SIRPB1 regulates inflammatory factor expression in the glioma microenvironment via SYK: functional and bioinformatics insights.

BACKGROUND: SIRPB1 expression is upregulated in various tumor types, including gliomas, and is known to contribute to tumor progression; nevertheless, its function in the immune milieu of gliomas is still mainly unknown. METHODS: This study, we analyzed 1152 normal samples from the GTEx database and 670 glioma samples from the TCGA database to investigate the relationship between the expression of SIRPB1 and clinicopathological features. Moreover, SIRPB1 gene knockout THP-1 cell lines were constructed using CRISPR/Cas9 and were induced into a co-culture of macrophages and glioma cells in vitro to learn more about the role of SIRPB1 in the glioma immune milieu. Lastly, we established a prognostic model to predict the effect of SIRPB1 on prognosis. RESULTS: Significantly higher levels of SIRPB1 expression were found in gliomas, which had an adverse effect on the immune milieu and correlated poorly with patient survival. SIRPB1 activation with certain antibodies results in SYK phosphorylation and the subsequent activation of calcium, MAPK, and NF-κB signaling pathways. This phenomenon is primarily observed in myeloid-derived cells as opposed to glioma cells. In vitro co-culture demonstrated that macrophages with SIRPB1 knockout showed decreased IL1RA, CCL2, and IL-8, which were recovered upon ectopic expression of SIRPB1 but reduced again following treatment with SYK inhibitor GS9973. Critically, a lower overall survival rate was linked to increased SIRPB1 expression. Making use of SIRPB1 expression along with additional clinicopathological variables, we established a nomogram that showed a high degree of prediction accuracy. CONCLUSIONS: Our study demonstrates that glioma cells can be activated by macrophages via SIRPB1, subsequently reprogramming the TME, suggesting that SIRPB1 could serve as a promising therapeutic target for gliomas.

CHRNA9 as a New Prognostic Marker and Potential Therapeutic Target in Glioma.

Background: The nicotinic acetylcholine receptor (nAChR) subunit alpha-9 (CHRNA9) is a unique cholinergic receptor, which is involved in tumor proliferation, apoptosis, metastasis and chemotherapy resistance. However, the correlation between the expression level of CHRNA9 in glioma and the clinical features and prognosis of glioma patients has not been clarified. The aim of this study was to verify the expression level of CHRNA9 in glioma and its effect on prognosis by bioinformatics methods. Methods: The RNA-seq data of glioma and normal samples were obtained from the TCGA and GTEx databases. Bioinformatics methods were utilized to analyze the differential expression of CHRNA9 between tumor samples and normal samples. The potential association between CHRNA9 and the clinicopathological features of glioma patients was also investigated. The Kaplan-Meier method and Cox regression were utilized to analyze the relationship between CHRNA9 expression level and survival time and prognostic value of glioma patients. Enrichment analysis was applied to predict gene function and signaling pathways associated with CHRNA9. Experimental verification was performed using tumor tissues and paracancerous tissues from glioma patients. Results: The results of bioinformatics analysis showed that the expression of CHRNA9 was increased in glioma tissues, correlating with poor prognosis and reduced patient survival time. Enrichment analysis suggested that CHRNA9 may interact with the JAK/STAT pathway. CHRNA9 was also found to be abnormally expressed in various other tumors and associated with the expression levels of numerous immune checkpoints in glioma. The findings from the analysis of clinical samples revealed that the expression levels of both mRNA and protein of CHRNA9 in glioma tissues were higher than those in paracancerous tissues. Similarly, the mRNA expression levels of STAT3, IL-6, and TNF-α, which are crucial factors in the STAT3 pathway, were elevated in glioma tissues compared to paracancerous tissues. Conclusion: CHRNA9 is a potential prognostic marker and immunotherapy target for glioma, with its mechanism of action potentially linked to the STAT3 pathway.

Enhanced Detection Precision of the Taiji Program by Frequency Setting Strategy Based on a Hierarchical Optimization Algorithm.

For space-based gravitational wave detection, a laser interferometric measurement system composed of a three-spacecraft formation offers the most rewarding bandwidth of astrophysical sources. There are no oscillators available that are stable enough so that each spacecraft could use its own reference frequency. The conversion between reference frequencies and their distribution between all spacecrafts for the synchronization of the different metrology systems is the job of the inter-spacecraft frequency setting strategy, which is important for continuously acquiring scientific data and suppressing measurement noise. We propose a hierarchical optimization algorithm to solve the frequency setting strategy. The optimization objectives are minimum total readout displacement noise and maximum beat-note frequency feasible range. Multiple feasible parameter combinations were obtained for the Taiji program. These optimized parameters include lower and upper bounds of the beat note, sampling frequency, pilot tone signal frequency, ultrastable clock frequencies, and modulation depth. Among the 20 Pareto optimal solutions, the minimum total readout displacement noise was 4.12 pm/Hz, and the maximum feasible beat-note frequency range was 23 MHz. By adjusting the upper bound of beat-note frequency and laser power transmitted by the telescope, we explored the effects of these parameters on the minimum total readout displacement noise and optimal local laser power in greater depth. Our results may serve as a reference for the optimal design of laser interferometry system instrument parameters and may ultimately improve the detection performance and continuous detection time of the Taiji program.

Advanced inter-spacecraft offset frequency setting strategy for the Taiji program based on a two-stage optimization algorithm.

For space-based gravitational wave (GW) detection, the continuity of detection data acquisition is crucial to the inversion of wave sources and the realization of scientific goals. To control the inter-spacecraft beat-note frequency in an appropriate range for continuous gravitational wave detection and to reduce the upper bound of the beat-note frequency for improving the detection capability, a two-stage optimization algorithm is proposed to solve the offset frequency setting strategy in the Taiji program. The optimization objectives are the maximum offset frequency duration and minimum upper bound of the beat-note frequency. Considering all feasible phase-locked schemes, Doppler frequency shift, and the bandwidth of the phasemeter, a series of offset frequency setting strategies satisfying the conditions was obtained. The solution results show that the upper bound can be reduced to 16 MHz and, in this case, the offset frequency changes nine times with a minimum and maximum offset frequency duration of 90 days and 713 days, respectively. If the Doppler frequency shift is constrained, the minimum upper bound can be reduced to 14 MHz. When the minimum duration is increased, the minimum upper bound is increased. These results show that, by varying the offset frequency a limited number of times, the data continuity requirements of the Taiji program can be satisfied, and the phasemeter development difficulty and detection capability can be balanced, and may provide a reference for the phasemeter design, the setting of phase-locking schemes, and inter-spacecraft offset frequency in the Taiji program.

Statins and risk of venous thromboembolic diseases: A two-sample mendelian randomization study.

BACKGROUND AND AIMS: In observational studies, statins have been suggested to have protective effects on venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). To this aim, we performed a two-sample mendelian randomization (MR) analysis to determine whether these associations were causal. METHODS AND RESULTS: Data on the single nucleotide polymorphisms (SNPs) related to statin medication were obtained from the FinnGen study, and data for VTE, PE and DVT of lower extremities (LEDVT) were from the UK Biobank study, respectively. Inverse variance weighted (IVW) method was used as the principal analysis of MR, and sensitivity analysis was performed to detect horizontal pleiotropy and heterogeneity. MR estimates showed an inverse causal association between statin medication and the risk of VTE (odds ratio [OR]: 0.999, 95% CI: 0.998-1.000, P = 0.004), PE (OR: 0.999, 95% CI: 0.999-1.000, P = 0.011) and LEDVT (OR: 0.999, 95% CI: 0.999-1.000, P = 0.008). CONCLUSION: Our findings provide direct evidence that statins might decrease the risk of VTE, PE and LEDVT in agreement with observational studies. The specific mechanism of statin therapy for venous thromboembolism needs to be further studied.

Mechanism of arterial injury exacerbated by hyperhomocysteinemia in spontaneously hypertensive rats.

Hypertension associated with hyperhomocysteinemia (HHcy) accounts for 75% of hypertension in China. HHcy plays a synergistic role with hypertension in vascular injury and significantly increases the incidence of cardiovascular and cerebrovascular diseases. The present study aimed to explore the molecular mechanism of HHcy-induced arterial injury in hypertension. Spontaneously hypertensive rats (SHR) were injected intraperitoneally with DL-homocysteine (Hcy) to construct the model of hypertension associated with HHcy (HHcy + SHR). Biological network was employed to identify the material basis of arterial injury in hypertension associated with HHcy. The prediction molecules in oxidative stress and inflammation pathways were experimentally verified by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB) analysis. The HHcy + SHR group significantly increased oxidative stress pathway molecules: nicotinamide adenine dinucleotide phosphate oxidase (Nox); inflammatory pathway molecules: vascular adhesion protein-1 (VAP-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a); as well as inflammatory pathway regulatory factors: nuclear factor-κ-gene binding (NF-κB) p65 and protein kinase B (Akt1). Among them, IL-6 was also significantly increased in the HHcy group. Both oxidative stress and inflammation contributed to the arterial injury of hypertension associated with HHcy, and inflammation mechanism might play a leading role in HHcy aggravating arterial injury, at least partially through the Akt1/NF-κB p65/IL-6 signaling pathway.

The role of microfibrillar-associated protein 2 in cancer.

Microfibrillar-associated protein 2 (MFAP2), a component of the extracellular matrix, is important in controlling growth factor signal transduction. Recent studies have shown that MFAP2, an effective prognostic molecule for various tumors, is associated with tumor occurrence and development and may be involved in remodeling the extracellular matrix and regulating proliferation, apoptosis, invasion, tumor cell metastasis, and tumor angiogenesis. However, MFAP2's specific mechanism in these tumor processes remains unclear. This article reviewed the possible mechanism of MFAP2 in tumorigenesis and progression and provided a reference for the clinical prognosis of patients with cancer and new therapeutic target discovery.

Microfibrillar-associated protein 2 is a prognostic marker that correlates with the immune microenvironment in glioma.

Aims: microfibrillar-associated protein 2 (MFAP2), a component of the extracellular matrix, plays key roles in regulating growth factor signal transduction and various malignant tumors. However, the clinicopathological features of microfibrillar-associated protein 2 in gliomas have not been elucidated to date. Methods: TCGA and CGGA databases were used to study the expression of microfibrillar-associated protein 2 in glioma and its relationship with clinicopathological features of patients with glioma. Western blotting was performed to detect the expression of microfibrillar-associated protein 2 protein in tissue samples from glioma patients. Gene set enrichment analysis (GSEA) was applied to detect biological processes and signal pathways related to microfibrillar-associated protein 2. Single-sample gene set enrichment analysis, TIMER 2.0, and TISIDB databases were used to evaluate the role of microfibrillar-associated protein 2 in tumor immune characteristics. The prognostic role of microfibrillar-associated protein 2 in glioma was analyzed using the Kaplan-Meier method and Cox regression. Survival data were used to establish a nomogram prediction model. Results: microfibrillar-associated protein 2 expression was significantly elevated in gliomas. receiver operating characteristic analysis revealed good discrimination of microfibrillar-associated protein 2 between glioma and normal tissues. High expression of microfibrillar-associated protein 2 was associated with malignant phenotypes, such as histological type. Based on gene set enrichment analysis, we identified pathways associated with high microfibrillar-associated protein 2 expression. High microfibrillar-associated protein 2 expression was related to the infiltration of tumor immune cells, including Th2 cells and macrophages, and correlated with key markers of T-cell exhaustion. Based on the TISIDB database, microfibrillar-associated protein 2 was observed to be associated with chemokines, chemokine receptors, and multiple immunoinhibitors in glioma. Kaplan-Meier survival analyses revealed that high microfibrillar-associated protein 2 expression predicted poor overall survival, DSS, and PFS in patients with glioma. By combining microfibrillar-associated protein 2 and other prognostic factors, a nomogram prognostic prediction model was constructed, which demonstrated an ideal prediction effect. Conclusion: microfibrillar-associated protein 2 is a potential prognostic marker that plays a key role in glioma development given its association with malignant phenotypes, cancer-related pathways and tumor immunity.

FRZB is Regulated by the Transcription Factor EGR1 and Inhibits the Growth and Invasion of Triple-Negative Breast Cancer Cells by Regulating the JAK/STAT3 Pathway.

BACKGROUND: To explore the expression of frizzled related protein (FRZB) in triple-negative breast cancer (TNBC) and role of FRZB in TNBC cell growth and invasion. METHODS: Breast cancer clinical data were downloaded from the Cancer Genome Atlas. FRZB and early growth response 1 (EGR1) mRNA levels in TNBC were measured by quantitative real-time polymerase chain reaction. FRZB protein level was measured by immunohistochemistry and western blot. Proliferation, migration, and invasion of TNBC cells were detected by colony formation, wound healing, and transwell assay, respectively. The protein levels of EGR1, E-cadherin, N-cadherin, Snail, p-JAK1/JAK1, p-JAK2/JAK2, and p-STAT3/STAT3 were measured by western blot. JASPAR was used to predict the binding site of FRZB and EGR1. The binding ability of FRZB and EGR1 was verified by dual-luciferase reporter gene assay and chromatin immunoprecipitation assay. RESULTS: FRZB was low expressed in TNBC tissues and cells. Silencing FRZB promoted cell proliferation, migration, invasion, and EMT and activated JAK/STAT pathway in MDA-MB-468 and MDA-MB-231 cells, but overexpression of FRZB acted opposite effects in MDA-MB-468 and MDA-MB-231 cells. EGR1 was low expressed in TNBC samples and positively correlated with FRZB. Moreover, EGR1 could recover the promotion of silencing FRZB on cell proliferation, migration, invasion, and JAK/STAT pathway in MDA-MB-468 cells, but silencing EGR1 led to the opposite results in MDA-MB-231 cells. CONCLUSION: FRZB was low expressed in TNBC and was regulated by EGR1, and FRZB inhibited TNBC cell growth and invasion by regulating the JAK/STAT3 pathway.

An Anti-Disturbance Resilience Enhanced Algorithm for UAV 3D Route Planning.

Considering that the actual operating environment of UAV is complex and easily disturbed by the space environment of urban buildings, the RoutE Planning Algorithm of Resilience Enhancement (REPARE) for UAV 3D route planning based on the A* algorithm and artificial potential fields algorithm is carried out in a targeted manner. First of all, in order to ensure the safety of the UAV design, we focus on the capabilities of the UAV body and build a risk identification, assessment, and modeling method such that the mission control parameters of the UAV can be determined. Then, the three-dimensional route planning algorithm based on the artificial potential fields algorithm is used to ensure the safe operation of the UAV online and in real time. At the same time, by adjusting the discriminant coefficient of potential risks in real time to deal with time-varying random disturbance encountered by the UAV, the resilience of the UAV 3D flight route planning can be improved. Finally, the effectiveness of the algorithm is verified by the simulation. The simulation results show that the REPARE algorithm can effectively solve the traditional route planning algorithm's insufficiency in anti-disturbance. It is safer than a traditional A* route planning algorithm, and its running time is shorter than that of the traditional artificial potential field route planning algorithm. It solves the problems of local optimization, enhances the UAV's ability to tolerate general uncertain disturbances, and eventually improves resilience of the system.

Inter-spacecraft offset frequency setting strategy in the Taiji program.

For controlling the beat frequency of heterodyne interferometry so that the Taiji program can detect gravitational waves in space, an offset frequency setting strategy based on a linear programming algorithm is proposed. Considering factors such as Doppler frequency shift, phase-locking scheme, laser relative intensity noise, and phase detector bandwidth, inter-spacecraft offset frequency setting results suitable for the Taiji program are obtained. During the six years of running the detection process, the use of frequency bounds in the range of [5 MHz, 25 MHz] showed that offset frequencies will remain unchanged for a maximum of 1931 days. If the upper and lower bounds are adjusted, and the relative motion between spacecraft is further constrained, the offset frequencies do not need to change during the time of the mission. These results may provide insights into selecting the phase detector and designing operation parameters such as orbit and laser modulation frequency in the Taiji program.

The protective mechanism of folic acid on hyperhomocysteinemia-related arterial injury in spontaneously hypertensive rats: Folic acid against arterial inflammation.

BACKGROUND: Hypertension associated with hyperhomocysteinemia (HHcy) is correlated with a high risk of vascular diseases. Studies found that folic acid (FA) supplementation can reduce the risk of cardiovascular and cerebrovascular events. The aim of the present study was to explore the potential mechanisms of FA attenuating HHcy-related arterial injury in spontaneously hypertensive rats (SHRs). METHODS: 24 SHRs were randomized into the control group, the HHcy group, and the HHcy + FA group (8 per group). The SHRs in the HHcy group and the HHcy + FA group were given DL-Hcy intraperitoneally to mimic hypertension associated with HHcy. The SHRs in the HHcy + FA group were given FA by gavage to mimic an FA-fortified diet. The histopathology and immunohistochemistry of rat aorta and carotid artery were analyzed, and the relative expression levels of immune/inflammation and oxidative stress molecules in arterial tissue were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. RESULTS: FA significantly reduced the expression levels of nuclear factor-κ-gene binding (NF-κB) p65/Rela and interleukin-6 (IL-6) in rat arterial tissues, as well as the levels of plasma HHcy and serum malondialdehyde (MDA) in hypertension associated with HHcy rats (p < 0.05). At the same time, FA significantly increased the serum superoxide dismutase (SOD) level in hypertension associated with HHcy rats, and even the SOD level of the HHcy + FA group was higher than that of the control group (p < 0.05). However, HHcy induced the opposite results of the above indicators in SHRs compared with the control group (p < 0.05). CONCLUSIONS: The arterial protection mechanisms of FA are related to reducing the concentration of HHcy to eliminate the tissue toxicity of HHcy, inhibiting NF-κBp65/Rela/IL-6 pathway molecules to regulate inflammatory response, and promoting the potential anti-oxidative stress pathway molecules to reduce oxidative stress level.

Effect of Alkali and 1,4-Butanediol Contents on the Extraction of Lignin and Lignin-Based Activated Carbon.

In the process of lignin extraction by the organic solvent method, the amount of alkali and the content of 1,4-butanediol are important conditions that affect lignin yield. The effects of alkali and alcohol contents on lignin recovery, removal rate, and structure were studied. In this reaction system, the removal rate of lignin increased with the increase of alkali content but decreased with the increase of alcohol content. Fourier transform infrared (FT-IR) analysis showed that the phenol hydroxyl group and the ether bond in lignin had different trends in different alkali and 1,4-butanediol environments, and four different infrared parameters in lignin had an obvious linear relationship. Gel permeation chromatography (GPC) results showed that high alkali content and high 1,4-butanediol content could lead to the fragmentation of lignin. In addition, lignin extracted from alkali-quantity factor series was selected to prepare activated carbon, CaCl2 was selected as the activator, and its effects were studied. Results showed that in the process of extracting lignin, on the one hand, NaOH content affects the functional groups of activated carbon by affecting the aromatic structure of lignin; on the other hand, the NaOH content affects the graphitization degree and specific surface area of activated carbon by affecting the removal rate and the molecular weight of lignin.

Subcutaneous panniculitis-like T-cell lymphoma invading central nervous system in long-term clinical remission with lenalidomide: A case report.

BACKGROUND: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) involvement in the central nervous system (CNS) is particularly rare. SPTCL with CNS involvement has an exceedingly poor prognosis, and no optimum therapeutic method has been discovered. To the best of our knowledge, this is the first reported case of SPTCL invading the CNS achieving long-term remission with lenalidomide maintenance therapy. CASE SUMMARY: A 63-year-old man diagnosed with SPTCL was admitted to the hospital with severe headache for 15 d after four cycles of chemotherapy. Subsequent to the treatment, the patient developed CNS involvement. Craniotomy biopsy was pathologically diagnosed as CNS T-cell lymphoma, and two courses of chemotherapy were performed postoperatively. Due to the intolerance of the side effects of chemotherapeutic drugs, the patient received lenalidomide instead. The magnetic resonance imaging of the head at the 8 mo follow-up indicated no signs of recurrence, and the vital signs were stable. CONCLUSION: Lenalidomide deserves further investigation as a targeted drug for SPTCL cases involving the CNS.

Breast cancer plasma biopsy by in situ determination of exosomal microRNA-1246 with a molecular beacon.

Liquid biopsy is becoming an innovative tool in precision oncology owing to its noninvasive identification of biomarkers circulating in the body fluid at various time points for continuous and real-time analysis of disease progression. MicroRNAs in blood exosomes are identified as a new promising class of potential biomarkers for cancer diagnostics and prognostics. Conventional detection of blood exosomal microRNAs need multiple-step, complicated, costly, and time-consuming sample preparation of exosomes isolation and RNA extract, which affect the accuracy and reproducibility of analytical results. In this work, we set up an in situ quantitative analysis of human plasma exosomal miR-1246 by a probe of 2'-O-methyl and phosphorothioate modified molecular beacon. The probe has outstanding nuclease resistance in highly active RNase A/T1/I, which makes it stable for direct application in blood samples. With rapid rupture of exosomes membrane by Triton X-100, the probe can enter exosomes to specifically target miR-1246 exhibiting quantitative fluorescent signals. Using the output signals as a diagnostic marker, we differentiated 33 breast cancer patients from 37 healthy controls with 97.30% sensitivity and 93.94% specificity at the best cutoff. The blood biopsy is simple without extracting plasma exosomes and their nucleic acids content, time-saving in about 2 h of total analysis process, and microvolumes needed for plasma sample, suggesting its good potential to clinical application.