Identifying the Preoperative Radiological Risk Features in Patients with Leptomeningeal Carcinomatosis Undergoing Cerebrospinal Fluid Drainage.

BACKGROUND: Patients with leptomeningeal carcinomatosis (LMC) experience a poor prognosis and rapid progression, and cerebrospinal fluid drainage (CSFD) is used to manage intracranial hypertension and hydrocephalus in LMC patients. This study aims to describe a novel discovery of preoperative radiological features in patients who underwent CSFD for LMC. METHODS: A retrospective review was conducted during the past 5 years of LMC patients with intracranial hypertension and hydrocephalus who underwent CSFD. We evaluated the patients' preoperative radiological features, clinical characteristics, and survival times. RESULTS: A total of 36 patients were included. Of the 36 patients, 34 underwent ventriculoperitoneal shunting, and 2 patients underwent only external ventricular drainage due to rapid progression. The median preoperative Karnofsky performance scale score was 40.0 (interquartile range [IQR], 20.0-40.0). The median survival time after surgery was 5 months (IQR, 0.00-10.43 months). Of the 36 patients, 24 (66.7%) had supratentorial cerebral edema before surgery, including 14 patients (38.9%) with features of disproportionately enlarged subarachnoid space hydrocephalus (DESH). Four patients (11.1%) exhibited cerebellar swelling and had a median survival time of 0.27 month (IQR, 0.00-0.56 month). Nine patients (25%) have enhancement lesions on the cerebellum. The survival curve analysis shows that patients with features of cerebellar enhancement have shorter survival times than other patients. Patients with DESH features have longer survival times compared with those with global cerebral edema. CONCLUSIONS: Patients with radiological features of cerebellar enhancement have shorter postoperative survival than other patients; however, those with supratentorial cerebral edema, especially features of DESH, could benefit from CSFD. Patients with cerebellar swelling should avoid undergoing CSFD.

Dysfunctional iron metabolism in pressure injuries is related to aberrant CD163 and Homx-1 signal transduction.

Dysregulation of iron metabolism has been associated with impaired chronic wound healing. However, changes in iron metabolism have yet to be reported in pressure injuries, a type of chronic wound. In this study, we aimed to investigate changes in iron metabolism and associated regulatory mechanisms in pressure injuries. We collected tissue biopsies and data from 20 consenting stage IV-pressure injuries patients and 5 non-pressure injuries patients hospitalised at the Affiliated Hospital of Qingdao University between March 2021 and June 2021. In addition, we measured the iron content by inductively coupled plasma mass spectrometry and Prussian blue staining in deep tissue pressure injury mouse models. An Enzyme-linked immune sorbent assay measured the expression of ferritin, ferroportin-1 and transferrin. Immunofluorescence staining, high-throughput transcriptome sequencing, Western blot and RT-qPCR further analysed the fundamental mechanisms regulating iron metabolism. In this study, we observed numerous inflammatory cells infiltrating the marginal tissues of stage IV pressure injury patients and in deep tissue pressure injury models. The expression levels of pro-inflammatory factors, such as inducible nitric oxide synthase and interleukin-6, were significantly increased (p < 0.05). The iron level was proportional to the degree of progression, with the most significant change appearing on the third day in deep tissue pressure injury models (p < 0.05). Enzyme-linked immune sorbent assay results suggested abnormal gene expression was related to iron metabolism, including a substantial increase in ferritin and a significant decrease in the expression of ferroportin-1 (p < 0.05). In addition, immunofluorescence staining and Western blot showed that the expression of macrophage membrane receptor CD163 was abnormally elevated (p < 0.05). Both high-throughput transcriptome sequencing and qRT-PCR results suggested aberrant expression of the CD163/Homx-1-mediated signalling pathway. Dysfunctional iron metabolism was suggested to be related to the aberrant CD163/Homx-1 signalling pathway in deep tissue pressure injury models.

Extracts of Portulaca oleracea promote wound healing by enhancing angiology regeneration and inhibiting iron accumulation in mice.

Objective: To investigate the role of Portulaca oleracea (POL) in promoting revascularization and re-epithelization as well as inhibiting iron aggregation and inflammation of deep tissue pressure injury (DTPI). Methods: The hydroalcoholic extract of POL (P) and aqueous phase fraction of POL (PD) were prepared based on maceration and liquid-liquid extraction. The number of new blood vessels and VEGF-A expression level were assessed using H&E stain and Western blot on injured muscle to examine the role of POL different extracts in vascularization. The iron distribution and total elemental iron of injured muscle were detected using laser ablation inductively coupled plasma mass spectrometry (ICP-MS) and Perls' staining to determine whether POL extracts can inhibit the iron accumulation. Besides, the ability of POL extracts to promote wound healing by combining re-epithelization time, inflammation degree and collagen deposition area were comprehensively evaluated. Results: In vitro, we observed a significant increase in HUVEC cell viability, migration rate and the number of the tube after P and PD treatment (P < 0.05). In vivo, administration of P and PD impacted vascularization and iron accumulation on injured tissue, evident from more new blood vessels, higher expression of VEGF-A and decreased muscle iron concentration of treatment groups compared with no-treatment groups (P < 0.05). Besides, shorter re-epithelization time, reduced inflammatory infiltration and distinct collagen deposition were associated with administration of P and PD (P < 0.05). Conclusion: POL extract administration groups have high-quality wound healing, which is associated with increased new blood vessels, collagen deposition and re-epithelization, along with decreased iron accumulation and inflammatory infiltration. Our results suggest that that POL extract is beneficial to repair injured muscle after ischemia-reperfusion, highlighting the potential of POL in the DTPI treatment.

Spliceosome-regulated RSRP1-dependent NF-κB activation promotes the glioblastoma mesenchymal phenotype.

BACKGROUND: The glioblastoma (GBM) mesenchymal (MES) phenotype, induced by NF-κB activation, is characterized by aggressive tumor progression and poor clinical outcomes. Our previous analysis indicated that MES GBM has a unique alternative splicing (AS) pattern; however, the underlying mechanism remains obscure. We aimed to reveal how splicing regulation contributes to MES phenotype promotion in GBM. METHODS: We screened novel candidate splicing factors that participate in NF-κB activation and MES phenotype promotion in GBM. In vitro and in vivo assays were used to explore the function of RSRP1 in MES GBM. RESULTS: Here, we identified that arginine/serine-rich protein 1 (RSRP1) promotes the MES phenotype by facilitating GBM cell invasion and apoptosis resistance. Proteomic, transcriptomic, and functional analyses confirmed that RSRP1 regulates AS in MES GBM through mediating spliceosome assembly. One RSRP1-regulated AS event resulted in skipping PARP6 exon 18 to form truncated, oncogenic PARP6-s. This isoform was unable to effectively suppress NF-κB. Cotreatment of cultured GBM cells and GBM tumor-bearing mice with spliceosome and NF-κB inhibitors exerted a synergistic effect on MES GBM growth. CONCLUSION: We identified a novel mechanism through which RSRP1-dependent splicing promotes the GBM MES phenotype. Targeting AS via RSRP1-related spliceosomal factors might constitute a promising treatment for GBM.

Automatic Premature Ventricular Contraction Detection Using Deep Metric Learning and KNN.

Premature ventricular contractions (PVCs), common in the general and patient population, are irregular heartbeats that indicate potential heart diseases. Clinically, long-term electrocardiograms (ECG) collected from the wearable device is a non-invasive and inexpensive tool widely used to diagnose PVCs by physicians. However, analyzing these long-term ECG is time-consuming and labor-intensive for cardiologists. Therefore, this paper proposed a simplistic but powerful approach to detect PVC from long-term ECG. The suggested method utilized deep metric learning to extract features, with compact intra-product variance and separated inter-product differences, from the heartbeat. Subsequently, the k-nearest neighbors (KNN) classifier calculated the distance between samples based on these features to detect PVC. Unlike previous systems used to detect PVC, the proposed process can intelligently and automatically extract features by supervised deep metric learning, which can avoid the bias caused by manual feature engineering. As a generally available set of standard test material, the MIT-BIH (Massachusetts Institute of Technology-Beth Israel Hospital) Arrhythmia Database is used to evaluate the proposed method, and the experiment takes 99.7% accuracy, 97.45% sensitivity, and 99.87% specificity. The simulation events show that it is reliable to use deep metric learning and KNN for PVC recognition. More importantly, the overall way does not rely on complicated and cumbersome preprocessing.

TMEFF2 promoter hypermethylation is an unfavorable prognostic marker in gliomas.

BACKGROUND: Transmembrane protein with EGF-like and two follistatin-like domains 2 (TMEFF2) is a transmembrane protein in the tomoregulin family. Little research has been performed to determine whether TMEFF2 methylation is a prognostic marker in adult diffuse gliomas. METHODS: In this study, we investigated TMEFF2 expression in surgical glioma tissue samples. In addition, we conducted bisulfite amplicon sequencing (BSAS) and methylation-specific PCR (MSP) to evaluate TMEFF2 methylation in glioblastoma (GBM) cells. Subsequently, we investigated the biological function of TMEFF2 in GBM cells. Moreover, we explored the prognostic significance of TMEFF2 in gliomas by analysing a cohort dataset from TCGA. RESULTS: Immunohistochemistry analysis of 75 paired glioma tumour and peritumoural tissues demonstrated that glioma tumour tissues expressed lower TMEFF2 levels than peritumoural tissues (P < 0.001). TMEFF2 promoter methylation levels were increased in glioblastoma cells compared with SVG p12 cells (P < 0.001). Inhibition of methylation reduced TMEFF2 methylation and increased its expression in LN229 and T98G cells (P < 0.05). Knockdown of TMEFF2 expression significantly promoted the proliferation of U87MG cells and primary GBM cells (P < 0.05). TMEFF2 methylation is negatively associated with IDH1, ATRX and TP53 mutations, and the subtype of glioma harbouring combined IDH1/ATRX/TP53 mutations was associated with low TMEFF2 methylation levels. Survival analysis confirmed that low TMEFF2 methylation levels are associated with good prognosis in glioma patients. CONCLUSIONS: Our results suggest that TMEFF2 DNA methylation might be associated with glioma tumour progression and could serve as a valuable prognostic marker for adult diffuse gliomas.

Combination of metronidazole and pearl powders for the treatment of stage 2 pressure injury wounds: Case report and literature review.

Pressure injury (PI) is a worldwide health problem that has attracted widespread attention from scientific and clinical research communities. PI incidence correlates with the increase of the aging population. In this situation, it is crucial to select effective and affordable drugs for patients and healthcare systems. Herein, we report a case of a 94-year-old female with a stage 2 PI wound, which was treated topically using a novel combination of mixed powders: metronidazole and nano pearl powders. Metronidazole is the preferred option to treat infected wounds due to its excellent antibacterial ability. However, some drawbacks have limited the use of metronidazole in PI wound management, such as its poor capacity to accelerate wound closure. Pearl powder has a strong capacity to promote wound healing and closure but has not been effective at resisting wound infection. To take advantage of powdered drugs' wound treatment properties and accelerate PI wound healing, we prepared powdered mixtures for wound application. Both drugs are cost-effective and were beneficial to wound healing. Therefore, the combination of metronidazole and pearl powders offer a promising choice to patients with PI wounds.

Tazarotene-loaded PLGA nanoparticles potentiate deep tissue pressure injury healing via VEGF-Notch signaling.

BACKGROUND AND PURPOSE: New capillaries are essential for deep tissue pressure injury wound healing. Tazarotene is a recently discovered small molecule drug and functions to promote neovascularization and tissue repair. At present, the application of tazarotene in the repair of pressure injuries has not previously been investigated. This study used poly (lactic-co-glycolic acid) (PLGA) as nanoparticle carriers loaded with tazarotene (Ta/PLGA NPs) for drug delivery and to overcome shortcomings associated with the low water solubility, short half-life, easy photolysis and low bioavailability of tazarotene itself. METHODS: The physicochemical properties, drug release and bioactivity of Ta/PLGA NPs were examined in vitro by transmission electron microscope, spectrophotometry and cell assays. Mouse models of deep tissue pressure injuries (DTPI) were established and the therapeutic effects and mechanisms of Ta/PLGA NPs in local wound repair were studied. RESULTS: The results showed that Ta/PLGA NPs were of uniform size and distribution and were non-toxic both in vitro and in vivo. In vivo experiments suggested that Ta/PLGA NPs significantly promoted DTPI wound repair through activation of the VEGF/VEGFR-Notch1/DLL4 signaling pathway. CONCLUSION: This study highlights the potential clinical significance of implementation of tazarotene small molecule drugs in combination with effective biomaterial carriers for the treatment of chronic refractory wounds, such as DTPI.

Establishment of age group classification for risk stratification in glioma patients.

BACKGROUND: Age is associated with the prognosis of glioma patients, but there is no uniform standard of age-group classification to evaluate the prognosis of glioma patients. In this study, we aimed to establish an age group classification for risk stratification in glioma patients. METHODS: 1502 patients diagnosed with gliomas at Nanfang Hospital between 2000 and 2018 were enrolled. The WHO grade of glioma was used as a dependent variable to evaluate the effect of age on risk stratification. The evaluation model was established by logistic regression, and the Akaike information criterion (AIC) value of the model was used to determine the optimal cutoff points for age-classification. The differences in gender, WHO grade, pathological subtype, tumor cell differentiation, tumor size, tumor location, and molecular markers between different age groups were analyzed. The molecular markers included GFAP, EMA, MGMT, P53, NeuN, Oligo2, EGFR, VEGF, IDH1, Ki-67, PR, CD3, H3K27M, TS, and 1p/19q status. RESULTS: The proportion of men with glioma was higher than that of women with glioma (58.3% vs 41.7%). Analysis of age showed that appropriate classifications of age group were 0-14 years old (pediatric group), 15-47 years old (youth group), 48-63 years old (middle-aged group), and ≥ 64 years old (elderly group).The proportions of glioblastoma and large tumor size (4-6 cm) increased with age (p = 0.000, p = 0.018, respectively). Analysis of the pathological molecular markers across the four age groups showed that the proportion of patients with larger than 10% area of Ki-67 expression or positive PR expression increased with age (p = 0.000, p = 0.017, respectively). CONCLUSIONS: Appropriate classifications of the age group for risk stratification are 0-14 years old (pediatric group), 15-47 years old (young group), 48-63 years old (middle age group) and ≥ 64 years old (elderly group). This age group classification is effective in evaluating the risk of glioblastoma in glioma patients.

Chitosan hydrogel encapsulated with LL-37 peptide promotes deep tissue injury healing in a mouse model.

BACKGROUND: LL-37 peptide is a member of the human cathelicidin family, and has been shown to promote the healing of pressure ulcers. However, the low stability of this peptide within the wound environment limits its clinical use. Chitosan (CS) hydrogel is commonly used as a base material for wound dressing material. METHODS: CS hydrogel (2.5% w/v) was encapsulated with LL-37. Cytotoxicity of the product was examined in cultured NIH3T3 fibroblasts. Effects on immune response was examined by measuring tumor necrosis factor-α (TNF-α) release from RAW 264.7 macrophages upon exposure to lipopolysaccharides. Antibacterial activity was assessed using Staphylococcus aureus. Potential effect on pressure ulcers was examined using a mouse model. Briefly, adult male C57BL/6 mice were subjected to skin pressure using magnets under a 12/12 h schedule for 21 days. Mice were randomized to receive naked LL-37 (20 µg), chitosan gel containing 20-µg LL-37 (LL-37/CS hydrogel) or hydrogel alone under the ulcer bed (n = 6). A group of mice receiving no intervention was also included as a control. RESULTS: LL-37/CS hydrogel did not affect NIH3T3 cell viability. At a concentration of 1-5 µg/ml, LL-37/CS inhibited TNF-α release from macrophage. At 5 µg/ml, LL-37/CS inhibited the growth of Staphylococcus aureus. The area of the pressure ulcers was significantly lower in mice receiving LL-37/CS hydrogel in comparison to all other 3 groups on days 11 (84.24% ± 0.25%), 13 (56.22% ± 3.91%) and 15 (48.12% ± 0.28%). Histological examination on days 15 and 21 showed increased epithelial thickness and density of newly-formed capillary with naked LL-37 and more so with LL-37/CS. The expression of key macromolecules in the process of angiogenesis (i.e., hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A)) in wound tissue was increased at both the mRNA and protein levels. CONCLUSION: Chitosan hydrogel encapsulated with LL-37 is biocompatible and could promote the healing of pressure ulcers.

Quantitative Proteomics Analysis Reveals Nuclear Perturbation in Human Glioma U87 Cells treated with Temozolomide.

Glioblastoma (GBM) is the most malignant and aggressive glioma, which has a very poor prognosis. Temozolomide (TMZ) is still a first-line treatment, but resistance is inevitable even in MGMT-deficient glioblastoma cells. The aims of this study were to comprehend the effect of TMZ on nucleus and the underlying mechanism of acquired TMZ resistance in MGMT-deficient GBM. We show the changes of nuclear proteome in the MGMT-deficient GBM U87 cells treated with TMZ for 1 week. Label-free-based quantitative proteomics were used to investigate nuclear protein abundance change. Subsequently, gene ontology function annotation, KEGG pathway analysis, protein-protein interaction (PPI) network construction analysis of DAPs, and immunofluorescence were applied to validate the quality of proteomics. In total, 457 (455 gene products) significant DAPs were identified, of which 327 were up-regulated and 128 were down-regulated. Bioinformatics analysis uncovered RAD50, MRE11, UBR5, MSH2, MSH6, DDB1, DDB2, RPA1, RBX1, CUL4A, and CUL4B mainly enriched in DNA damage repair related pathway and constituted a protein-protein interaction network. Ribosomal proteins were down-regulated. Cells were in a stress-responsive state, while the entire metabolic level was lowered. SIGNIFICANCE OF THE STUDY: In U87 cell treated with TMZ for 1 week, which resulted in DNA damage, we found various proteins dysregulated in the nucleus. Some proteins related to the DNA damage repair pathway were up-regulated, and there was a strong interaction. We believe this is the potential clues of chemotherapy resistance in tumour cells. These proteins can be used as indicators of tumour resistance screening in the future.

The combination of two-dimensional and three-dimensional analysis methods contributes to the understanding of glioblastoma spatial heterogeneity.

Heterogeneity is regarded as the major factor leading to the poor outcomes of glioblastoma (GBM) patients. However, conventional two-dimensional (2D) analysis methods, such as immunohistochemistry and immunofluorescence, have limited capacity to reveal GBM spatial heterogeneity. Thus, we sought to develop an effective analysis strategy to increase the understanding of GBM spatial heterogeneity. Here, 2D and three-dimensional (3D) analysis methods were compared for the examination of cell morphology, cell distribution and large intact structures, and both types of methods were employed to dissect GBM spatial heterogeneity. The results showed that 2D assays showed only cross-sections of specimens but provided a full view. To visualize intact GBM specimens in 3D without sectioning, the optical tissue clearing methods CUBIC and iDISCO+ were used to clear opaque specimens so that they would become more transparent, after which the specimens were imaged with a two-photon microscope. The 3D analysis methods showed specimens at a large spatial scale at cell-level resolution and had overwhelming advantages in comparison to the 2D methods. Furthermore, in 3D, heterogeneity in terms of cell stemness, the microvasculature, and immune cell infiltration within GBM was comprehensively observed and analysed. Overall, we propose that 2D and 3D analysis methods should be combined to provide much greater detail to increase the understanding of GBM spatial heterogeneity.

Degradation of α-terpineol in aqueous solution by UV/H2O2: kinetics, transformation products and pathways.

The monoterpene alcohol α-terpineol is extensively used as the foaming agent in mineral processing and can be released to environment along with the wastewater. This study evaluated the feasibility of eliminating α-terpineol in water by ultraviolet irradiation (UV) in combination with hydrogen peroxide (H2O2). Within an H2O2 dose of 10 mg/L and an UV fluence of 64.8 J/cm2, more than 95% of the α-terpineol can be removed. The reactions fitted well to pseudo-first-order kinetics, and the apparent rate constant was 0.0678 min-1. The effects of matrix species including various anions and humic acid (HA), were evaluated. The degradation rate decreased significantly with the addition of bicarbonate and HA. Further verification was carried out with three types of real water samples. In the ground water and the surface water, the degradation rate decreased likely due to the presence of natural organic matter. Finally, possible degradation pathways were proposed based on the identification of transformation products, and the occurrence of two main transformation products were monitored. This study demonstrated that the UV/H2O2 is an effective technology for the degradation of α-terpineol in water.