[Identification of Osteoarthritis Inflamm-Aging Biomarkers by Integrating Bioinformatic Analysis and Machine Learning Strategies and the Clinical Validation]. / ç”Ÿç‰©ä¿¡æ¯å­¦å’Œæœºå™¨å­¦ä¹ ç­–ç•¥è¯†åˆ«éª¨å ³èŠ‚ç‚Žç‚Žæ€§è¡°è€ç”Ÿç‰©æ ‡å¿—ç‰©ä¸Žä¸´åºŠéªŒè¯.

Objective: To identify inflamm-aging related biomarkers in osteoarthritis (OA). Methods: Microarray gene profiles of young and aging OA patients were obtained from the Gene Expression Omnibus (GEO) database and aging-related genes (ARGs) were obtained from the Human Aging Genome Resource (HAGR) database. The differentially expressed genes of young OA and older OA patients were screened and then intersected with ARGs to obtain the aging-related genes of OA. Enrichment analysis was performed to reveal the potential mechanisms of aging-related markers in OA. Three machine learning methods were used to identify core senescence markers of OA and the receiver operating characteristic (ROC) curve was used to assess their diagnostic performance. Peripheral blood mononuclear cells were collected from clinical OA patients to verify the expression of senescence-associated secretory phenotype (SASP) factors and senescence markers. Results: A total of 45 senescence-related markers were obtained, which were mainly involved in the regulation of cellular senescence, the cell cycle, inflammatory response, etc. Through the screening with the three machine learning methods, 5 core senescence biomarkers, including FOXO3, MCL1, SIRT3, STAG1, and S100A13, were obtained. A total of 20 cases of normal controls and 40 cases of OA patients, including 20 cases in the young patient group and 20 in the elderly patient group, were enrolled. Compared with those of the young patient group, C-reactive protein (CRP), interleukin (IL)-6, and IL-1ß levels increased and IL-4 levels decreased in the elderly OA patient group (P<0.01); FOXO3, MCL1, and SIRT3 mRNA expression decreased and STAG1 and S100A13 mRNA expression increased (P<0.01). Pearson correlation analysis demonstrated that the selected markers were associated with some indicators, including erythrocyte sedimentation rate (ESR), IL-1ß, IL-4, CRP, and IL-6. The area under the ROC curve of the 5 core aging genes was always greater than 0.8 and the C-index of the calibration curve in the nomogram prediction model was 0.755, which suggested the good calibration ability of the model. Conclusion: FOXO3, MCL1, SIRT3, STAG1, and S100A13 may serve as novel diagnostic biomolecular markers and potential therapeutic targets for OA inflamm-aging.

Ultrahigh sensitive and rapid-response self-powered flexible pressure sensor based on sandwiched piezoelectric composites.

Flexible sensors and actuators are the basis for realizing the Internet of Everything. This study identifies specific interfacial polarization and filler dispersion challenges in flexible sensors. A novel sandwich-structured flexible sensor with polydimethylsiloxane (PDMS)-filled Nb2CTx as the interlayer and poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE)]-filled barium titanate (BTO) as the upper and lower layers was designed and fabricated. The thickness of the interlayer was optimized to be 6.2 µm, resulting in an ultrahigh sensitivity of 16.05 V/N and ultrashort response time of 626 µs. The interlayer achieved an oriented arrangement of the dipoles in the upper and lower piezoelectric films through interfacial polarization, enhancing the piezoelectric output and sensitivity. The proposed mechanism was confirmed by the dielectric properties, local piezoelectric response, cross-sectional potential simulation, and interfacial electrical calculations. Additionally, the sensor effectively distinguishes various body movements, facial micro-expressions, and throat vibrations during vocalization, and can be applied to ultrahigh-sensitive self-powered flexible piezoelectric pressure sensors.

Integrating clinical data mining, network analysis and experimental validation reveal the anti-inflammatory mechanism of Huangqin Qingre Chubi Capsule in rheumatoid arthritis treatment.

ETHNOPHARMACOLOGICAL RELEVANCE: Huangqin Qingre Chubi Capsule (HQC) is a Chinese medicinal compound used for the treatment of damp-heat pattern rheumatism, guided by the traditional Chinese medicine syndrome differentiation practice. HQC has been used in the clinical treatment of rheumatic diseases for more than 20 years with remarkable efficacy. HQC has been experimentally shown to exert anti-arthritic effects via the Wnt signaling pathway. AIM OF THE STUDY: This study used clinical data mining, network analysis, and in vitro and in vivo tests to investigate the anti-arthritic and possible anti-inflammatory mechanism of HQC. Specifically, emphasis was placed on the function of the hsa_circ_0091,685/EIF4A3/IL-17 axis in the anti-inflammatory process. MATERIALS AND METHODS: A random walk model was used to evaluate the effects of HQC on clinical immune inflammatory marker function in patients with RA. Network analysis was used to predict the potential target genes and pathways of HQC. Hematoxylin & eosin, safranin O-fast green and toluidine blue staining, immunohistochemistry, and transmission electron microscopy were performed to evaluate the anti-arthritic effects of HQC in rat models. Cell Counting Kit-8 assay, quantitative real-time polymerase chain reaction, western blotting, enzyme-linked immunosorbent assay, and RNA pull-down were used to study the anti-proliferation and anti-inflammatory mechanisms of HQC. RESULTS: Patients with RA who underwent HQC treatment showed a significant reduction in inflammatory response levels, according to retrospective clinical study. Network analysis revealed that HQC potentially targeted genes and pathways related to inflammation, especially IL-6, IL-17, TNF-α, IL-23, and IL-17 signaling pathway. Animal experiments showed that HQC inhibits inflammation through the IL-17 signaling pathway in rat models. Cellular experiments showed that HQC-containing serum inhibited the inflammatory response in patients with RA-FLS or RA by blocking hsa_circ_0091,685 and EIF4A3 expression. CONCLUSION: In RA patients, HQC reduces the inflammatory response. The antiproliferative and anti-inflammatory qualities of HQC are responsible for its therapeutic impact. The suppression of the hsa_circ_0091,685/EIF4A3/IL-17 axis was linked to these favorable outcomes.

Association between traditional Chinese Medicine and osteoarthritis outcome: A 5-year matched cohort study.

Objective: The aim of this study was to investigate the relationship between Traditional Chinese medicine (TCM) and pain reduction, hospital readmission, and joint replacement in patients with osteoarthritis (OA). Chinese herbal medicine (CHM) prescription patterns were further analyzed to confirm the association with prognosis and quality of life in OA patients. Methods: We retrospectively followed 3,850 hospitalized patients with osteoarthritis between January 2018 and December 2022 using the hospital's HIS system. Propensity score matching (PSM) was used for data matching. Cox's proportional risk model was used to assess the impact of various factors on the outcomes of patients with OA, including pain worsening, readmission, and joint replacement. The Kaplan-Meier survival curve was applied to determine the impact of TCM intervention time on patient outcomes. Data mining methods including association rules, cluster analysis, and random walks have been used to assess the efficacy of TCM. Results: The utilization rate of TCM in OA patients was 67.01% (2,511/3,747). After PSM matching, 1,228 TCM non-user patients and 1,228 TCM user patients were eventually included. The outcomes of pain worsening, re-admission rate, and joint replacement rate of the TCM non-user group were observably higher than those of the TCM user group with OA (p < 0.05). Based on the Cox proportional risk model, TCM is an independent protective factor. Compared with non-TCM users, TCM users had 58.4% lower rates of pain, 51.1% lower rates of re-admission, and 42% lower rates of joint replacement. In addition, patients in the high-exposure subgroup (TCM＞24 months) had a markedly lower risk of outcome events than those in the low-exposure subgroup (TCM ≤24 months). Data mining methods have shown that TCM therapy can significantly improve immune-inflammatory indices, VAS scores, and SF-36 scale scores in OA patients. Conclusion: s TCM acts as a protective factor to improve the prognosis of patients with OA, and the benefits of long-term use of herbal medicines are even greater.

Systemic inflammation response index as an emerging biomarker in osteoarthritis patients: a bibliometric and large sample retrospective investigation.

OBJECTIVES: To determine the value of the whole-blood inflammatory response index as an emerging biomarker for the assessment of disease activity in osteoarthritis (OA). METHODS: Extensive analysis of the literature on OA and whole-blood inflammatory indicators were provided through a bibliometric approach. Clinical characteristics and indicators of OA patients and healthy controls (HC) were retrospectively analysed. Four whole-blood inflammatory response indices - neutrophil/lymphocyte count (NLR), platelet/lymphocyte count (PLR), monocyte/lymphocyte count (MLR), and systemic inflammation response index (SIRI), as well as clinical traits like the OA patient's self-perception and immune-inflammatory indicators were analysed for correlations. Cut-off values were determined using receiver operating characteristic (ROC) curves, and they were subsequently employed in logistic regression models to work out whole-blood inflammatory indices and disease activity. RESULTS: The pathophysiology of osteoarthritis has received most of the spotlight in literature studies of OA and whole-blood inflammation indicators. The "inflammation", "osteoarthritis" and "disease activity" were the top 3 key word clusters. Retrospective analysis showed that MLR, NLR, PLR, and SIRI were markedly higher in OA subjects compared to HC subjects. ROC curve consequences manifested that SIRI and NLR could separate OA from healthy controls. NLR, PLR, MLR, and SIRI proved to be related to immune-inflammatory markers, visual analogue scale (VAS) scores, and short-form (SF)-36 scores with regard to correlation analysis and association criteria. Logistic regression manifested that SIRI, NLR, and C-reactive protein (CRP) forecasted disease activity, however, the model that combined SIRI and CRP was superior to CRP alone. CONCLUSIONS: SIRI may serve as a non-invasive, appropriate biomarker to correlate with disease activity.

Huangqin Qingre Chubi Capsule is Associated with Reduced Risk of Readmission in Patients with Rheumatoid Arthritis: A Real-World Retrospective Cohort Study.

Purpose: The therapeutic effects of Huangqin Qingre Chubi (HQC) in rheumatoid arthritis (RA) have been documented. However, there is a lack of real-world clinical evidence supporting its efficacy. Methods: Patients diagnosed with RA were recruited from the First Affiliated Hospital of the Anhui University of Chinese Medicine. Patient information was obtained from the hospital's database. Propensity score matching (PSM), Kaplan-Meier curve, and Cox proportional hazards model were used to control confounding factors and analyze the factors influencing readmission. Association rule analysis and random walk evaluation models were used to evaluate the correlations among HQC treatment, inflammation indicators, and self-perception of patients (SPP) scale. Results: After PSM, 3423 patients were enrolled, with 1142 in the HQC group and 2281 in the non-HQC group. The readmission risk of the HQC group was significantly lower than that of the non-HQC group. Combined univariate and multivariate analysis results revealed that risk factors for readmission were age >60 years, female sex, hypertension, chronic gastritis, and elevated levels of laboratory indices, including anticyclic citrullinated peptide and complement component 3 (C3) and C4. HQC, disease-modifying antirheumatic drugs, nonsteroidal anti-inflammatory drugs, and glucocorticoid therapy were protective factors for readmission. HQC treatment was closely associated with improvements in many factors, including erythrocyte sedimentation rate, C-reactive protein, C3, rheumatoid factor levels, visual analog scale, depression self-assessment scale, and patient-reported activity index scores with RA. Conclusion: HQC treatment can reduce the risk of readmission and significantly improve immune inflammatory indicators and SPP in patients with RA, with no risk of hepatorenal toxicity.

Phase Conductance of BiFeO3 Film.

In this work, the local conductance of the tetragonal-like (T-like) and rhombohedral-like (R-like) phases of epitaxial BiFeO3 film is systematically studied via conductive atomic force microscopy. At higher tip voltage, there is a mutual transition between the T-like and R-like phases, which could be attributed to the strain relaxation in the T-like phase induced by electric poling, as well as local polarization switching. The T-like phase exhibits a higher conductance, which is related to the lower interface potential barrier between the tip and film surface. Reversible low- and high-current states in the T-like phase can be tuned by polarization switching. These results will be helpful for designing novel nanoelectronic devices, such as voltage and strain sensors.

A Flexible Magnetic Field Sensor Based on PZT/CFO Bilayer via van der Waals Oxide Heteroepitaxy.

Magnetoelectric (ME) magnetic field sensors utilize ME effects in ferroelectric ferromagnetic layered heterostructures to convert magnetic signals into electrical signals. However, the substrate clamping effect greatly limits the design and fabrication of ME composites with high ME coefficients. To reduce the clamping effect and improve the ME response, a flexible ME sensor based on PbZr0.2Ti0.8O3 (PZT)/CoFe2O4 (CFO) ME bilayered heterostructure was deposited on mica substrates via van der Waals oxide heteroepitaxy. A saturated magnetization of 114.5 emu/cm3 was observed in the bilayers. The flexible sensor exhibited a strong ME coefficient of 6.12 V/cm·Oe. The local ME coupling has been confirmed by the evolution of the ferroelectric domain under applied magnetic fields. The flexible ME sensor possessed a stable response with high sensitivity to both AC and DC weak magnetic fields. A high linearity of 0.9988 and sensitivity of 72.65 mV/Oe of the ME sensor were obtained under flat states. The ME output and limit-of-detection under different bending states showed an inferior trend as the bending radius increased. A flexible proximity sensor has been demonstrated, indicating a promising avenue for wearable device applications and significantly broadening the potential application of the flexible ME magnetic field sensors.

[Identification of Characteristic lncRNA Molecular Markers in Osteoarthritis by Integrating GEO Database and Machine Learning Strategies and Experimental Validation].

Objective: To screen for long non-coding RNA (lncRNA) molecular markers characteristic of osteoarthritis (OA) by utilizing the Gene Expression Omnibus (GEO) database combined with machine learning. Methods: The samples of 185 OA patients and 76 healthy individuals as normal controls were included in the study. GEO datasets were screened for differentially expressed lncRNAs. Three algorithms, the least absolute shrinkage and selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE), and random forest (RF), were used to screen for candidate lncRNA models and receiver operating characteristic (ROC) curves were plotted to evaluate the models. We collected the peripheral blood samples of 30 clinical OA patients and 15 health controls and measured the immunoinflammatory indicators. RT-PCR was performed for quantitative analysis of the expression of lncRNA molecular markers in peripheral blood mononuclear cells (PBMC). Pearson analysis was performed to examine the correlation between lncRNA and indicators for inflammation of the immune system. Results: A total of 14 key markers were identified with LASSO, 6 genes were identified with SVM-RFE, and 24 genes were identified with RF. Venn diagram was used to screen for overlapping genes identified with the three algorithms, showing HOTAIR, H19, MIR155 HG, and NKILA to be the overlapping genes. The ROC curves showed that these four lncRNAs all had an area under the curve ( AUC) greater than 0.7. The RT-PCR findings revealed relatively elevated expression of HOTAIR, H19, and MIR155HG and decreased expression of NKILA in the PBMC of OA patients compared with those of the normal group ( P<0.01). The results were consistent with the bioinformatics predictions. Pearson analysis showed that the candidate lncRNAs were correlated with clinical indicators for inflammation. Conclusion: HOTAIR, H19, MIR155 HG, and NKILA can be used as molecular markers for the clinical diagnosis of OA and are correlate with clinical indicators of inflammation of the immune system.

The Diagnostic Features of Peripheral Blood Biomarkers in Identifying Osteoarthritis Individuals: Machine Learning Strategies and Clinical Evidence.

BACKGROUND: People with osteoarthritis place a huge burden on society. Early diagnosis is essential to prevent disease progression and to select the best treatment strategy more effectively. In this study, the aim was to examine the diagnostic features and clinical value of peripheral blood biomarkers for osteoarthritis. OBJECTIVE: The goal of this project was to investigate the diagnostic features of peripheral blood and immune cell infiltration in osteoarthritis (OA). METHODS: Two eligible datasets (GSE63359 and GSE48556) were obtained from the GEO database to discern differentially expressed genes (DEGs). The machine learning strategy was employed to filtrate diagnostic biomarkers for OA. Additional verification was implemented by collecting clinical samples of OA. The CIBERSORT website estimated relative subsets of RNA transcripts to evaluate the immune-inflammatory states of OA. The link between specific DEGs and clinical immune-inflammatory markers was found by correlation analysis. RESULTS: Overall, 67 robust DEGs were identified. The nuclear receptor subfamily 2 group C member 2 (NR2C2), transcription factor 4 (TCF4), stromal antigen 1 (STAG1), and interleukin 18 receptor accessory protein (IL18RAP) were identified as effective diagnostic markers of OA in peripheral blood. All four diagnostic markers showed significant increases in expression in OA. Analysis of immune cell infiltration revealed that macrophages are involved in the occurrence of OA. Candidate diagnostic markers were correlated with clinical immune-inflammatory indicators of OA patients. CONCLUSION: We highlight that DEGs associated with immune inflammation (NR2C2, TCF4, STAG1, and IL18RAP) may be potential biomarkers for peripheral blood in OA, which are also associated with clinical immune-inflammatory indicators.

Caffeic acid phenethyl ester suppresses metastasis of breast cancer cells by inactivating FGFR1 via MD2.

BACKGROUND: Tumor metastasis is the main cause of death for breast cancer patients. Caffeic acid phenethyl ester (CAPE) has strong anti-tumor effects with very low toxicity and may be a potential candidate drug. However, the anti-metastatic effect and molecular mechanism of CAPE on breast cancer need more research. METHODS: MCF-7 and MDA-MB-231 breast cancer cells were used here. Wound healing and Transwell assay were used for migration and invasion detection. Western blot and RT-qPCR were carried out for the epithelial-to-myofibroblast transformation (EMT) process investigation. Western blot and immunofluorescence were performed for fibroblast growth factor receptor1 (FGFR1) phosphorylation and nuclear transfer detection. Co-immunoprecipitation was used for the FGFR1/myeloid differentiation protein2 (MD2) complex investigation. RESULTS: Our results suggested that CAPE blocks the migration, invasion, and EMT process of breast cancer cells. Mechanistically, CAPE inhibits FGFR1 phosphorylation and nuclear transfer while overexpression of FGFR1 reduces the anti-metastasis effect of CAPE. Further, we found that FGFR1 is bound to MD2, and silencing MD2 inhibits FGFR1 phosphorylation and nuclear transfer as well as cell migration and invasion. CONCLUSION: This study illustrated that CAPE restrained FGFR1 activation and nuclear transfer through MD2/FGFR1 complex inhibition and showed good inhibitory effects on the metastasis of breast cancer cells.

Identification and validation of the microRNAs and hub genes for pancreatic ductal adenocarcinoma by an integrated bioinformatic analysis.

Background: In the progression of pancreatic ductal adenocarcinoma (PDAC), aberrant micro RNAs (miRNAs) expression plays a crucial role. This study sought to identify and validate the key miRNAs and potential target genes involved in PDAC. A bioinformatic analysis was conducted to determine their potential use as biomarkers and therapeutic targets. Methods: Gene profiling data sets (GSE41372 and GSE32688) were retrieved from the Gene Expression Omnibus database. Differentially expressed miRNAs (DEMs) with a P value <0.05, and |fold change| >2 was identified. The prognostic value of the DEMs was accessed using the online server Kaplan-Meier plotter. Further, gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed using DAVID 6.7. The protein-protein interaction analyses were conducted with STRING, and miRNA-hub gene networks were constructed using Cytoscape software. The PDAC cells were transfected with miRNA inhibitors or mimics. Cell Counting Kit-8 assays and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to examine cell proliferation and apoptosis, respectively. Wound-healing assays were performed to evaluate cell migration. Results: Three DEMs (hsa-miR-21-5p, hsa-miR-135b-5p, and hsa-miR-222-3p) were identified. High expression levels of hsa-miR-21-5p, hsa-miR-135b-5p, or hsa-miR-222-3p predicted poor overall survival in PDAC patients. The pathway analysis revealed that the predicted target genes of the DEMs were closely related to several signaling pathways (including 'pathways in cancer', 'miRNAs in cancer', 'platinum drug resistance', 'lipid and atherosclerosis', and 'MAPK signaling pathway'). The MYC proto-oncogene (MYC), phosphate and tensin homolog gene (PTEN), poly(ADP-ribose) polymerase 1 (PARP1), von Hippel-Lindau (VHL), and fork head box p3 (FOXP3) were identified as potential target genes. The inhibition of hsa-miR-21-5p, hsa-miR-135b-5p, or hsa-miR-222-3p expression decreased cell proliferation. The overexpression of hsa-miR-21-5p, hsa-miR-135b-5p, or hsa-miR-222-3p facilitated PDAC cell migration. Conclusions: This study constructed the miRNA-hub gene network, which provides novel insights into the PDAC progression. Although further research is required, our results offer clues for new potential prognostic markers and therapeutic targets of PDAC.

Long Noncoding RNA LINC01614 is a Diagnostic and Prognostic Marker for Breast Cancer.

BACKGROUND: The long intergenic non-coding RNA 01614 (LINC01614) is aberrantly expressed in various malignancies, suggesting its role in oncogenesis. However, it has not been well studied in breast cancer. METHODS: The cancer genome atlas databases (TCGA) and public database of breast cancer gene-expression miner (bc-GenExMiner) were utilized to analyze the prognostic role of LINC01614 in breast cancer. Kaplan-Meier, and Cox regression analyses were conducted for survival analysis. Nomograms were built to predict survival. We used deconvolution-based methods, such as TIMER (Tumor Immune Estimation Resource) and CIBERSORT (cell-type identification by estimating relative subsets of RNA transcripts), to explore the relationship between LINC01614 and immune cell characteristics. RESULTS: The very abnormal expression of LINC01614 was found in 14 types of malignancy, including breast cancer. The LINC01614 was significantly overexpressed in human epidermal growth factor receptor 2 (HER2)+, estrogen receptor (ER)+, progesterone receptor (PR)+, and non-triple negative breast cancer (non-TNBC). According to survival analysis, the higher expression of LINC01614 was related with poor survival. The co-expressed genes analysis exhibited that LINC01614 was closely associated with the collagen-associated process and phosphoinositide 3-kinases-protein kinase B (PI3K-Akt) signaling pathway. Moreover, this study has explored the association among LINC01614 expression, tumor-infiltrating immune cells, and the efficacy of chemotherapeutics. CONCLUSIONS: Our data reveal the expression pattern of LINC01614 in breast carcinoma with different molecular subtypes. The results also indicated that the LINC01614 could be a novel diagnostic and prognostic marker for breast carcinoma.

ASPM promotes migration and invasion of anaplastic thyroid carcinoma by stabilizing KIF11.

Abnormal spindle-like microcephaly-associated (ASPM) protein is crucial to the mitotic spindle function during cell replication and tumor progression in multiple tumor types. However, the effect of ASPM in anaplastic thyroid carcinoma (ATC) has not yet been understood. The present study is to elucidate the function of ASPM in the migration and invasion of ATC. ASPM expression is incrementally upregulated in ATC tissues and cell lines. Knockout (KO) of ASPM pronouncedly attenuates the migration and invasion of ATC cells. ASPM KO significantly reduces the transcript levels of Vimentin, N-cadherin, and Snail and increases E-cadherin and Occludin, thereby inhibiting epithelial-to-mesenchymal transition (EMT). Mechanistically, ASPM regulates the movement of ATC cells by inhibiting the ubiquitin degradation of KIF11 and thus stabilizing it via direct binding to it. Moreover, xenograft tumors in nude mice proved that KO of ASPM could ameliorate tumorigenesis and tumor growth accompanied by a decreased protein expression of KIF11 and an inhibition of EMT. In conclusion, ASPM is a potentially useful therapeutic target for ATC. Our results also reveal a novel mechanism by which ASPM inhibits the ubiquitin process in KIF11.

Regulation of autophagy by circular RNAs in rheumatoid arthritis: Potential targets of action.

Previous studies have shown that autophagic pathogenesis of rheumatoid arthritis (RA) is regulated by circular RNAs (circRNAs), which accelerate bone damage by participating in the immune inflammatory response. Therefore, exploring the mechanisms underlying circRNA regulation of autophagy is essential for maintaining homeostasis of the skeletal microenvironment in RA and may improve our understanding of the specific pathways involved in the development of therapeutics. In this review, we discuss autophagic imbalance in RA and the regulatory mechanisms of circRNAs. We also explore possible targets for circRNA regulation of autophagy in RA, which may provide us with improved knowledge regarding the pathogenesis of RA.

Case report: complete remission with crizotinib in ROS1 fusion-positive sinonasal mucosal melanoma.

Introduction: Sinonasal mucosal melanoma (SNMM) originates from melanocytes. Currently, the main treatment methods, including surgery, radiotherapy and chemotherapy, have little effect on the recurrence and metastasis of SNMM. However, targeted therapy may be a breakthrough in treating SNMM. Methods: A SNMM patient with ROS1 fusion received 250mg Crizotinib capsule (2 times a day, 1 tablet each time) therapy. Results: The patient achieved partial remission after 4 months of treatment and complete remission after 8 months of treatment. Conclusion: Our findings suggest that crizotinib can be an option to improve overall survival and quality of life of patients with metastatic ROS1-fusion SNMM. We believe that our report will provide insights for the application of crizotini in the treatment of melanoma.

Impact of individualized pharmaceutical care on efficacy and safety of opioid-tolerant outpatients with cancer pain: a multicenter randomized controlled trial.

Background: Managing cancer pain is a growing challenge. Individualized pharmaceutical care is particularly important for opioid-tolerant outpatients due to variation in terms of their knowledge about pain, treatment adherence, and risk of experiencing inadequate analgesia and severe adverse events. This study aimed to determine the influence of individualized pharmaceutical care on outcomes in opioid-tolerant outpatients with cancer pain. Methods: A multicenter, open-label, randomized, controlled study was carried out. Opioid-tolerant outpatients experiencing chronic cancer pain and receiving sustained-release opioids were randomly assigned to the intervention group and the control group with a 1:1 ratio. The intervention group received individualized pharmaceutical care, while the control group received conventional care during 4-week period. The primary endpoint was medication adherence on the intention-to-treat (ITT) population. Secondary outcomes included the patients' knowledge of cancer pain and pain medications, pain score, frequency of breakthrough pain, quality of life (QoL) which were assessed on the ITT population. Adverse events were evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) version 4.0 on the per-protocol (PP) population. Results: A total of 118 patients were enrolled, and 102 patients (51 in each group) completed the 30-day follow-up from six oncology centers in China. The proportion of patients adhering to opioid medication increased to similar levels in the two groups during the 4 weeks (P=0.149). The intervention group had a significantly lower pain score at 4 weeks compared to the control group (P=0.015), and the proportion of participants without breakthrough pain was significantly higher at 4 weeks than at baseline in the intervention group (P=0.029), but not in the control group (P=0.322). The two groups did not differ significantly in terms of QoL or adverse events. Conclusions: Our results suggest that individualized pharmaceutical care can markedly reduce patient-related problems and significantly improve pain control in opioid-tolerant outpatients. These findings validate the recommendations to include clinical pharmacists in the management of cancer pain. Trial Registration: ClinicalTrials.gov identifier: NCT03439904.

Link between sterile inflammation and cardiovascular diseases: Focus on cGAS-STING pathway in the pathogenesis and therapeutic prospect.

Sterile inflammation characterized by unresolved chronic inflammation is well established to promote the progression of multiple autoimmune diseases, metabolic disorders, neurodegenerative diseases, and cardiovascular diseases, collectively termed as sterile inflammatory diseases. In recent years, substantial evidence has revealed that the inflammatory response is closely related to cardiovascular diseases. Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway which is activated by cytoplasmic DNA promotes the activation of interferon regulatory factor 3 (IRF3) or nuclear factor-κB (NF-κB), thus leading to upregulation of the levels of inflammatory factors and interferons (IFNs). Therefore, studying the role of inflammation caused by cGAS-STING pathway in cardiovascular diseases could provide a new therapeutic target for cardiovascular diseases. This review focuses on that cGAS-STING-mediated inflammatory response in the progression of cardiovascular diseases and the prospects of cGAS or STING inhibitors for treatment of cardiovascular diseases.

Slow spin dynamics of cluster spin-glass spinel Zn(Fe1-xRux)2O4: role of Jahn-Teller active spin-1/2 Cu2+ions at B-sites.

We report the slow spin dynamics of cluster spin-glass (SG) spinel Zn(Fe1-xRux)2O4by means of detaileddc-magnetization andac-susceptibility studies combined with the heat capacity analysis. Two specific compositions (x = 0.5, 0.75) have been investigated in detail along with the substitution of Jahn-Teller (JT) active spin-1/2 Cu2+ions at B-sites. Measurements based on the frequency and temperature dependence ofac-susceptibility (χac(f,T)) and the subsequent analysis using the empirical scaling laws such as: (a) Vogel-Fulcher law and (b) Power law reveal the presence of cluster SG state below the characteristic freezing temperatureTSG(17.77 K (x = 0.5) and 14 K (x = 0.75)). Relaxation dynamics of both the compositions follow the non-mean field de Almeida-Thouless (AT)-line approach(TSG(H)=TSG(0)(1-AH2/ϕ)), with an ideal value ofφ = 3. Nevertheless, the analysis of temperature dependent high fielddc-susceptibility,χhf(2kOe ⩽ HDC ⩽ 20kOe,T) provides evidence for Gabay-Toulouse type mixed-phase (coexistence of SG and ferrimagnetic (FiM)) behaviour. Further, in the case of Cu0.2Zn0.8FeRuO4system, slowly fluctuating magnetic clusters persist even above the short-range FiM ordering temperature (TFiM) and their volume fraction vanishes completely across ∼6TFiM. This particular feature of the dynamics has been very well supported by the time decay of the thermoremanent magnetization and heat-capacity studies. We employed the high temperature series expansion technique to determine the symmetric exchange coupling (JS) between the spins which yieldsJS=-3.02×10-5 eV for Cu0.2Zn0.8FeRuO4representing the dominant intra-sublattice ferromagnetic interactions due to the dilute incorporation of the JT active Cu2+ions. However, the antiferromagnetic coupling is predominant in ZnFeRuO4and Cu0.2Zn0.8Fe0.5Ru1.5O4systems. Finally, we deduced the magnetic phase diagram in theHDC-Tplane using the characteristic parameters obtained from the field variations of bothac- anddc-magnetization measurements.

Crosstalk between the gut microbiome and clinical response in locally advanced thoracic esophageal squamous cell carcinoma during neoadjuvant camrelizumab and chemotherapy.

Background: The gut microbiome is associated with the response to immunotherapy in a variety of advanced cancers. However, the influence of the gut microbiome on locally advanced esophageal squamous cell carcinoma (ESCC) during programmed cell death protein 1 (PD-1) antibody immunotherapy plus chemotherapy is not clearly demonstrated. To explore the crosstalk between the gut microbiome and clinical response in locally advanced thoracic ESCC during neoadjuvant camrelizumab and chemotherapy. Methods: Patients who were diagnosed with locally advanced thoracic ESCC and had not received treatment were enrolled. The treatment regimen was two cycles of camrelizumab combined with carboplatin and albumin paclitaxel before surgery. The research endpoints were pathological complete response (pCR) and major pathological response (MPR). Fecal samples were collected at three time points: before neoadjuvant therapy, after two cycles of neoadjuvant therapy, and after surgery. We performed 16S ribosomal ribonucleic acid (rRNA) V3-V4 sequencing of the gene amplicons of fecal samples, as well as bacterial diversity and differential abundance analyses. Results: A total of 46 patients were recruited, and 44, 42, and 35 fecal samples were collected at the three time points, respectively. Statistically significant differences were observed in the amplicon sequence variant (ASV)-level alpha diversity indices, including Chao1, Shannon, and Good's coverage, between the three time points. The non-pCR-enriched gut microbiota included Proteobacteria, Dialister, Aeromonadales, Pseudomonadales, Thermi, Deinococci, Moraxellaceae, Rhodocyclales, Rhodocyclaceae, and Acinetobacter. The non-MPR-enriched gut microbiota included Pseudomonadales and the mitochondria family. The MPR-enriched gut microbiota included the Barnesiellaceae, Pyramidobacter, Dethiosulfovibrionaceae, Odoribacteraceae, Butyricimonas, Prevotella, Barnesiella, and Odoribacter. Patients with ≥3 grade adverse events (AEs) exhibited enrichment in the Succiniclasticum, Nakamurella, Rhizobium, Granulicella, Phyllobacteriaceae, Pelagibacteraceae, Actinosynnemataceae, Aquirestis, Flavisolibacter, Chelativorans, Coxiellaceae Acidicapsa, Acidobacteriaceae, Lentzea, Staphylococcus, Plesiomonas, Dysgonomonas, Pseudonocardia, and Ellin6075. Conclusions: We found that the diversity of the gut microbiome declined after neoadjuvant PD-1 antibody immunotherapy plus chemotherapy and surgery. Patients with pCR had different types and proportions of gut microbiota before treatment compared to those without pCR. We also observed the difference between patients with or without ≥ grade 3 AEs. The taxonomic features of the gut microbiome are potential biomarkers that could predict the pathological response and AEs.