Expression and prognosis analysis of TBX2 subfamily in human lung carcinoma.

PURPOSE: Lung cancer has a high morbidity and mortality rate of all cancers worldwide. Therefore, there is an urgent need for reliable cancer markers for diagnosis and prognosis of patients with lung cancer. METHODS: In this study, we used the bioinformatics database to compare the expression of the TBX2 subfamily at the transcriptional and protein levels in non-small cell lung cancer. Then, to confirm our bioinformatics analysis above, we used western bloting to determine the expression of TBX2, TBX3, TBX4 and TBX5 in human lung squamous carcinoma cell lines. Besides, low expression of TBX2 subfamily predicted a poor prognosis of patients with lung cancer. Finally, The methylation database was used to explore the relationship between the low expression of TBX2 subfamily and methylation of gene promoter region. RESULTS: Our data showed a significant decrease of TBX2 subfamily expression in lung cancer tissues of several histological subtypes. Finally, the methylation of TBX2 subfamily members in the promoter region of NSCLC was significantly higher than that in normal tissues. CONCLUSION: Our research provided sufficient evidence that TBX2 subfamily might play an inhibitory role in malignancy progression of lung cancer, which is promising to shed light on discovering a novel reliable cancer marker for prognosis of lung cancer patients.

Factors That Influence the Tenure of Direct Support Professionals in New York State Provider Agencies.

The New York State Office for People With Developmental Disabilities seeks to better understand the direct support professional (DSP) workforce and offer data-informed strategies for DSP retention. We used the 2018 NCI-IDD Staff Stability Survey (now called State of the Workforce Survey) to investigate agency-level factors influencing DSP tenure. A total 303 provider agencies completed the survey in New York State, representing 72,252 DSPs. Multiple linear regression analysis revealed that selected agency-level variables explained 12.6% of the variance in DSP tenure, R2 = .16, Radj2 = .126, F (11, 260) = 4.54, p < .05. This study yielded strong empirical evidence consistent with existing national reports and research on the role that wages, benefits, and supervisory support play on DSP tenure.

High loadings of carbonaceous aerosols from wood smoke in the atmosphere of Beijing from 2015 to 2017: Implications for energy transition policy.

Recently, biomass has been regarded as a promising option for solid energy in China, which is promoted in the residential sector and firing power plants. We collected 200 PM2.5 samples (particulate matter with a aerodynamic diameter smaller than 2.5 µm) at multi-sites across Beijing from three individual sampling cases from 2015 to 2017. The levels of OC, OC fractions, EC, EC fractions, as well as K+ were measured. Then, we adopted the Positive Matrix Factorization 5.0 to apportion the sources of carbonaceous aerosols. The source apportionment results were compared with the estimates of source contribution using the bottom-up technical method with the latest emission inventories after the Action Plan was put into effect in 2013. Our results demonstrate that high pollution of carbonaceous aerosols originated from wood smoking based on the receptor modeling and bottom-up technical method in Beijing from 2015 to 2017. Future energy transition policy should focus on the technologies and regulations for reducing emissions from renewable biomass fuel combustion. This study highlights the importance of regulations that address emissions controls on fuels replacing coal combustion to meet the needs to mitigate air pollution from primary energy use.

Pachymic Acid Prevents Hemorrhagic Shock-Induced Cardiac Injury by Suppressing M1 Macrophage Polarization and NF-[Formula: see text]B Signaling Pathway.

Hemorrhagic shock (HS) is the leading cause of death in trauma patients. Inflammation following HS can lead to cardiac damage. Pachymic acid (PA), a triterpenoid extracted from Poria cocos, has been found to possess various biological activities, including anti-inflammatory and anti-apoptotic properties. Our research aims to investigate the protective effects of PA against HS-induced heart damage and the underlying mechanisms involved. Male Sprague-Dawley rats were intraperitoneally injected with PA (7.5 or 15[Formula: see text]mg/kg) daily for three days. Subsequently, we created a rat model of HS by drawing blood through a catheter inserted into the femoral artery followed by resuscitation. The results revealed that HS led to abnormalities in hemodynamics, serum cardiac enzyme levels, and cardiac structure, as well as induced cardiac apoptosis. However, pretreatment with PA effectively alleviated these effects. PA-pretreatment also suppressed mRNA and protein levels of interleukin (IL)-1[Formula: see text], IL-6, and tumor necrosis factor [Formula: see text] (TNF-[Formula: see text]) in the heart tissues of HS rats. Additionally, PA-pretreatment reduced inflammatory cell infiltration and M1 macrophage polarization while exaggerating M2 polarization in HS rat hearts. The study observed a decreased proportion of the expression of of M1 macrophages (CD86[Formula: see text]) and their marker (iNOS), along with an increased proportion of the expression of M2 macrophages (CD206[Formula: see text]) and their marker (Arg-1). Notably, PA-pretreatment suppressed NF-[Formula: see text]B pathway activation via inhibiting NF-[Formula: see text]B p65 phosphorylation and its nuclear translocation. In conclusion, PA-pretreatment ameliorates HS-induced cardiac injury, potentially through its inhibition of the NF-[Formula: see text]B pathway. Therefore, PA treatment holds promise as a strategy for mitigating cardiac damage in HS.

PR-957 retards rheumatoid arthritis progression and inflammation by inhibiting LMP7-mediated CD4+ T cell imbalance.

OBJECTIVE: Low molecular mass polypeptide 7 (LMP7) is an immunoproteasome subunit that regulates T cell amplification, differentiation, and inflammation and is involved in rheumatoid arthritis (RA) progression. This study intended to apply PR-957 (an anti-LMP7 agent) for RA treatment in vitro and in vivo and evaluate its interaction with LMP7-mediated CD4+ T cell imbalance. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from 30 RA patients and 30 healthy controls. RA fibroblast-like synoviocytes (RA-FLSs) and CD4+ T cells were isolated from RA patients and then cocultured with PR-957 and/or LMP7 overexpression adenovirus (Ad-LMP7). Collagen-induced arthritis (CIA) mice were constructed and then treated with PR-957 and/or Ad-LMP7. RESULTS: LMP7 was higher in RA patients (versus healthy controls) and positively correlated with T helper (Th)1 cells, the Th1/Th2 ratio, Th17 cells, and the Th17/Treg ratio but not with Th2 or T regulatory (Treg) cells. PR-957 reduced Th1 and Th17 cells but increased Th2 and Treg cells in RA-CD4+ T cells, and this effect was partially reversed by Ad-LMP7 transfection. Interestingly, when cocultured with RA-CD4+ T cells, PR-957 increased RA-FLS apoptosis and decreased its invasive ability, viability, and inflammation, as suggested by IL-6, CCL2, MMP1, and MMP3; however, these phenomena were weakened in RA-FLSs without RA-CD4+ T cell coculture. In addition, Ad-LMP7 transfection attenuated the above effects of PR-957. In CIA mice, PR-957 decreased the arthritis score, synovial hyperproliferation and articular injury, inflammation in the synovium and serum, and the imbalance of Th1/Th2 and Th17/Treg in the spleen, and these effects were attenuated by Ad-LMP7. CONCLUSION: PR-957 ameliorates RA progression and inflammation by repressing LMP7-mediated CD4+ T cell imbalance.

Compound 511 ameliorates MRSA-induced lung injury by attenuating morphine-induced immunosuppression in mice via PI3K/AKT/mTOR pathway.

BACKGROUND: Opioids are widely used in clinical practice. However, their long-term administration causes respiratory depression, addiction, tolerance, and severe immunosuppression. Traditional Chinese medicine (TCM) can alleviate opioid-induced adverse effects. Compound 511 is particularly developed for treating opioid addiction, based on Jiumi Liangfang, an ancient Chinese drug treatment and rehabilitation monograph completed in 1833 A.D. It is an herbal formula containing eight plants, each of them contributing to the overall pharmacological effect of the product: Panax ginseng C. A. Meyer (8.8%), Astragalus membranaceus (Fisch.) (18.2%), Datura metel Linn. (10.95%), Corydalis yanhusuo W. T. Wang (14.6%), Acanthopanar gracilistµlus W. W. Smith (10.95%), Ophiopogon japonicus (Linn. f.) Ker-Gawl. (10.95%), Gynostemma pentaphyllum (Thunb.) Makino (10.95%), Polygala arvensis Willd. (14.6%). This formula effectively ameliorates opioid-induced immunosuppression. However, the underlying mechanism remains unclear. PURPOSE: To reveal the effects of Compound 511 on the immune response of morphine-induced immunosuppressive mice and their potential underlying molecular mechanism. This study provides information for a better clinical approach and scientific use of opioids. METHODS: Immunosuppression was induced in mice by repeated morphine administration. Th1/Th2/Th17/Treg cell levels were measured using flow cytometry. Splenic transcription factors of Th1/Th2/Th17/Treg and outputs of the regulatory PI3K/AKT/mTOR signaling pathway were determined. Subsequently, methicillin-resistant Staphylococcus aureus (MRSA) was administered intranasally to morphine-induced immunosuppressive mice pretreated with Compound 511. Their lung inflammatory status was assessed using micro-computer tomography (CT), hematoxylin and eosin (H&E) staining, and enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared to morphine, Compound 511 significantly decreased the immune organ indexes of mice, corrected the Th1/Th2 and Treg/Th17 imbalance in the immune organs and peripheral blood, reduced the mRNA levels of FOXP3 and GATA3, and increased those of STAT3 and T-bet in the spleen. It improved immune function and reduced MRSA-induced lung inflammation. CONCLUSION: Compound 511 ameliorates opioid-induced immunosuppression by regulating the balance of Th1/Th2 and Th17/Treg via PI3K/AKT/mTOR signaling pathway. Thus, it effectively reduces susceptibility of morphine-induced immunosuppressive mice to MRSA infection.

The implication of long non-coding RNA expression profile in rheumatoid arthritis: Correlation with treatment response to tumor necrosis factor inhibitor.

OBJECTIVE: This study aimed to investigate the linkage of long non-coding RNA (lncRNA) expression profile with etanercept response in rheumatoid arthritis (RA) patients. METHODS: Peripheral blood mononuclear cell (PBMC) samples were collected from 80 RA patients prior to etanercept treatment. Samples from eight responders and eight non-responders at week 24 (W24) were proposed to RNA-sequencing, then 10 candidate lncRNAs were sorted and their PBMC expressions were validated by reverse transcription quantitative chain reaction (RT-qPCR) in 80 RA patients. Subsequently, clinical response by lncRNA (CRLnc) prediction model was established. RESULTS: RNA-sequencing identified 254 up-regulated and 265 down-regulated lncRNAs in W24 responders compared with non-responders, which were enriched in immune or joint related pathways such as B-cell receptor signaling, osteoclast differentiation and T-cell receptor signaling pathways, etc. By reverse transcription quantitative chain reaction (RT-qPCR) validation: Two lncRNAs were correlated with W4 response, three lncRNAs were correlated with W12 response, seven lncRNAs were correlated with W24 response. Subsequently, to construct and validate CRLnc prediction model, 80 RA patients were randomly divided into test set (n = 40) and validation set (n = 40). In the test set, lncRNA RP3-466P17.2 (OR = 9.743, P = .028), RP11-20D14.6 (OR = 10.935, P = .007), RP11-844P9.2 (OR = 0.075, P = .022), and TAS2R64P (OR = 0.044, P = .016) independently related to W24 etanercept response; then CRLnc prediction model integrating these four lncRNAs presented a good value in predicting W24 etanercept response (Area Under Curve (AUC): 0.956, 95%CI: 0.896-1.000). However, in the validation set, the CRLnc prediction model only exhibited a certain value in predicting W24 etanercept response (AUC: 0.753, 95%CI: 0.536-0.969). CONCLUSIONS: CRLnc prediction model is potentially a useful tool to instruct etanercept treatment in RA patients.

Identifying the Role of Oxidative Stress-Related Genes as Prognostic Biomarkers and Predicting the Response of Immunotherapy and Chemotherapy in Ovarian Cancer.

Background: Ovarian cancer (OC) is one of the most frequently seen and fatal gynecological malignancies, and oxidative stress (OS) plays a critical role in the development and chemoresistance of OC. Materials and Methods: OS-related genes (OSRGs) were obtained from the Molecular Signatures Database. Besides, gene expression profiles and clinical information from The Cancer Genome Atlas (TCGA) were selected to identify the prognostic OSRGs. Moreover, univariate Cox regression, LASSO, and multivariate Cox regression analyses were conducted sequentially to establish a prognostic signature, which was later validated in three independent Gene Expression Omnibus (GEO) datasets. Next, gene set enrichment analysis (GSEA) and tumor mutation burden (TMB) analysis were performed. Afterwards, immune checkpoint genes (ICGs) and the tumor immune dysfunction and exclusion (TIDE) algorithm, together with IMvigor210 and GSE78220 cohorts, were applied to comprehensively explore the role of OSRG signature in immunotherapy. Further, the CellMiner and Genomics of Drug Sensitivity in Cancer (GDSC) databases were also applied in investigating the significance of OSRG signature in chemotherapy. Results: Altogether, 34 prognostic OSRGs were identified, among which 14 were chosen to establish the most valuable prognostic signature. The Kaplan-Meier (KM) analysis suggested that patients with lower OS-related risk score had better prognosis. The area under the curve (AUC) values were 0.71, 0.76, and 0.85 in 3, 5, and 7 years separately, and the stability of this prognostic signature was confirmed in three GEO datasets. As revealed by GSEA and TMB analysis results, OC patients in low-risk group might have better immunotherapeutic response, which was consistent with ICG expression and TIDE analyses. Moreover, both IMvigor210 and GSE78220 cohorts demonstrated that patients with lower OS-related risk score were more likely to benefit from anti-PD-1/L1 immunotherapy. In addition, the association between prognostic signature and drug sensitivity was explored. Conclusion: According to our results in this work, OSRG signature can act as a powerful prognostic predictor for OC, which contributes to generating more individualized therapeutic strategies for OC patients.

Determination of 31 Polycyclic Aromatic Hydrocarbons in Plant Leaves Using Internal Standard Method with Ultrasonic Extraction-Gas Chromatography-Mass Spectrometry.

The method for the determination of 16 priority polycyclic aromatic hydrocarbons (PAHs) in plant leaves has been studied extensively, yet the quantitativemethod for measuring non-priority PAHs in plant leaves is limited. A method for the simultaneous determination of 31 polycyclic aromatic hydrocarbons (PAHs) in plant leaves was established using an ultrasonic extraction-gas chromatography-mass spectrometry-internal standard method. The samples of plant leaves were extracted with ultrasonic extraction and purified with solid-phase extraction columns. The PAHs were separated by using gas chromatography-mass spectrometry equipped with a DB-EUPAH capillary column (20 m × 0.18 mm × 0.14 µm) with a selective ion monitoring (SIM) detection mode, and quantified with an internal standard. The method had good linearity in the range of 0.005~1.0 µg/mL with correlation coefficients greater than 0.99, and the method detection limit and maximum quantitative detection limit were in the ranges of 0.2~0.7 µg/kg and 0.8~2.8 µg/kg, respectively. The method was verified with spiked recovery experiments. The average spiked recovery ranged from 71.0% to 97.6% and relative standard deviations (n = 6) were less than 14%. Herein, we established a quantitativemethod for the simultaneous determination of priority and non-priority PAHs in plant leaves using GC-MS. The method is highly sensitive and qualitatively accurate, and it is suitable for the determination of PAHs in plant leaves.

Direct measurement of the deposition of submicron soot particles on leaves of Platanus acerifolia tree.

Submicron soot particles (<1.0 µm in aerodynamic diameter) are responsible for global warming and health burdens worldwide. However, studies on bio-monitoring of submicron soot particles and their associated sources by using tree leaves are not comprehensively illustrated. Here, we determined the seasonal trends of submicron soot particles on the leaves of the Platanus acerifolia collected from two cities (Lu'an, Anhui Province, and Nanjing, Jiangsu Province) in the Yangtze River Delta region, China. The source apportionment of submicron soot particles was performed using stable carbon isotopic analyses. Significant seasonal trends of submicron soot particles were observed in two cities with averaged levels of 0.41-1.36 mg m-2 in cold seasons and averaged levels of 0.13-0.24 mg m-2 in warm seasons. The levels of δ13C for submicron soot at the suburban site of Lu'an city were observed to be in the range of -25.6‰ to -18.2‰ with fossil fuels dominated (∼58%) in summer and -23.0‰ to -15.6‰ with biomass burning dominated in winter (∼67%). In comparison, the ranges in the levels of δ13C in submicron soot were found to be from -26.5‰ to -20.4‰ in winter, and -24.2‰ to -17.9‰ in summer at the urban site of Nanjing. Fossil fuels accounted for a large fraction of submicron soot with average contributions of 53% in winter and 73% in summer, respectively. These findings demonstrate that Platanus acerifolia trees could be used as an effective and low-cost bio-monitoring tool for monitoring the pollution status of submicron soot and associated source contribution.

MALT1 regulates Th2 and Th17 differentiation via NF-κB and JNK pathways, as well as correlates with disease activity and treatment outcome in rheumatoid arthritis.

Objective: MALT1 regulates immunity and inflammation in multiple ways, while its role in rheumatoid arthritis (RA) is obscure. This study aimed to investigate the relationship of MALT1 with disease features, treatment outcome, as well as its effect on Th1/2/17 cell differentiation and underlying molecule mechanism in RA. Methods: Totally 147 RA patients were enrolled. Then their blood Th1, Th2, and Th17 cells were detected by flow cytometry. Besides, PBMC MALT1 expression was detected before treatment (baseline), at week (W) 6, W12, and W24. PBMC MALT1 in 30 osteoarthritis patients and 30 health controls were also detected. Then, blood CD4+ T cells were isolated from RA patients, followed by MALT1 overexpression or knockdown lentivirus transfection and Th1/2/17 polarization assay. In addition, IMD 0354 (NF-κB antagonist) and SP600125 (JNK antagonist) were also added to treat CD4+ T cells. Results: MALT1 was increased in RA patients compared to osteoarthritis patients and healthy controls. Meanwhile, MALT1 positively related to CRP, ESR, DAS28 score, Th17 cells, negatively linked with Th2 cells, but did not link with other features or Th1 cells in RA patients. Notably, MALT1 decreased longitudinally during treatment, whose decrement correlated with RA treatment outcome (treatment response, low disease activity, or disease remission). In addition, MALT1 overexpression promoted Th17 differentiation, inhibited Th2 differentiation, less affected Th1 differentiation, activated NF-κB and JNK pathways in RA CD4+ T cells; while MALT1 knockdown exhibited the opposite effect. Besides, IMD 0354 and SP600125 addition attenuated MALT1's effect on Th2 and Th17 differentiation. Conclusion: MALT1 regulates Th2 and Th17 differentiation via NF-κB and JNK pathways, as well as correlates with disease activity and treatment outcome in RA.

Systemic characterization of alternative splicing related to prognosis, immune infiltration, and drug sensitivity analysis in ovarian cancer.

Background: Alternative splicing (AS) plays an essential role in tumorigenesis and progression. This study intended to construct an innovative prognostic model based on AS events to gain more precise survival prediction and search for potential therapeutic targets in ovarian cancer. Methods: Seven types of AS events in ovarian serous cystadenocarcinoma (OV) patients with RNA-seq were obtained using The Cancer Genome Atlas (TCGA) SpliceSeq tool and database. Cox and Kaplan-Meier curve analyses were employed to establish the prognostic models. Relying on drug sensitivity data from the CellMiner database, Genomics of Drug Sensitivity (GDS) was adopted to estimate the platinum-sensitive analysis. Furthermore, a prognostic splicing factor (SF)-AS network was constructed using Cytoscape. Finally, in order to explore the influence of the tumor microenvironment on the prognosis of OV patients, we first combined a similar network fusion and consensus clustering (SNF-CC) algorithm to identify three OV subtypes based on survival-related AS events and then utilized single-sample Gene Set Enrichment Analysis (ssGSEA) method to perform immune cell infiltration analysis. Results: A total of 48,049 AS events and 21,841 related genes were selected from 318 OV samples, and 2,206 AS events associated with disease-free survival (DFS) were identified. Multivariate Cox and Kaplan-Meier curve analyses were then employed to establish the prognostic models. Receiver operating characteristic (ROC) analysis from 0.59 to 0.75 showed that these models were highly efficient in distinguishing patient survival. GDS was adopted with the CellMiner database to provide some insights for platinum-sensitive analysis of OV. Furthermore, a prognostic SF-AS network, which discovered a significant connection between SFs and prognostic AS genes, was constructed using Cytoscape. The combined SNF-CC algorithm revealed three distinct OV subtypes based on the prognostic AS events, and the associations between this novel molecular classification and immune cell infiltration were further explored. Conclusions: We developed a powerful prognostic AS signature for OV and provided a deeper understanding of SF-AS network regulatory mechanisms, as well as platinum-sensitive and cancer immune microenvironments. These results revealed various candidate biomarkers and potential targets for OV treatment strategies.

Ferroptosis-related genes identify tumor immune microenvironment characterization for the prediction of prognosis in cervical cancer.

Background: Cervical cancer (CC) is a disease that affects female health; therefore, timely prevention and diagnosis of CC are crucial to decrease its mortality. Ferroptosis, an iron-dependent form of non-apoptotic cell death, is involved in tumor progression. However, the role of ferroptosis-related genes (FRGs) in the immune microenvironment of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) remains unclear. Methods: The data sets of CESC patients, including RNA sequencing (RNA-seq) data and clinical information, were obtained from The Cancer Genome Atlas (TCGA). The ESTIMATE algorithm was used to determine the stromal score, immune score, estimate score, and tumor purity in the CESC patients' data. Additionally, FRGs were identified and used to construct a signature marker for the diagnosis and prognosis of CESC. Patients were assigned to a high- or low-risk group based on their median risk score. The tumor microenvironment (TME), immune infiltration, and functional enrichment were compared between the low- and high-risk groups. Functional analyses, including Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and single-sample Gene Set Enrichment Analysis (ssGSEA), were conducted to explore the underlying mechanisms in the development and prognosis of CESC. Results: The results showed that the estimate score was suitable for predicting the prognosis of CESC patients. Additionally, a prediction model involving four FRGs [phosphatidylethanolamine-binding protein 1 (PEBP1), dual oxidase 1 (DUOX1), iron-sulfur cluster assembly enzyme (ISCU), and cytochrome b (-245) beta subunit (CYBB)] was constructed. The performance of the prognostic model and significant clinical characteristics in predicting CESC prognosis was subsequently validated. Our results showed that the expression of CYBB affected immune cells. Gene functional enrichment analyses showed that these differentially expressed FRGs were mainly enriched in the immunity-related signaling pathways, which indicated that FRGs might affect the development and prognosis of CC by regulating the immune microenvironment. Conclusions: The expression profiles of FRGs are closely related to the TME and the prognostic survival of CESC patients. The interaction between ferroptosis and immunity in the development of CC provides new insight into the molecular mechanisms of CC.

Comparison of the prevalence and nature of potentially inappropriate medication use in geriatric outpatients between tertiary and community healthcare settings: a multicenter cross-sectional study.

Background Geriatric outpatients with polypharmacy have a high risk of potentially inappropriate medication (PIM) use. Aim To identify differences in both prevalence and patterns of PIMs and drug-related problems (DRPs) in older outpatients who visited the tertiary hospitals (THs) and community health centers (CHCs) and analyze associated factors. Method A prospective cross-sectional study was conducted in five THs and five CHCs from September 2018 to November 2019 in Beijing, China. Data were collected from outpatients aged ≥ 65 years with chronic diseases and polypharmacy. PIMs were evaluated using the 2015 and 2019 Beers Criteria and the Screening Tool of Older Persons' Prescriptions (STOPP) criteria. DRPs were classified using the Helper-Strand DRP Classification. The prevalence and types of PIMs and DRPs were compared, and relevant factors were analyzed. Results The prevalence of PIMs based on the 2015 Beers Criteria was higher in patients from the THs, while PIMs based on the 2019 Beers Criteria did not show a significant difference. PIM prevalence based on STOPP Criteria and DRPs was higher in patients from CHCs. Visiting CHCs was an independent factor of PIMs based on the 2015 Beers Criteria (OR 0.774, 95% CI 0.604-0.992) and the STOPP Criteria (OR 2.427, 95% CI 1.883-3.128), and DRPs (OR 3.612, 95% CI 2.682-4.865). Conclusion Differences in PIM and DRP might be due to the patients and settings. Specific measures to improve the appropriateness of medications in both settings should be used.

Puerarin alleviates cadmium-induced oxidative damage to bone by reducing autophagy in rats.

Autophagy is a regulatory mechanism involved in cadmium (Cd)-induced bone toxicity and is suppressed by various stimuli, including oxidative stress. Puerarin is an isoflavonoid compound isolated from Pueraria, a plant used in traditional Chinese medicine. The underlying mechanisms of action of puerarin remain unclear. The objective of this study was to explore the mitigating effects of puerarin on cadmium-induced oxidative damage in the bones of rats. Cadmium exposure increased oxidative damage in rat bones; this was markedly decreased by puerarin treatment, as demonstrated by changes in the activity of antioxidative enzymes. Cadmium-induced blockage of the expression of key bone regulatory proteins, autophagy-related markers, and signaling molecules was also alleviated by puerarin treatment. Additionally, cadmium reduced expression of the autophagic protein Rab7 and of late endosomal/lysosomal adaptor and MAPK and mTOR activator 1 (LAMTOR1); the decrease in these proteins was not restored by puerarin treatment. We speculate that puerarin relieves the inhibition of fusion of autophagosomes with lysosomes that is induced by cadmium; however, this specific effect of puerarin and downstream effects on bone regulatory mechanisms require further investigation. In conclusion, puerarin alleviates cadmium-induced oxidative damage in the bones of rats by attenuating autophagy, which is likely associated with the antioxidant activity of puerarin.

Effect of Electro-Acupuncture at ST36 and SP6 on the cAMP -CREB Pathway and mRNA Expression Profile in the Brainstem of Morphine Tolerant Mice.

Undoubtedly, opioid drugs have been the most popular treatment for refractory pain since found, such as morphine. However, tolerance to the analgesic effects caused by repeated use is inevitable, which greatly limits the clinical application of these drugs. Nowadays, it has become the focus of the world that further development of non-opioid-based treatment along with efficient strategies to circumvent opioid tolerance are urgently needed clinically. Fortunately, electro-acupuncture (EA) provides an alternative to pharmaceutic treatment, remaining its potential mechanisms unclear although. This study was aimed to observe the effects of EA on morphine-induced tolerance in mice and discover its underlying mechanism. Tail-flick assay and hot-plate test were conducted to assess the development of tolerance to morphine-induced analgesia effect. As a result of repeated administration scheme (10 mg/kg, twice per day, for 7 days), approximately a two-fold increase was observed in the effective dose of 50% (ED50) of morphine-induced antinociceptive effect. Interestingly, by EA treatment (2/100Hz, 0.5, 1.0, and 1.5 mA, 30 min/day for 7 days) at the acupoints Zusanli (ST36) and Sanyinjiao (SP6), morphine ED50 curves was remarkably leftward shifted on day 8. In addition, the RNA sequencing strategy was used to reveal the potential mechanisms. Due to the well described relevance of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), extracellular regulated protein kinases (ERK), and cAMP response element-binding (CREB) in brainstem (BS) to analgesia tolerance, the cAMP-PKA/ERK-CREB signaling was deeply concerned in this study. Based upon Enzyme-Linked Immunosorbent Assay, the up-regulation of the cAMP level was observed, whereas reversed with EA treatment. Similarly, western blot revealed the phosphorylation levels of PKA, ERK, and CREB were up-regulated in morphine tolerant mice, whereas the EA group showed a significantly reduced expression level instead. This study observed an attenuating effect of the EA at ST36 and SP6 on morphine tolerance in mice, and suggested several potential biological targets by RNA-seq, which include the cAMP-PKA/ERK-CREB signaling pathway, strongly supporting a useful treatment for combatting the opioid epidemic, and opioid-tolerant patients.

Bayesian variable selection for the Cox regression model with spatially varying coefficients with applications to Louisiana respiratory cancer data.

The Cox regression model is a commonly used model in survival analysis. In public health studies, clinical data are often collected from medical service providers of different locations. There are large geographical variations in the covariate effects on survival rates from particular diseases. In this paper, we focus on the variable selection issue for the Cox regression model with spatially varying coefficients. We propose a Bayesian hierarchical model which incorporates a horseshoe prior for sparsity and a point mass mixture prior to determine whether a regression coefficient is spatially varying. An efficient two-stage computational method is used for posterior inference and variable selection. It essentially applies the existing method for maximizing the partial likelihood for the Cox model by site independently first and then applying an Markov chain Monte Carlo algorithm for variable selection based on results of the first stage. Extensive simulation studies are carried out to examine the empirical performance of the proposed method. Finally, we apply the proposed methodology to analyzing a real dataset on respiratory cancer in Louisiana from the Surveillance, Epidemiology, and End Results (SEER) program.

Discovery and Optimization of 2H-1λ2-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer.

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2H-1λ2-quinoline-2,5(6H)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 (NCATS-SM5637, NSC 791985). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).

Interleukin-1ß Protection Against Experimental Sepsis in Mice.

The inflammatory response involving interleukin-1ß (IL-1ß) has been thought to play an important role in the development of late-phase sepsis. However, in this study, we wanted to explore the possibility of using IL-1ß to improve the prognosis of sepsis by triggering local differentiation of bone marrow cells (BMCs) into regulatory dendritic cells (DCs) in vivo, thereby reversing the immune paralysis in late-phase sepsis. Sepsis mouse models were induced by cecal ligation and puncture (CLP) and lethal Escherichia coli O18 infection. Mice were injected intraperitoneally with IL-1ß after CLP and after the lethal infection. Septic BMCs and liver immune cells were isolated at 0, 3, 6, 9, and 14 days post-CLP. BMCs and liver cells isolated from septic mice treated with IL-1ß were adoptively transferred into CLP mice. GFP+-C57BL/6 parabiosis models were established. Serum IL-1ß levels were determined by enzyme-linked immunosorbent assay (ELISA) kit, and the number, ratio, and phenotype of immune cells were observed by flow cytometry. IL-1ß treatment improved the survival of sepsis and increased the numbers of BMCs and liver immune cells in septic mice. Moreover, IL-1ß stimulation increased the number and the percentage of CD11c-CD45RBhigh DCs in septic BM and liver. Adoptive transfer of septic BMCs, liver immune cells, and CD11c-CD45RBhigh DCs treated with IL-1ß into CLP mice attenuated sepsis. IL-1ß triggered the redistribution of CD11c-CD45RBhigh DCs as well as BMCs in parabiosis models. IL-1ß protects against sepsis by stimulating local proliferation and differentiation of BMCs into CD11c-CD45RBhigh DCs at immune organs and non-immune organs.

BATF regulates innate lymphoid cell hematopoiesis and homeostasis.

Early hematopoietic progenitors undergo sophisticated developmental processes to become committed innate lymphoid cell (ILC) progenitors and ultimately mature ILC subsets in the periphery. Basic leucine zipper ATF-like transcription factor (Batf) plays important roles in lymphocyte biology. We report here that Batf regulates the production of bone marrow ILC progenitors and maintenance of peripheral ILCs. The expression of Batf is induced during ILC development at the α-lymphoid progenitor stage in response to the cytokine IL-7. As a potential mechanism, up-regulated Batf binds and activates transcription of the Nfil3 gene to promote ILC hematopoiesis. Batf is necessary to maintain normal numbers of early and late ILC progenitors in the bone marrow and mature ILC1, ILC2, ILC3, and NK cells in most peripheral tissues. Batf deficiency causes ILC lymphopenia, leading to defective ILC responses to inflammatory cytokines and defective immunity to enteric bacterial infections. Thus, Batf plays critical roles in bone marrow hematopoiesis, peripheral homeostasis, and effector functions of ILCs.