Proto-oncogene c-Myb potentiates cisplatin resistance of ovarian cancer cells by downregulating lncRNA NKILA and modulating cancer stemness and LIN28A-let7 axis.

Ovarian cancer is a major gynecological cancer that has poor prognosis associated mainly to its late diagnosis. Cisplatin is an FDA approved ovarian cancer therapy and even though the therapy is initially promising, the patients mostly progress to resistance against cisplatin. The underlying mechanisms are complex and not very clearly understood. Using two different paired cell lines representing cisplatin-sensitive and the cisplatin-resistant ovarian cancer cells, the ES2 and the A2780 parental and cisplatin-resistant cells, we show an elevated proto-oncogene c-Myb in resistant cells. We further show down-regulated lncRNA NKILA in resistant cells with its de-repression in resistant cells when c-Myb is silenced. NKILA negatively correlates with cancer cell and invasion but has no effect on cellular proliferation or cell cycle. C-Myb activates NF-κB signaling which is inhibited by NKILA. The cisplatin resistant cells are also marked by upregulated stem cell markers, particularly LIN28A and OCT4, and downregulated LIN28A-targeted let-7 family miRNAs. Whereas LIN28A and downregulated let-7s individually de-repress c-Myb-mediated cisplatin resistance, the ectopic expression of let-7s attenuates LIN28A effects, thus underlying a c-Myb-NKILA-LIN28A-let-7 axis in cisplatin resistance of ovarian cancer cells that needs to be further explored for therapeutic intervention.

Melatonin improves maternal sleep deprivation-induced learning and memory impairment, inflammation, and synaptic dysfunction in murine male adult offspring.

INTRODUCTION: Maternal sleep deprivation (MSD), which induces inflammation and synaptic dysfunction in the hippocampus, has been associated with learning and memory impairment in offspring. Melatonin (Mel) has been shown to have anti-inflammatory, antioxidant, and neuroprotective function. However, the beneficial effect of Mel on MSD-induced cognitive impairment and its mechanisms are unknown. METHODS: In the present study, adult offspring suffered from MSD were injected with Mel (20 mg/kg) once a day during postnatal days 61-88. The cognitive function was evaluated by the Morris water maze test. Levels of proinflammatory cytokines were examined by enzyme-linked immunosorbent assay. The mRNA and protein levels of synaptic plasticity associated proteins were examined using reverse transcription-polymerase chain reaction and western blotting. RESULTS: The results showed that MSD impaired learning and memory in the offspring mice. MSD increased the levels of interleukin (IL)-1creIL-6, and tumor necrosis factor-α and decreased the expression levels of brain-derived neurotrophic factor, tyrosine kinase receptor B, postsynaptic density protein-95, and synaptophysin in the hippocampus. Furthermore, Mel attenuated cognitive impairment and restored markers of inflammation and synaptic plasticity to control levels. CONCLUSIONS: These findings indicated that Mel could ameliorate learning and memory impairment induced by MSD, and these beneficial effects were related to improvement in inflammation and synaptic dysfunction.

Association between blood ethylene oxide levels and the prevalence of periodontitis: evidence from NHANES 2013-2014.

BACKGROUND: The study aimed to establish a link between blood ethylene oxide (EO) levels and periodontitis, given the growing concern about EO's detrimental health effects. MATERIALS AND METHODS: The study included 1006 adults from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) dataset. We assessed periodontitis prevalence across groups, used weighted binary logistic regression and restricted cubic spline fitting for HbEO-periodontitis association, and employed Receiver Operating Characteristic (ROC) curves for prediction. RESULTS: In the periodontitis group, HbEO levels were significantly higher (40.57 vs. 28.87 pmol/g Hb, P < 0.001). The highest HbEO quartile showed increased periodontitis risk (OR = 2.88, 95% CI: 1.31, 6.31, P = 0.01). A "J"-shaped nonlinear HbEO-periodontitis relationship existed (NL-P value = 0.0116), with an inflection point at ln-HbEO = 2.96 (EO = 19.30 pmol/g Hb). Beyond this, ln-HbEO correlated with higher periodontitis risk. A predictive model incorporating sex, age, education, poverty income ratio, alcohol consumption, and HbEO had 69.9% sensitivity and 69.2% specificity. The model achieved an area under the ROC curve of 0.761. CONCLUSIONS: These findings suggest a correlation between HbEO levels and an increased susceptibility to periodontitis.

Emerging evidence of context-dependent synapse elimination by phagocytes in the CNS.

Precise synapse elimination is essential for the establishment of a fully developed neural circuit during brain development and higher function in adult brain. Beyond immune and nutrition support, recent groundbreaking studies have revealed that phagocytic microglia and astrocytes can actively and selectively eliminate synapses in normal and diseased brains, thereby mediating synapse loss and maintaining circuit homeostasis. Multiple lines of evidence indicate that the mechanisms of synapse elimination by phagocytic glia are not universal but rather depend on specific contexts and detailed neuron-glia interactions. The mechanism of synapse elimination by phagocytic glia is dependent on neuron-intrinsic factors, many innate immune and local apoptosis related molecules. During development, microglial synapse engulfment in the visual thalamus is primarily influenced by the classic complement pathway, whereas in the barrel cortex, the fractalkine pathway is dominant. In Alzheimer's disease, microglia employ complement-dependent mechanisms for synapse engulfment in tauopathy and early ß-amyloid pathology. But microglia are not involved in synapse loss at late ß-amyloid stages. Phagocytic microglia also engulfment synapses in complement dependent way in schizophrenia, anxiety and stress. Besides, phagocytic astrocytes engulf synapses in a MEGF10 dependent way during visual development, memory and stroke. Furthermore, the mechanism of a phenomenon that phagocytes selectively eliminating excitatory and inhibitory synapses is also emphasized in this review. We hypothesize that elucidating context-dependent synapse elimination by phagocytic microglia and astrocytes may reveal the molecular basis of synapse loss in neural disorders and provide a rationale for developing novel candidate therapies that target synapse loss and circuit homeostasis.

Contrast-enhanced Imaging in Peripheral Pulmonary Lesions: The Role in US-guided Biopsies.

Purpose To compare the tissue adequacy and diagnostic accuracy of US-guided biopsies of peripheral pulmonary lesions (PPLs) with and without contrast agents. Materials and Methods A retrospective study was conducted at four medical centers in patients with PPLs who underwent US-guided percutaneous transthoracic needle biopsy (PTNB) between January 2017 and October 2022. The patients were divided into contrast-enhanced US (CEUS) and US groups based on whether prebiopsy CEUS evaluation was performed. Tissue adequacy and the diagnostic accuracy of PTNB, stratified by lesion size, were analyzed and compared between groups. A propensity score matching (PSM) analysis was conducted using the nearest-neighbor matching method. Results A total of 1027 lesions were analyzed, with 634 patients (mean age, 59.4 years ± 13.0 [SD]; 413 male) in the US group and 393 patients (mean age, 61.2 years ± 12.5; 270 male) in the CEUS group. The CEUS group produced more acceptable samples than the US group (98.2% vs 95.7%; P = .03) and achieved higher diagnostic accuracy (96.9% vs 94.2%; P = .04), with no evidence of a difference in sensitivity (96.7% vs 94.0%; P = .06). PSM and stratified analyses (n = 358 per group) indicated higher tissue adequacy (99.0% vs 95.7%; P = .04) and diagnostic accuracy (98.5% vs 92.9%; P = .006) in the CEUS group compared with the US group for 2-7-cm PPLs but not for lesions larger than 7 cm. Conclusion PTNB with prebiopsy CEUS evaluation demonstrated significantly better tissue adequacy and diagnostic accuracy compared with US guidance alone for PPLs ranging from 2 to 7 cm, with similar biopsy performance achieved between groups for lesions larger than 7 cm. Keywords: Contrast Material, Thoracic Diseases, Ultrasonography, Image-Guided Biopsy © RSNA, 2024.

GLP-1 modulated the firing activity of nigral dopaminergic neurons in both normal and parkinsonian mice.

The spontaneous firing activity of nigral dopaminergic neurons is associated with some important roles including modulation of dopamine release, expression of tyrosine hydroxylase (TH), as well as neuronal survival. The decreased neuroactivity of nigral dopaminergic neurons has been revealed in Parkinson's disease. Central glucagon-like peptide-1 (GLP-1) functions as a neurotransmitter or neuromodulator to exert multiple brain functions. Although morphological studies revealed the expression of GLP-1 receptors (GLP-1Rs) in the substantia nigra pars compacta, the possible modulation of GLP-1 on spontaneous firing activity of nigral dopaminergic neurons is unknown. The present extracellular in vivo single unit recordings revealed that GLP-1R agonist exendin-4 significantly increased the spontaneous firing rate and decreased the firing regularity of partial nigral dopaminergic neurons of adult male C57BL/6 mice. Blockade of GLP-1Rs by exendin (9-39) decreased the firing rate of nigral dopaminergic neurons suggesting the involvement of endogenous GLP-1 in the modulation of firing activity. Furthermore, the PKA and the transient receptor potential canonical (TRPC) 4/5 channels are involved in activation of GLP-1Rs-induced excitatory effects of nigral dopaminergic neurons. Under parkinsonian state, both the exogenous and endogenous GLP-1 could still induce excitatory effects on the surviving nigral dopaminergic neurons. As the mild excitatory stimuli exert neuroprotective effects on nigral dopaminergic neurons, the present GLP-1-induced excitatory effects may partially contribute to its antiparkinsonian effects.

Risk factors and prediction model construction for peripherally inserted central catheter-related infections.

Objective: To establish a predictive modeling for the risk of bloodstream infection associated with peripherally inserted central catheter (PICC). Methods: Patients receiving PICC treatment in Shenzhen People's Hospital from June 2020 to December 2020 were retrospectively enrolled and divided into the infection group and the non-infection group according to the presence and absence of PICC-related infections. Then, relevant clinical information of patients was collected and the predictors of PICC-related infection were screened by the least absolute shrinkage and selection operator regression (LASSO) model. Besides, multivariate logistic regression was used to analyze the influencing factors of PICC-related infection, A nomogram was constructed based on the results of the multivariate analysis. Ultimately, a receiver operating characteristic (ROC) curve was plotted to analyze the application value of influencing factors to predict PICC-related infections. Results: A total of 505 patients were included, including 75 patients with PICC-related infections (14.85%). The main pathogen was gram-positive cocci. The predictors screened by LASSO included age >60 years, catheter movement, catheter maintenance cycle, insertion technique, immune function, complications, and body temperature ≥37.2 °C before PICC placement. Multivariate logistic regression analysis showed that independent risk factors of infections related to PICC included age >60 years [odds ratio (OR) = 1.722; 95% confidence interval (CI) = 1.312-3.579; P = 0.006], catheter movement (OR = 1.313; 95% CI = 1.119-3.240; P = 0.014), catheter maintenance cycle >7 days (OR = 2.199; 95% CI = 1.677-4.653; P = 0.000), direct insertion (OR = 1.036; 95% CI = 1.019-2.743; P = 0.000), poor immune function (OR = 2.322; 95% CI = 2.012-4.579; P = 0.000), complications (OR = 1.611; 95% CI = 1.133-3.454; P = 0.019), and body temperature ≥37.2 °C before PICC placement (OR = 1.713; 95% CI = 1.172-3.654; P = 0.012). Besides, the area under the ROC curve was 0.889. Conclusion: PICC-related infections are associated with factors such as age >60 years, catheter movement, catheter maintenance cycle, insertion technique, immune function, complications, and body temperature ≥37.2 °C before PICC placement. Additionally, the LASSO model is moderately predictive for predicting the occurrence of PICC-related infections.

Effects of Lactobacillus paracasei N1115 on gut microbial imbalance and liver function in patients with hepatitis B-related cirrhosis.

BACKGROUND: Hepatitis B cirrhosis (HBC) is a chronic disease characterized by irreversible diffuse liver damage and aggravated by intestinal microbial imbalance and metabolic dysfunction. Although the relationship between certain single probiotics and HBC has been explored, the impact of the complex ready-to-eat Lactobacillus paracasei N1115 (LP N1115) supplement on patients with HBC has not been determined. AIM: To compare the changes in the microbiota, inflammatory factor levels, and liver function before and after probiotic treatment in HBC patients. METHODS: This study included 160 HBC patients diagnosed at the General Hospital of Ningxia Medical University between October 2018 and December 2020. Patients were randomly divided into an intervention group that received LP N1115 supplementation and routine treatment and a control group that received routine treatment only. Fecal samples were collected at the onset and conclusion of the 12-wk intervention period. The structure of the intestinal microbiota and the levels of serological indicators, such as liver function and inflammatory factors, were assessed. RESULTS: Following LP N1115 intervention, the intestinal microbial diversity significantly increased in the intervention group (P < 0.05), and the structure of the intestinal microbiota was characterized by an increase in the proportions of probiotic microbes and a reduction in harmful bacteria. Additionally, the intervention group demonstrated notable improvements in liver function indices and significantly lower levels of inflammatory factors (P < 0.05). CONCLUSION: LP N1115 is a promising treatment for ameliorating intestinal microbial imbalance in HBC patients by modulating the structure of the intestinal microbiota, improving liver function, and reducing inflammatory factor levels.

Host response during unresolved urinary tract infection alters female mammary tissue homeostasis through collagen deposition and TIMP1.

Exposure to pathogens throughout a lifetime influences immunity and organ function. Here, we explore how the systemic host-response to bacterial urinary tract infection (UTI) induces tissue-specific alterations to the mammary gland. Utilizing a combination of histological tissue analysis, single cell transcriptomics, and flow cytometry, we identify that mammary tissue from UTI-bearing mice displays collagen deposition, enlarged ductal structures, ductal hyperplasia with atypical epithelial transcriptomes and altered immune composition. Bacterial cells are absent in the mammary tissue and blood of UTI-bearing mice, therefore, alterations to the distal mammary tissue are mediated by the systemic host response to local infection. Furthermore, broad spectrum antibiotic treatment resolves the infection and restores mammary cellular and tissue homeostasis. Systemically, unresolved UTI correlates with increased plasma levels of the metalloproteinase inhibitor, TIMP1, which controls extracellular matrix remodeling and neutrophil function. Treatment of nulliparous and post-lactation UTI-bearing female mice with a TIMP1 neutralizing antibody, restores mammary tissue normal homeostasis, thus providing evidence for a link between the systemic host response during UTI and mammary gland alterations.

Hybrid Membrane-Coated Nanoparticles for Precise Targeting and Synergistic Therapy in Alzheimer's Disease.

The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane-coated nanoparticles derived from different cell types can mimic the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C-C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single-mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug-loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane-coated nanomaterials offer new opportunities for precise drug delivery and disease-specific targeting, which represent a versatile platform for targeted therapy in AD.

High dimensional proteomic mapping of bone marrow immune characteristics in immune thrombocytopenia.

To investigate the role of co-stimulatory and co-inhibitory molecules on immune tolerance in immune thrombocytopenia (ITP), this study mapped the immune cell heterogeneity in the bone marrow of ITP at the single-cell level using Cytometry by Time of Flight (CyTOF). Thirty-six patients with ITP and nine healthy volunteers were enrolled in the study. As soluble immunomodulatory molecules, more sCD25 and sGalectin-9 were detected in ITP patients. On the cell surface, co-stimulatory molecules like ICOS and HVEM were observed to be upregulated in mainly central memory and effector T cells. In contrast, co-inhibitory molecules such as CTLA-4 were significantly reduced in Th1 and Th17 cell subsets. Taking a platelet count of 30×109 L-1 as the cutoff value, ITP patients with high and low platelet counts showed different T cell immune profiles. Antigen-presenting cells such as monocytes and B cells may regulate the activation of T cells through CTLA-4/CD86 and HVEM/BTLA interactions, respectively, and participate in the pathogenesis of ITP. In conclusion, the proteomic and soluble molecular profiles brought insight into the interaction and modulation of immune cells in the bone marrow of ITP. They may offer novel targets to develop personalized immunotherapies.

Characteristics and risk factors for invasive fungal infection in hospitalized patients with acute-on-chronic hepatitis B liver failure: a retrospective cohort study from 2010 to 2023.

Background and aim: The global burden of invasive fungal infections (IFIs) is emerging in immunologic deficiency status from various disease. Patients with acute-on-chronic hepatitis B liver failure (ACHBLF) are prone to IFI and their conditions are commonly exacerbated by IFI. However, little is known about the characteristics and risk factors for IFI in hospitalized ACHBLF patients. Methods: A total of 243 hospitalized ACHBLF patients were retrospectively enrolled from January 2010 to July 2023. We performed restricted cubic spline analysis to determine the non-linear associations between independent variables and IFI. The risk factors for IFI were identified using logistic regression and the extreme gradient boosting (XGBoost) algorithm. The effect values of the risk factors were determined by the SHapley Additive exPlanations (SHAP) method. Results: There were 24 ACHBLF patients (9.84%) who developed IFI on average 17.5 (13.50, 23.00) days after admission. The serum creatinine level showed a non-linear association with the possibility of IFI. Multiple logistic regression revealed that length of hospitalization (OR = 1.05, 95% CI: 1.02-1.08, P = 0.002) and neutrophilic granulocyte percentage (OR = 1.04, 95% CI: 1.00-1.09, P = 0.042) were independent risk factors for IFI. The XGBoost algorithm showed that the use of antibiotics (SHAP value = 0.446), length of hospitalization (SHAP value = 0.406) and log (qHBV DNA) (SHAP value = 0.206) were the top three independent risk factors for IFI. Furthermore, interaction analysis revealed no multiplicative effects between the use of antibiotics and the use of glucocorticoids (P = 0.990). Conclusion: IFI is a rare complication that leads to high mortality in hospitalized ACHBLF patients, and a high neutrophilic granulocyte percentage and length of hospitalization are independent risk factors for the occurrence of IFI.

RNAi efficiency is enhanced through knockdown of double-stranded RNA-degrading enzymes in butterfly Papilio xuthus.

The efficiency of RNA interference (RNAi) has always limited the research on the phenotype innovation of Lepidoptera insects. Previous studies have found that double-stranded RNA-degrading enzyme (dsRNase) is an important factor in RNAi efficiency, but there have been no relevant reports in butterflies (Papilionoidea). Papilio xuthus is one of the important models in butterflies with an extensive experimental application value. To explore the effect of dsRNase in the RNAi efficiency on butterflies, six dsRNase genes (PxdsRNase 1-6) were identified in P. xuthus genome, and their dsRNA-degrading activities were subsequently detected by ex vivo assays. The result shows that the dsRNA-degrading ability of gut content (<1 h) was higher than hemolymph content (>12 h). We then investigated the expression patterns of these PxdsRNase genes during different tissues and developmental stages, and related RNAi experiments were carried out. Our results show that different PxdsRNase genes had different expression levels at different developmental stages and tissues. The expression of PxdsRNase2, PxdsRNase3, and PxdsRNase6 were upregulated significantly through dsGFP injection, and PxdsRNase genes can be silenced effectively by injecting their corresponding dsRNA. RNAi-of-RNAi studies with PxEbony, which acts as a reporter gene, observed that silencing PxdsRNase genes can increase RNAi efficiency significantly. These results confirm that silencing dsRNase genes can improve RNAi efficiency in P. xuthus significantly, providing a reference for the functional study of insects such as butterflies with low RNAi efficiency.

[Characteristics, Sources Apportionment, and Health Risks of PM2.5-bound PAHs and Their Derivatives Before and After Heating in Zibo City].

Atmospheric polycyclic aromatic hydrocarbons (PAHs) and their derivatives are a global problem that influences the environment and threatens human health. To investigate the characteristics, sources, and health risk assessment of PM2.5-bound PAHs and their derivatives, PM2.5 were collected at an urban site in Zibo from November 5 to December 26, 2020, and the concentrations of 16 conventional PAHs, nine NPAHs, and five OPAHs in PM2.5 were analyzed using gas chromatography-mass spectrometry. Source apportionment of PAHs and their derivatives was conducted using diagnostic ratios and a PMF model, and the health risks of PAHs and their derivatives to adult men and women were evaluated using the source-dependent incremental lifetime cancer risk (ILCR) model. The results showed that the average concentrations of ∑16pPAHs, ∑9NPAHs, and ∑5OPAHs in PM2.5 of Zibo City during the sampling period were (41.61 ± 13.40), (6.38 ± 5.70), and (53.20 ± 53.47) ng·m-3, respectively. The concentrations of the three PAHs increased significantly after heating, which were 1.31, 2.04, and 5.24 times larger than those before heating. During the sampling period, Chr, BaP, and BaA were the dominant components of pPAHs; 9N-Ant and 2N-Flt + 3N-Flt were the dominant components of NPAHs; and ATQ and BZO were the dominant components of OPAHs. Source apportionment results showed that motor vehicles were the main source of PAHs and their derivatives in PM2.5 before heating, whereas after heating, the main sources were the mixed source of coal and biomass combustion and secondary formation. The total BaP equivalent (TEQ) was 14.5 ng·m-3 during the sampling period, and the TEQ increased significantly after heating, which was approximately 1.2 times of that before heating. Assisted by the individual PAH source apportionment results, the ILCR of PM2.5-boundPAHs and NPAHs in Zibo City had a certain potential carcinogenic risk for adult males (1.06 × 10-5) and females (9.32 × 10-6). Among them, the health risks of PAHs from gasoline vehicles, diesel vehicles, and coal/biomass combustion were significantly higher than those from other emission sources.

Ba-Qi-Rougan formula alleviates hepatic fibrosis by suppressing hepatic stellate cell activation via the MSMP/CCR2/PI3K pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The Ba-Qi-Rougan formula (BQRGF) is a traditional and effective compound prescription from Traditional Chinese Medicine (TCM) utilized in treating hepatic fibrosis (HF). AIM OF THE STUDY: We aimed to evaluate the therapeutic efficacy of BQRGF on HF and explore the underlying mechanisms of action. MATERIALS AND METHODS: UPLC-Q-TOF-MS technology was employed to identify the material basis of BQRGF. Mice with carbon tetrachloride (CCl4)-induced HF received BQRGF at three doses (3.87, 7.74, and 15.48 g/kg per day). We examined serum and liver biochemical indicators and liver histology to assess the therapeutic impact. Primary mouse cells were isolated and utilized for experimental analysis. MSMP expression levels were examined in vitro and in vivo experimental models, including human and mouse tissue. Furthermore, lentivirus and small interfering RNA (siRNA) transfections were employed to manipulate microseminoprotein (MSMP) expression in LO2 cells (human normal liver cells). These manipulated LO2 cells were then co-cultured with LX2 human hepatic stellate cells (HSCs). Through the modulation of MSMP expression in co-cultured cells, administering recombinant MSMP (rMSMP) with or without BQRGF-medicated serum, and using specific pathway inhibitors or agonists in LX2 cells, we elucidated the underlying mechanisms. RESULTS: A total of 48 compounds were identified from BQRGF, with 12 compounds being absorbed into the bloodstream and 9 compounds being absorbed into the liver. Four weeks of BQRGF treatment in the HF mouse model led to significant improvements in biochemical and molecular assays and histopathology, particularly in the medium and high-dose groups. These improvements included a reduction in the level of liver injury and fibrosis-related factors. MSMP levels were elevated in human and mouse fibrotic liver tissues, and this increase was mitigated in HF mice treated with BQRGF. Moreover, primary cells and co-culture studies revealed that BQRGF reduced MSMP expression, decreased the expression of the hepatic stellate cell (HSC) activation markers, and suppressed critical phosphorylated protein levels in the CCR2/PI3K/AKT pathway. These findings were further validated using CCR2/PI3K/AKT signaling inhibitors and agonists in MSMP-activated LX2 cells. CONCLUSIONS: Collectively, our results suggest that BQRGF combats HF by diminishing MSMP levels and inhibiting MSMP-induced HSC activation through the CCR2/PI3K/AKT pathway.

Nomogram Based on US and Clinicopathologic Characteristics: Axillary Nodal Evaluation Following Neoadjuvant Chemotherapy in Patients With Node-Positive Breast Cancer.

BACKGROUND: To develop a convenient modality to predict axillary response to neoadjuvant chemotherapy (NAC) in breast cancer patients. MATERIALS AND METHODS: In this multi-center study, a total of 1019 breast cancer patients with biopsy-proven positive lymph node (LN) receiving NAC were randomly assigned to the training and validation groups at a ratio of 7:3. Clinicopathologic and ultrasound (US) characteristics of both primary tumors and LNs were used to develop corresponding prediction models, and a nomogram integrating clinicopathologic and US predictors was generated to predict the axillary response to NAC. RESULTS: Axillary pathological complete response (pCR) was achieved in 47.79% of the patients. The expression of estrogen receptor, human epidermal growth factor receptor -2, Ki-67 score, and clinical nodal stage were independent predictors for nodal response to NAC. Location and radiological response of primary tumors, cortical thickness and shape of LNs on US were also significantly associated with nodal pCR. In the validation cohort, the discrimination of US model (area under the curve [AUC], 0.76) was superior to clinicopathologic model (AUC, 0.68); the combined model (AUC, 0.85) demonstrates strong discriminatory power in predicting nodal pCR. Calibration curves of the nomogram based on the combined model demonstrated that substantial agreement can be observed between the predictions and observations. This nomogram showed a false-negative rates of 16.67% in all patients and 10.53% in patients with triple negative breast cancer. CONCLUSION: Nomogram incorporating routine clinicopathologic and US characteristics can predict nodal pCR and represents a tool to aid in treatment decisions for the axilla after NAC in breast cancer patients.

Alpha 2-adrenoceptor participates in anti-hyperalgesia by regulating metabolic demand.

The α2-adrenoceptor agonist dexmedetomidine is a commonly used drug for sedatives in clinics and has analgesic effects; however, its mechanism of analgesia in the spine remains unclear. In this study, we systematically used behavioural and transcriptomic sequencing, pharmacological intervention, electrophysiological recording and ultrasound imaging to explore the analgesic effects of the α2-adrenoceptor and its molecular mechanism. Firstly, we found that spinal nerve injury changed the spinal transcriptome expression, and the differential genes were mainly related to calcium signalling and tissue metabolic pathways. In addition, α2-adrenoceptor mRNA expression was significantly upregulated, and α2-adrenoceptor was significantly colocalised with markers, particularly neuronal markers. Intrathecal dexmedetomidine suppressed neuropathic pain and acute inflammatory pain in a dose-dependent manner. The transcriptome results demonstrated that the analgesic effect of dexmedetomidine may be related to the modulation of neuronal metabolism. Weighted gene correlation network analysis indicated that turquoise, brown, yellow and grey modules were the most correlated with dexmedetomidine-induced analgesic effects. Bioinformatics also annotated the involvement of metabolic processes and neural plasticity. A cardiovascular-mitochondrial interaction was found, and ultrasound imaging revealed that injection of dexmedetomidine significantly enhanced spinal cord perfusion in rats with neuropathic pain, which might be regulated by pyruvate dehydrogenase kinase 4 (pdk4), cholesterol 25-hydroxylase (ch25 h) and GTP cyclohydrolase 1 (gch1). Increasing the perfusion doses of dexmedetomidine significantly suppressed the frequency and amplitude of spinal nerve ligation-induced miniature excitatory postsynaptic currents. Overall, dexmedetomidine exerts analgesic effects by restoring neuronal metabolic processes through agonism of the α2-adrenoceptor and subsequently inhibiting changes in synaptic plasticity.

Systemic Immune-Inflammation Index and Systemic Inflammation Response Index are Associated With Periodontitis: Evidence From NHANES 2009 to 2014.

INTRODUCTION AND AIMS: Periodontitis, a chronic inflammatory condition affecting the supporting structures of the teeth, is a substantial public health burrden whilst impacting the life quality of those affected. Elevated levels of systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI) have been implicated in various inflammatory conditions. This study aimed to investigate the relationship between SII and SIRI with periodontitis. METHODS: The study examined a total of 8666 participants in the 2009 to 2014 National Health and Nutrition Examination Survey (NHANES). The study compared the weighted prevalence of periodontitis among various groups. The association between SII, SIRI levels, and periodontitis was analyzed using binary logistic regression. Additionally, we explored nonlinear relationships between SII, SIRI, and the prevalence of periodontitis using restricted cubic spline (RCS) plots. RESULTS: Among participants in the fourth quartile (Q4) of SII and SIRI, the highest prevalence of periodontitis was observed, with rates of 44.87% and 48.41%, respectively. After adjusting for all covariates, the odds ratio (OR) for periodontitis associated with SII Q4 was 1.19 (95% CI 1.02, 1.39, P = .03), while for SIRI Q4, it was 1.18 (95% CI 1.01, 1.39, P = .04). In addition, the results of sensitivity analysis revealed consistent findings, indicating that after adjusting for all covariates, the OR for periodontitis associated with SII Q4 and SIRI Q4 remained statistically significant. Specifically, the OR for periodontitis associated with SII Q4 was 1.19 (95% CI 1.02, 1.39, P = .03), while for SIRI Q4, it was 1.19 (95% CI 1.01, 1.40, P = .04). CONCLUSIONS: These results indicate that elevated SII and SIRI levels are associated with an increased prevalence of periodontitis. CLINICAL RELEVANCE: These findings suggest a potential connection between systemic inflammation and periodontitis, highlighting the importance of periodontitis patients being aware of their systemic diseases that are inflammatory in nature such as chronic cardiovascular afflictions.

Mitochondrial antioxidant elamipretide improves learning and memory impairment induced by chronic sleep deprivation in mice.

BACKGROUND: The inflammation and synaptic dysfunction induced by mitochondrial dysfunction play essential roles in the learning and memory impairment associated with sleep dysfunction. Elamipretide (SS-31), a novel mitochondrion-targeted antioxidant, was proven to improve mitochondrial dysfunction, the inflammatory response, synaptic dysfunction, and cognitive impairment in models of cerebral ischemia, sepsis, and type 2 diabetes. However, the potential for SS-31 to improve the cognitive impairment induced by chronic sleep deprivation (CSD) and its underlying mechanisms is unknown. METHODS: Adult c57BL/6J mice were subjected to CSD for 21 days using an activity wheel accompanied by daily intraperitoneal injection of SS-31 (5 mg/kg). The novel object recognition and Morris water maze test were used to evaluate hippocampus-dependent cognitive function. Western blotting and reverse transcription-quantitative polymerase chain reaction assays were used to determine the effects of CSD and SS-31 on markers of mitochondria, inflammation response, and synaptic function. Enzyme-linked immunosorbent assays were used to examine the levels of proinflammatory cytokines. RESULTS: SS-31 could improve the cognitive impairment induced by CSD. In particular, SS-31 treatment restored the CSD-induced decrease in sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor γ coactivator alpha levels and the increase in levels nuclear factor kappa-B and inflammatory cytokines, including interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha. Furthermore, SS-31 significantly increased the levels of brain-derived neurotrophic factor, postsynaptic density protein-95, and synaptophysin in CSD mice. CONCLUSION: Taken together, these results suggest that SS-31 could improve CSD-induced mitochondrial biogenesis dysfunction, inflammatory response, synaptic dysfunction, and cognitive impairment by increasing SIRT1 expression levels.

LncRNA MRAK052509 competitively adsorbs miR-204-3p to regulate silica dust-induced EMT process.

Silicosis is a systemic disease caused by long-term inhalation of free SiO2 and retention in the lungs. At present, it is still the most important occupational health hazard disease in the world. Existing studies have shown that non-coding RNA can also participate in complex fibrosis regulatory networks. However, its role in regulating silicotic fibrosis is still unclear. In this study, we constructed a NR8383/RLE-6TN co-culture system to simulate the pathogenesis of silicosis in vitro. Design of miR-204-3p mimics and inhibitors to overexpress or downregulate miR-204-3p in RLE-6TN cells. Design of short hairpin RNA (sh-RNA) to downregulate MRAK052509 in RLE-6TN cells. The regulatory mechanism of miR-204-3p and LncRNA MRAK052509 on EMT process was studied by Quantitative real-time PCR, Western blotting, Immunofluorescence and Cell scratch test. The results revealed that miR-204-3p affects the occurrence of silica dust-induced cellular EMT process mainly through regulating TGF-ßRΙ, a key molecule of TGF-ß signaling pathway. In contrast, Lnc MRAK052509 promotes the EMT process in epithelial cells by competitively adsorbing miR-204-3p and reducing its inhibitory effect on the target gene TGF-ßRΙ, which may influence the development of silicosis fibrosis. This study perfects the targeted regulation relationship between LncRNA MRAK052509, miR-204-3p and TGF-ßRΙ, and may provide a new strategy for the study of the pathogenesis and treatment of silicosis.