT) with low- and intermediate-risk prostate cancer were included for analysis. In the intermediate-risk group, 5- and 10-year bFFS was 96%, 89% and 86%, 61% for LDR-BT and EBRT, respectively. LDR-BT was associated with a statistically significant improvement of bFFS in the intermediate-risk cohort (HR 2.7, p = 0.02). In the low-risk cohort, no difference of bFFS was found between LDR-BT and EBRT (HR 1.9, p = 0.08). Hormone therapy was more common in EBRT than LDR-BT for intermediate-risk group (71% versus 44%, p < 0.05). Prostate cancer-specific mortality was low in both EBRT (1%) and LDR-BT (2%) cohorts. No significant difference in OS was found between LDR-BT and EBRT in low- and intermediate-risk group (HR 2.1, p = 0.2 and HR = 1.7, p = 0.3). CONCLUSION: In our retrospective study, LDR-BT is associated with superior bFFS compared with EBRT in Asian men with intermediate-risk prostate cancer.

Puerarin reduces impairment of intestinal and adipose immune responses to influenza virus infection in mice.

Influenza is an acute viral respiratory disease that can also cause gastroenteritis-like symptoms, such as abdominal pain, nausea, vomiting, and diarrhea. Immune dysfunction of adipose tissue is involved in the occurrence and prognosis of influenza viral pneumonia. In this study, we analyzed intestinal and adipose immune responses in mice infected with influenza virus and found that the impairment of intestinal and adipose immunity to influenza virus infection could be reversed by treatment with puerarin, a medicinal compound isolated from Pueraria lobata (called "gegen" in Chinese). We found that the lungs, small intestines (duodenum, ileum, jejunum) and large intestines (colon and rectum) of infected mice showed obvious inflammatory lesions, with significantly increased levels of virus, inflammatory cytokines (interleukin [IL]-6, IL-17, and tumor necrosis factor-α), Toll-like receptors 3, 4, and 9, and integrin αvß3 and α4, and a decreased level of secreted IgA compared to the normal control group (NC) (P < 0.05-0.001). Influenza virus infected mesenteric lymph nodes and adipose tissue, and adipokines (leptin, visfatin, "chemerin", and adiponectin) of lung and mesenteric adipose tissue were dysregulated. Puerarin treatment reversed the impairment of the intestinal and adipose immune responses in mice infected with influenza virus. Our findings suggest that influenza virus can infect adipose tissue and lead to intestinal adipose immune dysfunction in normal-weight mice and that the impairment of the intestinal and adipose immune response to influenza virus infection can be reversed by puerarin treatment.

A potential antiviral activity of Esculentoside A against binding interactions of SARS-COV-2 spike protein and angiotensin converting enzyme 2 (ACE2).

The recent emergence of the novel coronavirus (SARS-CoV-2) has resulted in a devastating pandemic with global concern. However, to date, there are no regimens to prevent and treat SARS-CoV-2 virus. There is an urgent need to identify novel leads with anti-viral properties that impede viral pathogenesis in the host system. Esculentoside A (EsA), a saponin isolated from the root of Phytolacca esculenta, is known to exhibit diverse pharmacological properties, especially anti-inflammatory activity. To our knowledge, SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) to enter host cells. This is mediated through the proteins of SARS-CoV-2, especially the spike glycoprotein receptor binding domain. Thus, our primary goal is to prevent virus replication and binding to the host, which allows us to explore the efficiency of EsA on key surface drug target proteins using the computational biology paradigm approach. Here, the anti-coronavirus activity of EsA in vitro and its potential mode of inhibitory action on the S-protein of SARS-CoV-2 were investigated. We found that EsA inhibited the HCoV-OC43 coronavirus during the attachment and penetration stage. Molecular docking results showed that EsA had a strong binding affinity with the spike glycoprotein from SARS-CoV-2. The results of the molecular dynamics simulation revealed that EsA had higher stable binding with the spike protein. These results demonstrated that Esculentoside A can act as a spike protein blocker to inhibit SARS-CoV-2. Considering the poor bioavailability and low toxicity of EsA, it is suitable as novel lead for the inhibitor against binding interactions of SARS-CoV-2 of S-protein and ACE2.

Antiviral activity of puerarin as potent inhibitor of influenza virus neuraminidase.

Puerarin is a major isofiavone compound isolated from the root of Pueraria lobata. It was reported that puerarin had antioxidant, antiinflammatory, antitumor, cholesterol lowering, liver protective, and neuroprotective properties. However, few studies have explored the antiviral effect of puerarin and its target mechanism related to influenza virus. Here, the antiinfluenza activity of puerarin in vitro and in vivo and its mode of action on the potential inhibition of neuraminidase (NA) were investigated. Puerarin displayed an inhibitory effect on A/FM/1/1947(H1N1) (EC50 = 52.06 µM). An indirect immunofluorescence assay indicated that puerarin blocked the nuclear export of viral NP. The inhibition of NA activity confirmed that puerarin can block the release of newly formed virus particles from infected cells. Puerarin (100 and 200 mg/kg/d) exhibited effective antiviral activity in mice, conferring 50% and 70% protection from death against H1N1, reducing virus titers, and effectively alleviating inflammation in the lungs. The molecular docking results showed that puerarin had a strong binding affinity with NA from H1N1. The results of the molecular dynamics simulation revealed that puerarin had higher stable binding at the 150-loop region of the NA protein. These results demonstrated that puerarin acts as a NA blocker to inhibit influenza A virus both in cellular and animal models. Thus, puerarin has potential utility for the treatment of the influenza virus infection.

A Cohort Study on Associations between Fundus/intraocular Pressure Abnormality and Medical Check-up Items.

PURPOSE: To evaluate the associations between medical check-up items (MCI) for fundus and intraocular pressure abnormality (FIPA) diseases in the Department of Health Management Centre, the Fifth Affiliated Hospital of Sun Yat-sen University (DHMC-FHS). PATIENTS AND METHODS: Individuals who visited DHMC-FHS and underwent MCI between June 2017 to May 2019 were included, 3237 subjects. A total of 356 participants were diagnosed as FIPA and enrolled. The general clinical characteristics were collected. Diseases for FIPA diagnosed included five cohort, high intraocular pressure, diabetic retinopathy, hypertension fundus arteriosclerosis, large eye cup, and high myopia fundus changes. Possible impact factors of MCI included blood routine, B-ultrasound, heart rate, hypertension, hyperlipidemia, standard vision, cerebral arteriosclerosis, body mass, arterial/carotid arteriosclerosis, etc. Further, the Pearson's correlation coefficients and logistic regression analyses were used to examine associations between MCI and FIPA. RESULTS: The weighted study population who belonged to FIPA included 356 subjects. There were significant differences in age, IOP, habitual exercise, smoking, sleep duration (P˂0.05) between FIPA and without FIPA. And RBC, Hemoglobin, B-ultrasound abnormal event, heart rate, systolic pressure, diastolic pressure, TC, LDL-C, standard vision, cerebral arteriosclerosis, body mass index, carotid arteriosclerosis were positively correlated with high intraocular pressure, hypertension fundus arteriosclerosis and high myopia fundus changes (P < .05). Possible prognosis risk factors, higher IOP, habitual exercise and more frequent smoking affect FIPA prognosis significantly [Odds ratio (OR) = 0.53, P = .01; OR = 0.13, P = .03; OR = 0.83; P = .04, respectively]. CONCLUSION: Of FIPA participants, high intraocular pressure, hypertension fundus arteriosclerosis and high myopia fundus changes were shown a positive relationship with MCI. Control IOP, habitual exercise and less frequent smoking were regarded as positive associations with decreased FIPA. These findings could help us prevent and diagnose FIPA diseases in time via MCI.