Hidden blood loss and its influencing factors after cement augmentation for vertebral metastasis.

Introduction: Few studies have focused on the risk factors for hidden blood loss (HBL) during cement augmentation surgery for pathologic vertebral compression fraction (PVCFs). Method: From January 2014 to December 2020, the clinical data of 169 PVCF patients (283 levels) who underwent cement augmentation were retrospectively analysed. HBL was calculated according to the linear Gross formula using the patient's average Hct during the perioperative course and PBV. Multivariate linear regression analysis was performed to evaluate the independent factors associated with HBL. Results: The mean HBL was 448.2 ± 267.2 ml, corresponding to 10.8% ± 6.2% of the patient blood volume (PBV). There were significant differences between pre- and postoperative haematocrit (Hct) (P < 0.001) and Hb (P < 0.001), and 132 patients developed anaemia postoperatively, while 79 patients had anaemia preoperatively (P < 0.001). Multivariate linear regression revealed that bone lesion quality (p = 0.028), number of PVCFs (p = 0.002), amount of bone cement (p = 0.027), bone cement leakage (p = 0.001), and percentage of vertebral height loss (VHL) (p = 0.011) were independent risk factors for HBL. Conclusion: In conclusion, patients with lytic vertebral destruction, larger amounts of bone cement, greater amounts of bone cement leakage, more PVCF(s), and greater percentages of VHL may be more prone to HBL.

Assessing the Feasibility of Simplifying the Scanning Protocol for Spinal Metastases With Vertebral Compression Fractures Using Only the Dixon T2-Weighted Sequence.

OBJECTIVE: Conventional imaging protocols, including sagittal T1-weighted imaging (T1WI) and water-only T2-weighted imaging (T2WI), are time consuming when screening for spinal metastases with vertebral compression fractures (VCFs). In this study, we aimed to assess the accuracy of using only the Dixon T2-weighted sequence in the diagnosis of spinal metastases with VCFs to determine its suitability as a simplified protocol for this task. METHODS: This retrospective study included 27 patients diagnosed with spinal metastases and VCFs. Qualitative analysis was performed separately by two musculoskeletal radiologists, who independently performed diagnostic evaluations of each vertebra using both conventional and simplified protocols. McNemar's test was then used to compare the differences in diagnostic results, and Cohen's kappa coefficient was used to assess interobserver and interprotocol agreement. Diagnostic performance values for both protocols, including sensitivity, specificity, and area under the curve, were then determined based on the reference standard. Quantitative image analysis was performed randomly for 30 metastases on T1WI and fat-only T2WI to measure the signal intensity, signal-to-noise ratio, and contrast-to-noise ratio. RESULTS: The diagnosis of VCFs by both radiologists was in full agreement with the reference standard. The classification of spinal metastases and diagnostic performance values determined by both radiologists were not significantly different between the two protocols (all P > 0.05), and the consistency between observers and protocols was excellent (κ = 0.973-0.991). The contrast-to-noise ratio of fat-only T2WI was significantly higher than that of T1WI (P < 0.001). CONCLUSIONS: The Dixon T2-weighted sequence alone performed well in diagnosing spinal metastases with VCFs, performing no worse than the conventional protocol (T1WI and water-only T2WI). This suggests that the Dixon T2-weighted sequence alone can serve as a simplified protocol for the diagnosis of spinal metastases with VCFs, thereby avoiding the need for more intricate scanning procedures.

Kellerin alleviates cerebral ischemic injury by inhibiting ferroptosis via targeting Akt-mediated transcriptional activation of Nrf2.

BACKGROUND: Ischemic stroke (IS) is characterized as a detrimental cerebrovascular disease with high mortality and disability. Ferroptosis is a novel mechanism involved in neuronal death. There is a close connection between IS and ferroptosis, and inhibiting ferroptosis may provide an effective strategy for treating IS. Our previous investigations have discovered that kellerin, the active compound of Ferula sinkiangensis K. M. Shen, possesses the capability to shield against cerebral ischemia injury. PURPOSE: Our objective is to clarify the relationship between the neuroprotective properties of kellerin against IS and its ability to modulate ferroptosis, and investigate the underlying regulatory pathway. STUDY DESIGN: We investigated the impact and mechanism of kellerin in C57BL/6 mice underwent middle cerebral artery occlusion/reperfusion (MCAO/R) as well as SH-SY5Y cells exposed to oxygen-glucose deprivation/ re-oxygenation (OGD/R). METHODS: The roles of kellerin on neurological severity, cerebral infarction and edema were investigated in vivo. The regulatory impacts of kellerin on ferroptosis, mitochondrial damage and Akt/Nrf2 pathway were explored. Molecular docking combined with drug affinity responsive target stability assay (DARTS) and cellular thermal shift assay (CETSA) were performed to analyze the potential target proteins for kellerin. RESULTS: Kellerin protected against IS and inhibited ferroptosis in vivo. Meanwhile, kellerin improved the neuronal damage caused by OGD/R and suppressed ferroptosis by inhibiting the production of mitochondrial ROS in vitro. Further we found that kellerin directly interacted with Akt and enhanced its phosphorylation, leading to the increase of Nrf2 nuclear translocation and its downstream antioxidant genes expression. Moreover, kellerin's inhibitory effect on ferroptosis and mitochondrial ROS release was eliminated by inhibiting Akt/Nrf2 pathway. CONCLUSIONS: Our study firstly demonstrates that the neuroprotective properties of kellerin against IS are related to suppressing ferroptosis through inhibiting the production of mitochondrial ROS, in which its modulation on Akt-mediated transcriptional activation of Nrf2 plays an important role. This finding shed light on the potential mechanism that kellerin exerts therapeutic effects in IS.

A benchmarking framework for the accurate and cost-effective detection of clinically-relevant structural variants for cancer target identification and diagnosis.

BACKGROUND: Accurate clinical structural variant (SV) calling is essential for cancer target identification and diagnosis but has been historically challenging due to the lack of ground truth for clinical specimens. Meanwhile, reduced clinical-testing cost is the key to the widespread clinical utility. METHODS: We analyzed massive data from tumor samples of 476 patients and developed a computational framework for accurate and cost-effective detection of clinically-relevant SVs. In addition, standard materials and classical experiments including immunohistochemistry and/or fluorescence in situ hybridization were used to validate the developed computational framework. RESULTS: We systematically evaluated the common algorithms for SV detection and established an expert-reviewed SV call set of 1,303 tumor-specific SVs with high-evidence levels. Moreover, we developed a random-forest-based decision model to improve the true positive of SVs. To independently validate the tailored 'two-step' strategy, we utilized standard materials and classical experiments. The accuracy of the model was over 90% (92-99.78%) for all types of data. CONCLUSION: Our study provides a valuable resource and an actionable guide to improve cancer-specific SV detection accuracy and clinical applicability.

De Novo Generation and Identification of Novel Compounds with Drug Efficacy Based on Machine Learning.

One of the main challenges in small molecule drug discovery is finding novel chemical compounds with desirable activity. Traditional drug development typically begins with target selection, but the correlation between targets and disease remains to be further investigated, and drugs designed based on targets may not always have the desired drug efficacy. The emergence of machine learning provides a powerful tool to overcome the challenge. Herein, a machine learning-based strategy is developed for de novo generation of novel compounds with drug efficacy termed DTLS (Deep Transfer Learning-based Strategy) by using dataset of disease-direct-related activity as input. DTLS is applied in two kinds of disease: colorectal cancer (CRC) and Alzheimer's disease (AD). In each case, novel compound is discovered and identified in in vitro and in vivo disease models. Their mechanism of actionis further explored. The experimental results reveal that DTLS can not only realize the generation and identification of novel compounds with drug efficacy but also has the advantage of identifying compounds by focusing on protein targets to facilitate the mechanism study. This work highlights the significant impact of machine learning on the design of novel compounds with drug efficacy, which provides a powerful new approach to drug discovery.

Hedgehog target genes regulate lipid metabolism to drive basal cell carcinoma and medulloblastoma.

Hedgehog (Hh) signaling is essential for development, homeostasis, and regeneration1. Misactivation of the Hh pathway underlies medulloblastoma, the most common malignant brain tumor in children, and basal cell carcinoma (BCC), the most common cancer in the United States2. Primary cilia regulate Hh signal transduction3, but target genes that drive cell fate decisions in response to ciliary ligands or oncogenic Hh signaling are incompletely understood. Here we define the Hh gene expression program using RNA sequencing of cultured cells treated with ciliary ligands, BCCs from humans, and Hh-associated medulloblastomas from humans and mice (Fig. 1a). To validate our results, we integrate lipidomic mass spectrometry and bacterial metabolite labeling of free sterols with genetic and pharmacologic approaches in cells and mice. Our results reveal novel Hh target genes such as the oxysterol synthase Hsd11ß1 and the adipokine Retnla that regulate lipid metabolism to drive cell fate decisions in response to Hh pathway activation. These data provide insights into cellular mechanisms underlying ciliary and oncogenic Hh signaling and elucidate targets to treat Hh-associated cancers.

Iron level participates in the pathological damages of dental caries in infant rats by affecting enamel mineralization.

Iron deficiency anemia (IDA) is a common nutritional disease associated with early childhood caries. This study aimed to explore the role of iron levels in pathological changes of dental caries in childhood. Rats were divided into four groups based on their iron content: IDA, positive control (PC), high iron (HI), and negative control (NC). Except for the rats in the NC group, rats in the other groups were inoculated with Streptococcus mutans and fed cariogenic high-sugar fodder to induce caries. Three months later, the caries status of the molars was evaluated at both the smooth and sulcal surfaces according to Keyes scores. Scanning electron microscopy (SEM) was performed to reveal microstructural changes in caries. Energy-dispersive spectroscopy (EDS) was used to determine the elemental composition of the enamel and dentin. In addition, the histopathology of the salivary gland was detected using hematoxylin and eosin (HE) staining.The results showed that rats in the PC group exhibited obvious carious lesions. The carious score was significantly higher in the IDA group than in the PC group but was lower in the HI group. SEM revealed complete destruction of the enamel and damage to the middle dentin in the IDA group. In contrast, the molars in the HI group exhibited some degree of enamel demineralization, but the underlying dentin was almost intact. In addition, the elemental compositions of the enamel and dentin were similar among the four groups, and iron was detected only in the HI group. No differences were observed in the morphological structures of the salivary glands of rats from the different groups. In conclusion, ID enhanced the pathological damage of caries, whereas HI weakened it. Iron may participate in the pathological damage caused by childhood caries by affecting enamel mineralization.

Tracking the Metabolic Fate of Exogenous Arachidonic Acid in Ferroptosis Using Dual-Isotope Labeling Lipidomics.

Lipid metabolism is implicated in a variety of diseases, including cancer, cell death, and inflammation, but lipidomics has proven to be challenging due to the vast structural diversity over a narrow range of mass and polarity of lipids. Isotope labeling is often used in metabolomics studies to follow the metabolism of exogenously added labeled compounds because they can be differentiated from endogenous compounds by the mass shift associated with the label. The application of isotope labeling to lipidomics has also been explored as a method to track the metabolism of lipids in various disease states. However, it can be difficult to differentiate a single isotopically labeled lipid from the rest of the lipidome due to the variety of endogenous lipids present over the same mass range. Here we report the development of a dual-isotope deuterium labeling method to track the metabolic fate of exogenous polyunsaturated fatty acids, e.g., arachidonic acid, in the context of ferroptosis using hydrophilic interaction-ion mobility-mass spectrometry (HILIC-IM-MS). Ferroptosis is a type of cell death that is dependent on lipid peroxidation. The use of two isotope labels rather than one enables the identification of labeled species by a signature doublet peak in the resulting mass spectra. A Python-based software, D-Tracer, was developed to efficiently extract metabolites with dual-isotope labels. The labeled species were then identified with LiPydomics based on their retention times, collision cross section, and m/z values. Changes in exogenous AA incorporation in the absence and presence of a ferroptosis inducer were elucidated.

Risk factors for pulmonary cement embolism after percutaneous vertebroplasty and radiofrequency ablation for spinal metastases.

Objective: Pulmonary cement embolism is a rare but underestimated complication of vertebroplasty due to the relative lack of study and examination. This study aims to investigate the incidence of pulmonary cement embolism in patients with spinal metastasis who undergo PVP with RFA and to analyze the relative risk factors. Methods: A total of 47 patients were retrospectively included and classified into pulmonary cement embolism (PCE) group and non-pulmonary cement embolism (NPCE) group by comparing pre- and postoperative pulmonary CT scan images. The demographic and clinical information of the patients was obtained. Demographic data in the two groups were compared using the chi-square test for qualitative data and the unpaired t test for quantitative data. Multiple logistic regression analysis was used to identify risk factors related to pulmonary cement embolism. Results: Pulmonary cement embolism was detected in 11 patients (23.4%), and all patients were asymptomatic and followed up regularly. Risk analysis showed that multiple segments (≥3, p=0.022), thoracic vertebrae (p=0.0008), and unipedicular puncture approach (p=0.0059) were risk factors for pulmonary cement embolism. There was a high incidence of pulmonary cement embolism if bone cement leaked into the para vertebral venous plexus in the thoracic vertebra (p<0.0001). Vein leakage of cement was related to the integrity of the vertebral cortex. Conclusion: The number of involved vertebrae, lesion location, and puncture approach are independent risk factors for pulmonary cement embolism. There was a high incidence of pulmonary cement embolism if bone cement leaked into the para vertebral venous plexus in the thoracic vertebra. Surgeons should consider these factors when formulating therapeutic strategies.

Loureirin C inhibits ferroptosis after cerebral ischemia reperfusion through regulation of the Nrf2 pathway in mice.

BACKGROUND: Ischemic stroke (IS) is considered as a serious cerebral vascular disease. Ferroptosis is a novel type of regulated cell death (RCD), that closely related to the occurrence and progress of IS. Loureirin C, a type of dihydrochalcone compound derived from the Chinese Dragon's blood (CDB). The effective components extracted from CDB have shown neuroprotective effects in ischemia reperfusion models. However, the role of Loureirin C in mice after IS is not well understood. Thus, it is worth to identify the effect and mechanism of Loureirin C on IS. PURPOSE: The present research aims to prove the existence of ferroptosis in IS and explore whether Loureirin C can inhibit ferroptosis by regulating nuclear factor E2 related factor 2 (Nrf2) pathway in mice and exert neuroprotective effects on IS models. METHODS: Middle cerebral artery occlusion and reperfusion (MCAO/R) model was established to evaluate the occurrence of ferroptosis and the potential Loureirin C brain-protective effect in vivo. The analysis of free iron, glutamate content, reactive oxygen species (ROS) and lipid peroxidation levels, along with transmission electron microscope (TEM) was applied to prove the existence of ferroptosis. The function of Loureirin C on Nrf2 nuclear translocation was verified by immunofluorescence staining. In vitro, primary neurons and SH-SY5Y cells were processed with Loureirin C after oxygen and glucose deprivation-reperfusion (OGD/R). ELISA kits, western blotting, co-immunoprecipitation (Co-IP) analysis, immunofluorescence, and quantitative real-time PCR were devoted to proving the neuroprotective effects of Loureirin C on IS via regulating ferroptosis and Nrf2 pathways. RESULTS: The results showed that Loureirin C not only dramatically alleviated brain injury and inhibited neurons ferroptosis in mice after MCAO/R, but also dose-dependently reduce ROS accumulation in ferroptosis after OGD/R. Further, Loureirin C inhibits ferroptosis by activating Nrf2 pathway, and promoting nuclear translocation of Nrf2. Besides, Loureirin C increases heme oxygenase 1 (HO-1), quinone oxidoreductase 1 (NQO1) and glutathione peroxidase 4 (GPX4) content after IS. Intriguingly, the anti-ferroptosis effect of Loureirin C is weakened by Nrf2 knockdown. CONCLUSION: Our discoveries first revealed that the inhibitory action of Loureirin C on ferroptosis may greatly depend on its adjusting effect on the Nrf2 pathway, suggesting that Loureirin C could act as a novel anti-ferroptosis candidate and play a therapeutic role in IS. These novel discoveries on the role of Loureirin C on IS models reveal an innovative method that may contribute to neuroprotection for the prevention of IS.

Low-frequency ultrasound irradiation increases paclitaxel-induced sarcoma cells apoptosis and facilitates the transmembrane delivery of drugs.

Sarcoma is a malignant tumor derived from interstitial tissues and requires comprehensive treatment including chemotherapy. Paclitaxel (PTX) is an active agent against sarcoma, but its effect is not sufficiently acceptable and needs to be improved. Low-frequency ultrasound (LFU) has been documented to improve the efficacy of drugs by inducing reversible changes in membrane permeability; however, the effects of the combined use of LFU and PTX for sarcoma tumors remain unclear and warrant further investigation. We investigated the effects of 30 kHz LFU treatment combined with PTX on sarcoma cells A-204 and HT-1080 by analyzing in vitro apoptosis and cell growth inhibition rates, and determined their antitumor effects by examining tumor weights with or without LFU in the S180 sarcoma xenograft model. Drug concentrations in the subcutaneous tumors were measured using high performance liquid chromatography (HPLC). LFU combined with PTX significantly induced cell apoptosis, and blocked the cell cycle of sarcoma cells in G2/M phase, and furthermore, inhibited the activation of JAK2/STAT3 signaling pathway. Meanwhile, LFU combined with PTX inhibited the expression of PD-L1 in vitro, suggesting the potential of enhanced antitumor immunity by this treatment. LFU combined with PTX significantly inhibited the growth of S180 tumors transplanted subcutaneously in Institute of Cancer Research (ICR) mice, and its enhanced effect may be associated with increased local concentrations of PTX in tumor tissues in vivo, with no significant adverse subsequences on body weight observed. We conclude that the combination of LFU and PTX has synergistic antitumor effects and is a candidate for subcutaneous treatment of sarcoma by further increasing the intracellular concentration of PTX.

Establish a New Diagnosis of Sarcopenia Based on Extracted Radiomic Features to Predict Prognosis of Patients With Gastric Cancer.

Background: Preoperative sarcopenia is a prognostic risk factor for gastric cancer (GC). This study aimed to determine whether radiomic sarcopenia features on computed tomography (CT) could be used to diagnose sarcopenia preoperatively, and whether they could be used to accurately predict the postoperative survival and complication prognosis of patients with GC. Methods: We retrospectively analyzed data of 550 patients with GC who underwent radical gastrectomy. The patients were divided into training (2014-2016) and validation (2017-2019) cohorts. We established a radiomics-based diagnosis tool for sarcopenia. Thereafter, univariate and multivariate analyses of diagnostic factors were carried out. Receiver operator characteristic (ROC) curves and area under the curve (AUC) were used to compare different diagnostic models. The Kaplan-Meier method was used to estimate the survival curve. Results: Radiomic sarcopenia correlated with complications and long-term survival. Skeletal muscle index, grip strength, and walking speed were correlated with postoperative complications in both cohorts (AUCs: 0.632, 0.577, and 0.614, respectively in the training cohort; 0.570, 0.605, 0.546, respectively, in the validation cohort), and original sarcopenia was more accurate than any of these indicators. However, radiomic sarcopenia has a higher AUC in predicting short-term complications than original sarcopenia in both groups (AUCs: 0.646 vs. 0.635 in the training cohort; 0.641 vs. 0.625 in the validation cohort). In the training cohort, the overall survival time of patients with original sarcopenia was shorter than normal patients (hazard ratio, HR = 1.741; 95% confidence interval [CI], 1.044-2.903; p = 0.031). While radiomic sarcopenia had a greater prognostic significance, the overall survival time of patients with radiomic sarcopenia was significantly worse than normal patients (HR, 1.880; 95% CI, 1.225-2.885, p = 0.003). Conclusion: Extracted sarcopenia features based on CT can predict long-term survival and short-term complications of GC patients after surgery, and its accuracy has been verified by training and validation groups. Compared with original sarcopenia, radiomic sarcopenia can effectively improve the accuracy of survival and complication prediction and also shorten the time and steps of traditional screening, thereby reducing the subjectivity effects of sarcopenia assessment.

Undifferentiated pleomorphic sarcoma of the extremity and trunk: a retrospective cohort study of 166 cases in a large institution.

Background: An imperative need for better management strategies to improve the survival in patients with undifferentiated pleomorphic sarcoma (UPS). Methods: The retrospective analysis of clinicopathological data of 166 UPS patients, who have undergone surgical treatment in our hospital, was carried out from January 2005 to January 2018. Cox regression model and Kaplan-Meier method were employed to identify the relevant factors affecting the rate of local recurrence (LR), distant metastasis (DM), and overall survival (OS) via univariate and multivariate analysis. The P<0.05 were found to be statistically considerable. Results: At the end of follow-up, the rate of LR, DM and OS in 166 UPS patients was 22.9% (38/166), 32.5% (54/166) and 75.3% (125/166) with a median follow-up time of 55 months. The existing study reveals that the UPS in trunk, tumor size ≥5 cm and R1/R2 resection margin are the prognostic markers of poor survival rate. Women are more susceptible to LR, and R1/R2 resection margin is significantly correlated with a high rate of LR. Old Patients (>60 years), the UPS in trunk and R1/R2 resection margin are susceptible to DM. Conclusions: R0 resection margin was an only independent favorable prognostic factor, which was correlated with LRFS, DMFS, and OS.

Lower Expression of GBP2 Associated With Less Immune Cell Infiltration and Poor Prognosis in Skin Cutaneous Melanoma (SKCM).

Guanylate binding protein 2 (GBP2) could bind to guanine nucleotides (GMP, GDP, and GTP) and exhibits antiviral activity against influenza virus through the innate immune response. Some researchers have demonstrated that the value of GBP2 in predicting the prognosis of multiple cancers and the complex correlation with immune response. However, the correlation of GBP2 to prognosis and immune cell infiltration level were unknown in skin cutaneous melanoma (SKCM). The GBP2 expression in multiple cancers were evaluated through Tumor Immune Estimation Resource (TIMER) and Oncomine. We also evaluated the influence of GBP2 on overall survival in multiple caners through GEPIA, TIMER, and tissue microarray. The correlation between GBP2 expression level and immune cell or gene markers of immune infiltration level was explored on TIMER and GEPIA. Gene set enrichment analysis was performed using the TCGA dataset. The GBP2 expression level represented a significant reduction and the GBP2 expression was lower compared with the SKCM-Metastasis with P<0.01. Lower GBP2 expression was significantly correlated with the poor overall survival of SKCM patients. Simultaneously, higher GBP2 expression predicted the better SKCM-free survival with P=0.019. GBP2 expression was positively correlated with the infiltration cells of B-cell, CD8+ T-cell, CD4+ T-cell, macrophage, neutrophil, and dendritic cell in SKCM. And there was a significant negative correlation between the expression of GBP2 and DNA methylation in the cBioPortal database (P=3.39e-42). Gene set enrichment analysis revealed that GBP2 was closely correlated with multiple pathways of immune response in cancer. In conclusion, Lower expression of GBP2 associated with less immune cell infiltration and poor prognosis in SKCM and the high promoter methylation of GBP2 represented a promising biomarker for poor prognostication in SKCM.

Melanoma Molecular Subtypes and Development of Prognostic and Immunotherapy-Related Genetic Characteristics by Ferroptosis Gene Analysis.

The dissimilarity is a major problem in clinical therapy of skin cutaneous melanoma (SKCM). Objective and reproducible classification systems may help decode SKCM heterogeneity. ConsensusClusterPlus was used to establish a stable immune molecular classification based on ferroptosis-related genes that had been acquired from FerrDb. Moreover, the prognosis, somatic mutations, immune microenvironment characteristics, functional enrichment, and clinical responsiveness to the immune checkpoint blockade of different subtypes in two independent melanin datasets were compared. Kaplan-Meier curves, univariate, multivariate, least absolute contraction, and selection operator (LASSO) Cox regression analysis were used to develop a molecular model for predicting survival, which was verified by a nomogram on the basis of independent prognostic indicators. Two molecular subtypes (C1 and C2) for SKCM were first identified according to ferroptosis-related genes; C1 showed a poor prognosis, with lower infiltration degree of immune cells and TIED score and higher homologous recombination defects, fraction altered, the number of segments, and copy number amplification and deletion. These characteristics of C2 were the opposite of C1. A ferroptosis-related prognosis risk score (FPRS) model was constructed using 6 of 463 genes with differential expression between C1 and C2. This model splits patients into low- and high-risk cohorts. There were significant differences in the infiltration and proportion of immune cells, immune checkpoint gene expression, responsiveness to immune checkpoint therapy, and sensitivity to chemotherapeutic medications between low- and high-risk cohorts. This model was an independent prognostic marker for SKCM and has a high AUC. In summary, we have identified two subtypes of SKCM with different molecular and immune characteristics on the basis of ferroptosis-related genes and further developed and verified an FPRS model, which might independently serve as a prognostic marker for SKCM.

CNPY4 inhibits the Hedgehog pathway by modulating membrane sterol lipids.

The Hedgehog (HH) pathway is critical for development and adult tissue homeostasis. Aberrant HH signaling can lead to congenital malformations and diseases including cancer. Although cholesterol and several oxysterol lipids have been shown to play crucial roles in HH activation, the molecular mechanisms governing their regulation remain unresolved. Here, we identify Canopy4 (CNPY4), a Saposin-like protein, as a regulator of the HH pathway that modulates levels of membrane sterol lipids. Cnpy4-/- embryos exhibit multiple defects consistent with HH signaling perturbations, most notably changes in digit number. Knockdown of Cnpy4 hyperactivates the HH pathway in vitro and elevates membrane levels of accessible sterol lipids, such as cholesterol, an endogenous ligand involved in HH activation. Our data demonstrate that CNPY4 is a negative regulator that fine-tunes HH signal transduction, revealing a previously undescribed facet of HH pathway regulation that operates through control of membrane composition.

Correlation Between Components of Malnutrition Diagnosed by Global Leadership Initiative on Malnutrition Criteria and the Clinical Outcomes in Gastric Cancer Patients: A Propensity Score Matching Analysis.

Objective: Malnutrition is recognized as a risk factor for poor outcome in patients with gastric cancer (GC). In 2018, the Global Leadership Initiative on Malnutrition (GLIM) published standardized criteria for the diagnosis of malnutrition. Our aim was to investigate whether any of the components of the GLIM diagnostic criteria were related to worse clinical outcomes in patients with GC. Methods: This study analyzed patients with GC who underwent radical gastrectomy in our hospital between 2014 and 2019. A preoperative nutritional assessment was performed for each patient. Matching was based on the presence of three GLIM components: high weight loss (WL), low body mass index (BMI), and low skeletal muscle index (SMI). Results: The analysis included 1,188 patients, including 241 (20.3%) with high WL, 156 (13.1%) with low BMI, and 355 (29.9%) with low SMI. Before matching, patients who met the GLIM component criteria were mostly associated with older age, low nutritional reserves, and late tumor progression. After matching, the clinical characteristics of the three cohorts were balanced. In the matched queue, the survival prognosis of the high WL group was worse than that of the non-WL group, and the postoperative complication rate was higher in the low SMI group than in the normal SMI group (P <0.05). In addition, the clinical outcomes in the low and normal BMI groups were similar (P >0.05). Conclusion: Of the GLIM criteria, high WL and low SMI may be associated with poor clinical outcomes in patients with GC, while a low BMI may not be associated with outcome.

Effect of Short-Term Preoperative Parenteral Nutrition Support for Gastric Cancer Patients with Sarcopenia: a Propensity Score Matching Analysis.

INTRODUCTION: Sarcopenia is well recognized as an unfavorable prognostic marker for gastric cancer (GC) patients. Currently, few nutritional interventions-such as parenteral nutrition-exist for the treatment of patients with sarcopenia. This study aimed to estimate the effectiveness of short-term preoperative parenteral nutrition (PN) in GC patients with sarcopenia. MATERIALS AND METHODS: We collected data on GC patients with sarcopenia who underwent radical gastrectomy at our hospital from 2010 to 2018. A 1:1 ratio propensity score matching (PSM) was applied to establish the PN and control groups. Data were analyzed using the chi-squared, Mann-Whitney U, and Fisher's exact tests. RESULTS: In total, 428 patients met the inclusion criteria, and the propensity scores identified 166 matched pairs of patients with sarcopenia. The overall incidence of postoperative complications between both groups was not significantly different (P = 0.728). The PN group had a lower rate of intra-abdominal infection (P = 0.032) and higher hospitalization costs (P < 0.001) than the control group. Multivariate analysis demonstrated that age, Charlson score, and TNM stage were independent risk factors for postoperative complications. Additionally, subgroup analysis revealed that short-term preoperative PN support is associated with decreased postoperative surgical complications in patients with albumin levels < 35 g/L (P = 0.025). CONCLUSION: Short-term preoperative PN support is not associated with reduction of overall complication rate in patients with GC and sarcopenia. However, those with sarcopenia and hypoalbuminemia benefited from preoperative PN support.

Comparison of the clinical outcomes of percutaneous kyphoplasty for the management of osteolytic and osteoblastic-related metastatic vertebral lesions.

OBJECTIVE: To retrospectively compare the clinical efficacy and safety of percutaneous kyphoplasty (PKP) for the management of osteolytic and osteoblastic-related metastatic vertebral lesions. METHODS: A total of 117 patients with osteolytic (87 cases, 159 lesions, OL group) or osteoblastic-related (30 cases, 56 lesions, OB group) metastatic vertebral lesions underwent PKP. The clinical efficacy was assessed based on parameters including Visual Analog Scale (VAS), Oswestry Disability Index (ODI), vertebral body height (VBH) variation, and quality of life (QoL). Major and minor complications were systematically evaluated to assess the safety of the procedure. RESULTS: No significant differences were found in the age, sex, or amount of bone cement between both groups (p>0.05). Compared with the OB group, the OL group was superior in operation duration (p<0.05) but was inferior in inflation pressure (p<0.05). Both groups experienced significant pain relief and improvement in the ODI, VBH, and QoL after PKP (p<0.05). The OB group had a better pain relief according to the VAS score but a poorer VBH restoration than the OL group throughout the follow-up period (p<0.05). No significant differences were observed in ODI and QoL between the two groups (p>0.05). The incidence of complications in the OL group was significantly higher than that in the OB group (p<0.05). CONCLUSIONS: PKP can safely achieve pain relief, functional improvement, VBH restoration, and QoL improvement for patients with osteolytic or osteoblastic-related metastatic vertebral lesions. Patients with osteolytic metastatic vertebral lesions showed better VBH restoration and had a shorter operation time but experienced less pain relief and had a greater incidence of complications than patients with osteoblastic-related metastatic vertebral lesions after PKP.

Impact of malnutrition diagnosed using Global Leadership Initiative on Malnutrition criteria on clinical outcomes of patients with gastric cancer.

OBJECTIVE: Our objective is to validate the effectiveness of the Global Leadership Initiative on Malnutrition (GLIM) criteria in malnutrition diagnosis compared with Patient-Generated Subjective Global Assessment (PG-SGA) and assess the impact of malnutrition diagnosed using GLIM criteria on the clinical outcomes of patients with GC. METHODS: We retrospectively analyzed the data of 895 patients who underwent radical gastrectomy at the First Affiliated Hospital of Wenzhou Medical University. Nutrition assessment was performed on all patients according to the GLIM criteria and PG-SGA. The κ statistic was used to evaluate the agreement between two methods. Multivariate logistic regression and Cox regression based on single-factor analysis were used to predict postoperative complications and overall survival rates. RESULTS: Based on the GLIM criteria, 38.3% of the patients were diagnosed as malnourished, including 21.7% Stage I (moderate malnutrition) and 16.6% Stage II (severe malnutrition). GLIM criteria had a moderate agreement with PG-SGA (κ = 0.548). Patients in the Stage II malnutrition group had a higher incidence of complications, a longer postoperative length of stay, and higher hospitalization costs. Logistic regression showed that Stage II malnutrition was an independent risk predictor of postoperative complications (odds ratio, 3.28; 95% confidence interval [CI], 2.18-4.94). Furthermore, Cox regression analysis showed that both Stage I (hazard ratio [HR], 1.52; 95% CI, 1.11-2.07; P = .009) and Stage II (HR, 1.85; 95% CI, 1.34-2.53; P < .001) malnutrition were independent risk predictors of overall survival. CONCLUSION: Diagnosis of malnutrition according to the GLIM criteria is useful in predicting the adverse postoperative clinical outcomes of patients with gastric cancer.