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The mechanisms underlying stimuli-induced dynamic structural remodeling of RNAs for the maintenance of cellular physiological function and survival remain unclear. Here, we showed that in MGMT promoter-methylated glioblastoma (GBM), the RNA helicase DEAD-box helicase 46 (DDX46) is phosphorylated by temozolomide (TMZ)-activated checkpoint kinase 1 (CHK1), resulting in a dense-to-loose conformational change and an increase in DDX46 helicase activity. DDX46-mediated tertiary structural remodeling of LINC01956 exposes the binding motifs of LINC01956 to the 3' untranslated region of O 6 -methylguanine DNA methyltransferase ( MGMT ). This accelerates recruitment of MGMT mRNA to the RNA export machinery and transportation of MGMT mRNA from the nucleus to the cytoplasm, leading to increased MGMT abundance and TMZ resistance. Using patient-derived xenograft (PDX) and tumor organoid models, we found that treatment with the CHK1 inhibitor SRA737abolishes TMZ-induced structural remodeling of LINC01956 and subsequent MGMT up-regulation, resensitizing TMZ-resistant MGMT promoter-methylated GBM to TMZ. In conclusion, these findings highlight a mechanism underlying temozolomide-induced RNA structural remodeling and may represent a potential therapeutic strategy for patients with TMZ-resistant MGMT promoter-methylated GBM.

Background and Aim: Although various randomized controlled trials (RCTs) have evaluated the effect of raloxifene on apolipoproteins and lipoprotein(a) concentrations in postmenopausal women, the results have been inconsistent and inconclusive. Therefore, we conducted this meta-analysis of RCTs to investigate the effect of raloxifene administration on apolipoproteins and lipoprotein(a) [Lp(a)] concentrations in postmenopausal women., Methods: Two independent researchers systematically searched the scientific literature (including PubMed/Medline, Scopus, Web of Science, and EMBASE) for English-language randomized controlled trials (RCTs) published up to June 2024. We included RCTs reporting the impact of raloxifene on apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB), and Lp(a) levels in postmenopausal women. The primary outcome of interest was change in Lp(a), and the secondary outcomes were changes in ApoA-I and ApoB., Findings: The present meta-analysis incorporated 12 publications with 14 RCT arms. The comprehensive outcomes derived from the random-effects model revealed a statistically significant increase in ApoA-I (WMD: 6.06 mg/dL, 95% CI: 4.38, 7.75, P < 0.001) and decrease in ApoB concentrations (WMD: -8.48 mg/dL, 95% CI: -10.60, -6.36, P < 0.001) and Lp(a) (WMD: -3.02 mg/dL, 95% CI: -4.83, -1.21, P < 0.001) following the administration of raloxifene in postmenopausal women. In the subgroup analyses, the increase in ApoA-I and the decrease in ApoB and Lp(a) levels were greater in RCTs with a mean participant age of ≥60 years and a duration of ≤12 weeks., Implications: The current meta-analysis of RCTs demonstrates that treatment with raloxifene reduces ApoB and Lp(a) levels while increasing ApoA-I levels in postmenopausal women. Since these effects on lipid components are associated with a reduced risk of cardiovascular disease (CVD), raloxifene could be a suitable therapy for postmenopausal women who are at an increased risk of CVD and have other medical indications for raloxifene administration., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: The consistent use of metformin has been linked to a reduced incidence of neoplastic diseases among diabetic populations. As a preventive intervention, metformin may offer a more favorable risk-benefit profile. Here, we explored the efficacy of metformin in the primary prevention of cholangiofibrosis, which can precede the carcinogen-induced development of cholangiocarcinoma (CCA). Our objective was to assess the potential of metformin to act as an intervention prior to the onset of these conditions., Methods: A rat model of thioacetamide (TAA)-induced cholangiofibrosis was utilized to assess the impact of metformin on the induction process of cholangiocarcinoma (CCA). Liver tissues were harvested and analyzed histologically using light microscopy, complemented by a deep-learning convolutional neural network for enhanced evaluation. Additionally, RNA sequencing (RNA-seq) was performed to investigate the genetic alterations associated with metformin treatment in this TAA-induced cholangiofibrosis model., Results: In the rat model, the TAA control group exhibited an increased incidence and average count of cholangiofibrosis cases in the liver, with rates of 100 % and an average of 12.0, compared to the metformin-treated group, which showed an incidence of 70 % and an average of 3.3. Notably, the progression from normal cholangioles to cholangiofibrosis was associated with the upregulation of several proteins critical for metabolic processes and the tumor microenvironment. These alterations were significantly mitigated by metformin treatment., Conclusions: Long-term metformin use may offer protective benefits against cholangiofibrosis, partially by regulating metabolic processes and improving the tumor microenvironment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Facing complex and variable emerging antibiotic pollutants, the traditional development of functional materials is a "trial-and-error" process based on physicochemical principles, where laborious steps and long timescales make it difficult to accelerate technical breakthroughs. Notably, natural biomolecular coronas derived from highly tolerant organisms under significant contamination scenarios can be used in conjunction with nanotechnology to tackling emerging contaminants of concern. Here, super worms ( Tubifex tubifex ) with high pollutant tolerance were integrated with nano-zero valent iron (nZVI) to effectively reduce the content of 17 antibiotics in wastewater within 7 d. Inspired by the synergistic remediation, nZVI-augmented worms were constructed as biological nanocomposites. Neither nZVI (0.3 to 3 g/L) nor worms (10 4 to 10 5 per liter) alone efficiently degraded florfenicol (FF, as a representative antibiotic), while their composite removed 87% of FF (3 μmol/L). Under antibiotic exposure, biomolecules secreted by worms formed a corona on and modified the nZVI particle surface, enabling the nano-bio interface greater functionality, including responsiveness, enrichment, and reduction. Mechanistically, FF exposure activated glucose-alanine cycle pathways that synthesize organic acids and amines as major metabolites, which were assembled into vesicles and secreted, thereby interacting with nZVI in a biologically response design strategy. Lactic acid and urea formed hydrogen bonds with FF, enriched analyte presence at the heterogeneous interface. Succinic and lactic acids corroded the nZVI passivation layer and promoted electron transfer through surface conjugation. This unique strategy highlights biomolecular coronas as a complex resource to augment nano-enabled technologies and will provide shortcuts for rational manipulation of nanomaterial surfaces with coordinated multifunctionalities., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Middle-aged and elderly individuals are the most susceptible groups for metabolic diseases, with their dietary behaviors being significant influencing factors. Exploring the association between overall dietary behaviors and obesity metabolic phenotypes is crucial for early prevention and control of chronic diseases, precision treatment and personalized interventions., Methods: We conducted a cross-sectional study of 15,160 middle-aged and older adults between June 2019 and August 2021 to collect information on their body mass index (BMI), biochemical indices and disease history. The population was classified into four categories by the criteria of obesity metabolic phenotypes: metabolically healthy non-obesity (MHNO), metabolically unhealthy non-obesity (MUNO), metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). Scores were calculated based on compliance with healthy eating behavior patterns (appropriate or light dietary taste, moderately soft and hard food, slightly hot food temperature, medium or slow eating speed, daily intake of dietary supplements and eating with others), and the population was categorized into subgroups 0-2 (did not meet and met only 1 or 2), 3-4 (met 3 or 4), 5-6 (met 5 or 6). The relationship between dietary behavior patterns and different obesity metabolic phenotypes in middle-aged and elderly people were analyzed by multi-categorical logistic regression model., Results: Compared with the 5-6 subgroup, the dietary behavior patterns of 0-2 and 3-4 scores were risk factors for MUNO, MHO and MUO (P < 0.05), and the lower the scores of the dietary behavior patterns, the higher the multiplicity of the occurrence of MUNO, MHO and MUO, especially for females and adults between 45-60 years old. Appropriate or light dietary taste, moderately soft and hard food, and slightly hot food temperature were protective factors for MUNO and MUO (P < 0.05); medium or slow eating speed and daily intake of dietary supplements were protective factors for MUNO, MHO and MUO (P < 0.05)., Conclusion: Dietary behavior patterns in middle-aged and older adults are associated with different obesity metabolic phenotypes, and healthy dietary behaviors may be beneficial for the prevention and control of MUNO, MHO and MUO., (© 2024. The Author(s).)

Purpose: Microvascular invasion (MVI) is a major unfavorable prognostic factor for intrahepatic metastasis and postoperative recurrence of hepatocellular carcinoma (HCC). However, the intervention and preoperative prediction for MVI remain clinical challenges due to the absent precise mechanism and molecular marker(s). Herein, we aimed to investigate the mechanisms underlying vascular invasion that can be applied to clinical intervention for MVI in HCC., Experimental Design: The histopathologic characteristics of clinical MVI+/HCC specimens were analyzed using multiplex immunofluorescence staining. The liver orthotopic xenograft mouse model and mechanistic experiments on human patient-derived HCC cell lines, including coculture modeling, RNA-sequencing, and proteomic analysis, were used to investigate MVI-related genes and mechanisms., Results: IQGAP3 overexpression was correlated significantly with MVI status and reduced survival in HCC. Upregulation of IQGAP3 promoted MVI+-HCC cells to adopt an infiltrative vessel co-optive growth pattern and accessed blood capillaries by inducing detachment of activated hepatic stellate cells (HSC) from the endothelium. Mechanically, IQGAP3 overexpression contributed to HCC vascular invasion via a dual mechanism, in which IQGAP3 induced HSC activation and disruption of the HSC-endothelial interaction via upregulation of multiple cytokines and enhanced the trans-endothelial migration of MVI+-HCC cells by remodeling the cytoskeleton by sustaining GTPase Rac1 activity. Importantly, systemic delivery of IQGAP3-targeting small-interfering RNA nanoparticles disrupted the infiltrative vessel co-optive growth pattern and reduced the MVI of HCC., Conclusions: Our results revealed a plausible mechanism underlying IQGAP3-mediated microvascular invasion in HCC, and provided a potential target to develop therapeutic strategies to treat HCC with MVI., (©2024 American Association for Cancer Research.)

The mechanisms underlying the dynamic remodelling of cellular membrane phospholipids to prevent phospholipid peroxidation-induced membrane damage and evade ferroptosis, a non-apoptotic form of cell death driven by iron-dependent lipid peroxidation, remain poorly understood. Here we show that lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a critical role in ferroptosis resistance by increasing membrane phospholipid saturation via the Lands cycle, thereby reducing membrane levels of polyunsaturated fatty acids, protecting cells from phospholipid peroxidation-induced membrane damage and inhibiting ferroptosis. Furthermore, the enhanced in vivo tumour-forming capability of tumour cells is closely associated with the upregulation of LPCAT1 and emergence of a ferroptosis-resistant state. Combining LPCAT1 inhibition with a ferroptosis inducer synergistically triggers ferroptosis and suppresses tumour growth. Therefore, our results unveil a plausible role for LPCAT1 in evading ferroptosis and suggest it as a promising target for clinical intervention in human cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Nutrition and exercise are important interventions for sarcopenia. There were few studies on oral oligopeptide nutrition preparations combined with exercise to intervene in the older people with sarcopenia. The aim of this study was to verify the effectiveness of oligopeptide nutrition preparation combined with exercise intervention on the older people with sarcopenia in community., Methods: A total of 219 subjects aged 65 years or older with sarcopenia were randomly divided into 4 groups. The nutrition group (n = 58) was given individualized nutrition education and oral oligopeptide nutrition preparation. The exercise group (n = 50) received exercise intervention. The combined group (n = 52) received both oral nutrition preparation and exercise interventions. The control group (n = 59) only received individualized nutrition education. The nutrition preparation can provide energy 185kcal and protein 24.2g per day. The exercise intervention including warm-up exercise, resistance exercise and aerobic exercise, the training time was 60min for 5 times every week. The intervention lasted for 16 weeks. Hand grip strength, gait speed, body composition and hematology parameters were measured before and after intervention., Results: A total of 159 subjects completed the study. Compared with baseline, the left grip strength and 6-m walking speed of the subjects in nutrition group increased significantly after the intervention, and the grip strength of both hands in exercise group and combined group increased significantly. The body weight of the subjects in nutrition group, exercise group and combined group increased significantly after intervention, but no increase in soft lean mass (SLM) and skeletal muscle mass (SMM) was observed in any of the four groups. The fat-free mass (FFM) of the legs of the control group, exercise group and nutrition group decreased after intervention, and only the FFM of the legs of the combined group maintained the level before the intervention., Conclusion: Both oral peptide nutrition and exercise interventions can improve the muscle strength or function of the older people with sarcopenia. However, there were no increases in muscle mass observed., Trial Registration: ChiCTR, ChiCTR2100052135. Registered 20 October 2021, https://www.chictr.org.cn/showproj.html?proj=135743., (© 2024. The Author(s).)

The effect of low-FODMAPs diet on irritable bowel syndrome (IBS) in Western China has not been reported. We aimed to investigate the effect of low-FODMAPs diet on IBS patients in the area and whether low-FODMAPs diet-induced alterations of microbiota could be improved through probiotics. IBS patients were randomized to the control group, low-FODMAPs diet group, probiotics group, or combined group. IBS Symptom Severity Score questionnaire (IBS-SSS) and IBS Quality of Life Score questionnaire (IBS-QOL) were completed at baseline, 2 and 4 weeks to evaluate the severity of symptoms. Fresh feces were collected for analyses of gut microbiota and short-chain fatty acids at baseline and 4 weeks after intervention. Seventy-three patients were included in the per protocol analysis. After intervention, there was significant improvement in IBS-SSS in the low-FODMAPs group (37.5%, 44.2%), probiotics group (51.4%, 62.0%), and combined group (34.1%, 40.4%) at both 2 weeks and 4 weeks, compared with the baseline ( p  < .05). In the low-FODMAPs group, the abundance of several microbiota ( Lachnoclostridium , Enterococcus , etc.) was significantly decreased. Furthermore, after the supplementation of probiotics in the combined group, the abundance of Genus&#95; Ruminococcus , Coprococcus , Acidaminococcus , Ruminiclostridium , Akkermansia , Eggerthella , and Oxalobacter was significantly increased, which was associated with the improvements of symptoms score in the Pearson correlation analysis. Our study confirmed the effectiveness and safety of short-term low-FODMAPs diet in IBS symptoms based on the Chinese diet in Western China. The combination of low-FODMAPs and probiotics plays a beneficial role in gut microbiota in IBS., Competing Interests: None., (© 2024 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Loss of Protocadherin 9 (PCDH9) is associated with the metastasis and the prognosis of gastric cancer patients, while the molecular mechanism of PCDH9-impaired gastric cancer metastasis remains unclear. Here we show that PCDH9 is cleaved in gastric cancer cells. Intracellular domain of PCDH9 translocates into nucleus, where it interacts with DNA methyltransferase 1 (DNMT1) and increases DNMT1 activity. Activated DNMT1 downregulates cadherin 2 ( CDH2 ) expression by increasing DNA methylation at its promoter, thereby dampening the migration and in vivo metastasis of gastric cancer cells. In addition, the levels of nuclear PCDH9 correlate with CDH2 expression, lymph node metastasis, and the prognosis of gastric cancer patients. Our finding demonstrates a unique mechanism of nuclear PCDH9-impaired gastric cancer metastasis by promoting DNA methylation of CDH2 promoter., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

The bone is the most common site of distant metastasis of breast cancer, which leads to serious skeletal complications and mortality. Understanding the mechanisms underlying breast cancer bone metastasis would provide potential strategies for the prevention and treatment of breast cancer bone metastasis. In this study, we identified a circular RNA that we named circMMP2(6,7) that was significantly upregulated in bone metastatic breast cancer tissues and correlated with breast cancer-bone metastasis. Upregulation of circMMP2(6,7) dramatically enhanced the metastatic capability of breast cancer cells to the bone via inducing bone metastatic niche formation by disrupting bone homeostasis. Mechanistically, circMMP2(6,7) specifically bound to the promoters of bone-remodeling factors calcium-binding protein S100A4 and carbohydrate-binding protein LGALS3 and formed a complex with β-catenin and arginine methyltransferase PRMT5, eliciting histone H3R2me1/H3R2me2s-induced transcriptional activation. Treatment with GSK591, a selective PRMT5 inhibitor, effectively inhibited circMMP2(6,7)/β-catenin/PRMT5 complex-induced breast cancer bone metastasis. These findings reveal a role for circMMP2(6,7) in bone homeostasis disruption and shed light on the mechanisms driving breast cancer bone metastasis., Significance: Upregulation of bone-remodeling factors S100A4 and LGALS3 mediated by a circMMP2(6,7)/β-catenin/PRMT5 complex generates a niche that supports breast cancer bone metastasis, identifying PRMT5 as a promising target for treating metastasis., (©2023 American Association for Cancer Research.)

Background: Histone lysine lactylation (Kla) is a newly identified histone modification, which plays a crucial role in cancer progression. Hence, we determined the prognostic value of Kla in breast cancer (BC)., Methods: We obtained RNA expression profiles of BC from The Cancer Genome Atlas (TCGA), following screening out Kla-specific genes. Furthermore, we determined the prognostic value of Kla by constructing a cox model based on Kla-specific genes. Subsequently, we identified expression of lactate accumulation-related genes and prognostic Kla-specific genes through Human Protein Atlas (HPA), and further performed a correlation analysis based on their expression. Meanwhile, we explored the effects of Kla on BC tumor microenvironment (TME), drug therapy and immunotherapy. Moreover, we predicted the pathways influenced by Kla via gene set enrichment analysis (GSEA)., Results: A total of 1073 BC samples and 112 normal controls were obtained from TCGA, and 23 tumor samples were removed owing to inadequate clinical information. We identified 257 differentially expressed Kla-specific genes (DEKlaGs) in BC. A cox model involved with CCR7, IGFBP6, NDUFAF6, OVOL1 and SDC1 was established, and risk score could be visualized as an independent biomarker for BC. Meanwhile, Kla was remarkably associated with BC immune microenvironment, drug therapy and immunotherapy. Kla was identified to be related to activation of various BC-related KEGG pathways., Conclusion: In conclusion, Kla contributes to drug resistance and undesirable immune responses, and plays a crucial role in BC prognosis, suggesting that Kla was expected to be a new therapeutic target for BC., (© 2023. The Author(s).)

Serine/arginine-rich splicing factor 7 (SRSF7), a known splicing factor, has been revealed to play oncogenic roles in multiple cancers. However, the mechanisms underlying its oncogenic roles have not been well addressed. Here, based on N 6 -methyladenosine (m 6 A) co-methylation network analysis across diverse cell lines, we find that the gene expression of SRSF7 is positively correlated with glioblastoma (GBM) cell-specific m 6 A methylation. We then indicate that SRSF7 is a novel m 6 A regulator, which specifically facilitates the m 6 A methylation near its binding sites on the mRNAs involved in cell proliferation and migration, through recruiting the methyltransferase complex. Moreover, SRSF7 promotes the proliferation and migration of GBM cells largely dependent on the presence of the m 6 A methyltransferase. The two m 6 A sites on the mRNA for PDZ-binding kinase (PBK) are regulated by SRSF7 and partially mediate the effects of SRSF7 in GBM cells through recognition by insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). Together, our discovery reveals a novel role of SRSF7 in regulating m 6 A and validates the presence and functional importance of temporal- and spatial-specific regulation of m 6 A mediated by RNA-binding proteins (RBPs)., (Copyright © 2023 Beijing Institute of Genomics. Published by Elsevier B.V. All rights reserved.)

Rationale: Hyperparathyroidism is caused by parathyroid tumors combined with gastroenteropancreatic tumors and pituitary tumors, which is common in patients with multiple endocrine neoplasia 1 syndrome (MEN-1). As its main pathogenic factor involves genetic mutations, it can cause a variety of different clinical symptoms. However, cases with negative genetic testing results and multiple nonfunctional malignant neuroendocrine tumors (NETs) with metastasis are relatively rare., Patient Concerns: A 33-year-old man was admitted to the hospital for hyperparathyroidism. Imaging examination revealed multiple nodules in the parathyroid gland, pancreas, thymus, and adrenal gland, and multiple metastases to the lung, liver, thoracolumbar, as well as mediastinal lymph nodes., Diagnoses: After multidisciplinary consultation, this patient was diagnosed with MEN-1 syndrome with various original tumors and multiple systemic metastases., Interventions: The patient underwent parathyroid tumor resection and metastasis biopsy., Outcomes: The patient received denosumab and sorafenib treatment., Lessons: As an autosomal dominant hereditary disease, MEN-1 patients present with parathyroid hyperplasia, pancreatic and intestinal tumors, pituitary tumors, and so on, which are caused by genetic mutations. These patients would have hyperparathyroidism, hypoglycemia, gastric ulcer, and gastrointestinal diseases. However, some patients with MEN-1 syndrome cannot be diagnosed by genetic testing and simultaneously present with multiple nonfunctional NETs with systemic metastasis. This increases the difficulty of diagnosis and the subsequent treatment., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

The chemoresistance of temozolomide-based therapy is a serious limitation for lasting effective treatment of gliomas, while the underlying mechanisms remain unclear. In this study, we showed that downregulation of BASP1 correlated negatively with the response to temozolomide therapy and disease-free survival (DFS) of patients with gliomas. Silencing BASP1 significantly enhanced the temozolomide resistance of glioma cells both in vitro and in vivo through repair of temozolomide-induced DNA damage via activation of the FBXO32/NF-κB/MGMT axis in both MGMT-methylated and -unmethylated gliomas. We demonstrated that loss of BASP1 resulted in removal of TRIM37/EZH2 complex-induced repressive histone modifications, including H2A-ub and H3K27me3, but addition of WDR5/MLL complex-mediated active histone modifications, including H3K4me3 and H3K9ac, on the FBXO32 promoter, which elicited in FBXO32 upregulation and further activated NF-κB/MGMT signaling via ubiquitin-dependent degradation of IκBα. Importantly, treatment with OICR-9429, an antagonist of the WDR5-MLL interaction, impaired the FBXO32/NF-κB/MGMT axis-mediated repair of temozolomide-induced DNA damage, leading to significant apoptosis of BASP1-downregulated glioma cells. These findings shed light on the molecular mechanism underlying BASP1-mediated epigenetic transcriptional repression and may represent a potential strategy in the fight against temozolomide-resistant gliomas., Implications: BASP1 downregulation promotes temozolomide resistance in gliomas through WDR5/MLL complex-mediated epigenetic activation of the FBXO32/NF-κB/MGMT axis, providing new target for improving outcomes in patients with temozolomide-resistant gliomas., (©2023 American Association for Cancer Research.)

Aberrant lipid metabolism mediated by the selective transport of fatty acids plays vital roles in cancer initiation, progression, and therapeutic failure. However, the biological function and clinical significance of abnormal fatty acid transporters in human cancer remain unclear. In the present study, we reported that solute carrier family 27 member 4 (SLC27A4) is significantly overexpressed in 21 types of human cancer, especially in the fatty acids-enriched microenvironment surrounding hepatocellular carcinoma (HCC), breast cancer, and ovarian cancer. Upregulated SLC27A4 expression correlated with shorter overall and relapse-free survival of patients with HCC, breast cancer, or ovarian cancer. Lipidomic analysis revealed that overexpression of SLC27A4 significantly promoted the selective uptake of mono-unsaturated fatty acids (MUFAs), which induced a high level of MUFA-containing phosphatidylcholine and phosphatidylethanolamine in HCC cells, consequently resulting in resistance to lipid peroxidation and ferroptosis. Importantly, silencing SLC27A4 significantly promoted the sensitivity of HCC to sorafenib treatment, both in vitro and in vivo. Our findings revealed a plausible role for SLC27A4 in ferroptosis defense via lipid remodeling, which might represent an attractive therapeutic target to increase the effectiveness of sorafenib treatment in HCC., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Heatstroke is a life-threatening illness involving extreme hyperthermia and multi-organ failure, and it is associated with high mortality. The immune profiles of heatstroke have not been fully elucidated, and diagnostic and prognostic biomarkers of heatstroke are lacking. This study will analyze immune profiles in heatstroke patients as they differ from profiles in patients with sepsis or aseptic inflammation patients in order to identify diagnostic and prognostic biomarkers., Methods: This exploratory, case-control study will recruit patients with heatstroke, patients with sepsis, patients undergoing cardiopulmonary bypass as well as healthy controls at West China Hospital of Sichuan University from 1 January 2023 to 31 October 2023. The four cohorts will be profiled at one time point in terms of lymphocytes, monocytes, natural killer cells, and granulocytes using flow cytometry, and cell populations will be visualized in two dimensions using t-SNE and UMAP, then clustered using PhenoGraph and FlowSOM. Gene expression in the specific immune cell populations will also be compared across the four cohorts, as will levels of plasma cytokines using enzyme-linked immunosorbent assays. Outcomes in the cohorts will be monitored during 30-day follow-up., Discussion: This trial is, to our knowledge, the first attempt to improve the diagnosis of heatstroke and prediction of prognosis based on immune cell profiles. The study is also likely to generate new insights into immune responses during heatstroke, which may help clarify the disease process and lay the foundation for immunotherapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Yang, Wang, Wu, Liao, Yao and Du.)

Background: The COVID-19 pandemic has become a serious public health concern for older adults and amplified the value of deploying telehealth solutions. The purpose of this study was to investigate telehealth offered by providers among U.S. Medicare beneficiaries aged 65 years and older during the COVID-19 pandemic., Methods: This cross-sectional study analyzed Medicare beneficiaries aged 65 years and older using data from the Medicare Current Beneficiary Survey, Winter 2021 COVID-19 Supplement ([Formula: see text]). We identified variables that were associated with telehealth offered by primary care physicians and beneficiaries' access to the Internet through a multivariate classification analysis utilizing Random Forest machine learning techniques., Findings: For study participants interviewed by telephone, 81.06% of primary care providers provided telehealth services, and 84.62% of the Medicare beneficiaries had access to the Internet. The survey response rates for each outcome were 74.86% and 99.55% respectively. The two outcomes were positively correlated ([Formula: see text]). The Our machine learning model predicted the outcomes accurately utilizing 44 variables. Residing area and race/ethnicity were most informative for predicting telehealth coverage, and Medicare-Medicaid dual eligibility and income were most informative for predicting Internet access. Other strong correlates included age, ability to access basic needs and certain mental and physical health conditions. Interactions were found among statuses of residing area, age, Medicare Advantage and heart conditions that intensified the disparity of outcomes., Conclusions: We found that telehealth offered by providers likely increased during the COVID-19 pandemic for older beneficiaries, providing important access to care for certain subgroups. Policymakers must continue to identify effective means of delivering telehealth services, modernize the framework of regulatory, accreditation and reimbursement, and address disparities in access to telehealth with a particular focus on underserved communities., (© 2023. The Author(s).)

In this study, MnCl 2 -impregnated biomass was oxygen-limited pyrolyzed to produce manganese oxide-loaded biochar (MBC), its adsorption behaviors and influencing factors on tetracycline (TTC), norfloxacin (NOR), and sulfamethoxazole (SMX) were systematically investigated. Three antibiotics exhibited enhanced adsorption behavior on MBC, with maximum adsorption capacity as accurately described by Sips isotherm: TTC (534 mg/g) > NOR (67 mg/g) > SMX (28 mg/g). Hydrogen bonding, n/π-π interactions, electrostatic interaction, surface coordination, and hydrophobic interaction are the major mechanisms for the improved adsorption. Manganese oxide particles on MBC promoted surface coordination and hydrogen bonding. Antibiotic molecules with more hydroxyl oxygen-containing functional groups are more susceptible to migrate to biochar surfaces and to be adhered. Moreover, the quantitative structure-property relationship (QSPR) model was constructed and revealed that hydrogen bonding and π-π interactions were crucial for tetracycline antibiotics selective adsorption. Hence, MBC was a prospective adsorbent with promising applications for antibiotic removal in sewage processing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Tumor-derived extracellular vesicles (EVs) function as critical mediators in selective modulation of the microenvironment of distant organs to generate a pre-metastatic niche that facilitates organotropic metastasis. Identifying the organ-specific molecular determinants of EVs can develop potential anti-metastatic therapeutic targets. In the current study, large oncosomes (LOs), atypically large cancer-derived EVs, are found to play a crucial role in facilitating bone-tropic metastasis of hepatocellular carcinoma (HCC) cells by engineering an osteoclastic pre-metastatic niche and establishing a vicious cycle between the osteoclasts and HCC cells. Transmembrane protein, VAMP-associated protein A (VAPA), is significantly enriched on LOs surface via direct interaction with LOs marker αV-integrin. VAPA-enriched LOs-induced pre-metastatic education transforms the bone into a fertile milieu, which supports the growth of metastatic HCC cells. Mechanically, LOs-delivered VAPA integrates to plasma membrane of osteoclasts and directly interacts with and activates neural Wiskott-Aldrich syndrome protein (N-WASP) via dual mechanisms, consequently resulting in ARP2/3 complex-mediated reorganization of actin cytoskeleton in osteoclasts and osteoclastogenesis. Importantly, treatment with N-WASP inhibitor 187-1-packaged LOs (LOs/187-1) dramatically abolishes the inductive effect of VAPA-enriched LOs on pre-metastatic niche formation and precludes HCC bone metastasis. These findings reveal a plausible mechanism for bone-tropism of HCC and can represent a potential strategy to prevent HCC bone metastasis., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: The coronavirus disease 2019 (COVID-19) public health emergency has amplified the potential value of deploying telehealth solutions. Less is known about how trends in access to care through telehealth changed over time., Objectives: To investigate trends in forgone care and telehealth coverage among Medicare beneficiaries during the COVID-19 pandemic., Methods: A cross-sectional study design was used to analyze the outcomes of 31,907 Medicare beneficiaries using data from three waves of survey data from the Medicare Current Beneficiary Survey COVID-19 Supplement (Summer 2020, Fall 2020, and Winter 2021). We identified informative variables through a multivariate classification analysis utilizing Random Forest machine learning techniques., Findings: The rate of reported forgone medical care because of COVID-19 decreased largely (22.89-3.31%) with a small increase in telehealth coverage (56.24-61.84%) from the week of June 7, 2020, to the week of April 4 to 25, 2021. Overall, there were 21.97% of respondents did not know whether their primary care providers offered telehealth services; the rates of forgone care and telehealth coverage were 11.68 and 59.52% (11.73 and 81.18% from yes and no responses). Our machine learning model predicted the outcomes accurately utilizing 43 variables. Informative factors included Medicare beneficiaries' age, Medicare-Medicaid dual eligibility, ability to access basic needs, certain mental and physical health conditions, and interview date., Conclusions: This cross-sectional survey study found proliferation and utilization of telehealth services in certain subgroups during the COVID-19 pandemic, providing important access to care. There is a need to confront traditional barriers to the proliferation of telehealth. Policymakers must continue to identify effective means of maintaining continuity of care and growth of telehealth services., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lu and Liao.)

Sustaining DNA damage response (DDR) signalling via retention of DDR factors at damaged sites is important for transmitting damage-sensing and repair signals. Herein, we found that DNA damage provoked the association of ribosomes with IRES region in lncRNA CTBP1-DT, which overcame the negative effect of upstream open reading frames (uORFs), and elicited the novel microprotein DNA damage-upregulated protein (DDUP) translation via a cap-independent translation mechanism. Activated ATR kinase-mediated phosphorylation of DDUP induced a drastic 'dense-to-loose' conformational change, which sustained the RAD18/RAD51C and RAD18/PCNA complex at damaged sites and initiated RAD51C-mediated homologous recombination and PCNA-mediated post-replication repair mechanisms. Importantly, treatment with ATR inhibitor abolished the effect of DDUP on chromatin retention of RAD51C and PCNA, thereby leading to hypersensitivity of cancer cells to DNA-damaging chemotherapeutics. Taken together, our results uncover a plausible mechanism underlying the DDR sustaining and might represent an attractive therapeutic strategy in improvement of DNA damage-based anticancer therapies., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: β-Elemene, an effective anticancer component isolated from the Chinese herbal medicine Rhizoma Zedoariae, has been proved to have therapeutic potential against multiple cancers by extensive clinical trials and experimental research. However, its preventive role in cholangiocarcinoma (CCA) and the mechanisms of action of β-elemene on CCA need to be further investigated., Methods: A thioacetamide (TAA)-induced pre-CCA animal model was well-established, and a low dosage of β-elemene was intragastrically (i.g.) administered for 6 months. Livers were harvested and examined histologically by a deep-learning convolutional neural network (CNN). cDNA array was used to analyze the genetic changes of CCA cells following β-elemene treatment. Immunohistochemical methods were applied to detect β-elemene-targeted protein PCDH9 in CCA specimens, and its predictive role was analyzed. β-Elemene treatment at the cellular or animal level was performed to test the effect of this traditional Chinese medicine on CCA cells., Results: In the rat model of pre-CCA, the ratio of cholangiolar proliferation lesions was 0.98% ± 0.72% in the control group, significantly higher than that of the β-elemene (0. 47% ± 0.30%) groups ( p = 0.0471). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the top 10 pathways affected by β-elemene treatment were associated with energy metabolism, and one was associated with the cell cycle. β-Elemene inactivated a number of oncogenes and restored the expression of multiple tumor suppressors. PCDH9 is a target of β-elemene and displays an important role in predicting tumor recurrence in CCA patients., Conclusions: These findings proved that long-term use of β-elemene has the potential to interrupt the progression of CCA and improve the life quality of rats. Moreover, β-elemene exerted its anticancer potential partially by restoring the expression of PCDH9., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wu, Shi, Pan, Liao, Xu, Gu, Yu, Chen and Yu.)

The extract of Marsdenia tenacissima (Roxb.) Moon [Apocynaceae] (MTE) has shown a significant anti-cancer effect on hepatocellular carcinoma (HCC), but its mechanism remains unclear. In this study, we used transcriptomics methods to investigate the underlying mechanism of MTE against HCC. Both MHCC97H and HepG2 cell lines were treated with MTE. The cell viability and migration were measured using the cell counting kit-8 assay and transwell assay. RNA-sequencing was used to identify differentially expressed genes (DEGs) between HepG2 cells treated with and without MTE. The expression levels of selected DEGs-vascular endothelial growth factor-A (VEGFA), platelet-derived growth factor receptor-β (PDGFRB), and von Willebrand factor (VWF)-were verified by RT-PCR and Western blot. The effect of conditioned medium from HCC cells with MTE treatment (CM-MTE) on blood vessels was observed by tube formation assay of HUVECs and chick chorioallantoic membrane (CAM) assay. A mouse model of HCC patient-derived tumor xenograft (PDX) was established and treated with MTE. The effect of MTE on the growth and angiogenesis of HCC-PDX was analyzed. The results demonstrated that MTE inhibited the viability and migration of HCC cells. RNA-seq showed that MTE treatment downregulated multiple genes associated with metabolism and angiogenesis. The expression levels of VEGFA, VWF, PDGFB, and PDGFRB in HCC cells were significantly suppressed by MTE. Meanwhile, MTE effectively inhibited the tube-forming capability of HUVECs and the angiogenesis of chick CAM. In vivo experiments revealed that the extract reduced tumor volume, inhibited the proliferation of HCC cells, and expanded the necrotic area of the tumor. Immunohistochemical results showed that the expression levels of CD31, PDGFB, VEGF, VWF, and PDGFRB in the HCC-PDX tumor tissues were all downregulated by MTE in a dose-dependent manner. Taken together, MTE could inhibit angiogenesis by repressing the expression of VEGF, VWF, PDGF, and PDGFRB in HCC cells, a mechanism that may enable MTE to counter HCC development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pan, Liao, Yang, Zhang, Wang, Zheng, Yu and Song.)

Metabolic enzyme-genes (MEs) play critical roles in various types of cancers. However, MEs have not been systematically and thoroughly studied in pancreatic cancer (PC). Global analysis of MEs in PC will help us to understand PC progressing and provide new insights into PC therapy. In this study, we systematically analyzed RNA sequencing data from The Cancer Genome Atlas (TCGA) (n = 180 + 4) and GSE15471 (n = 36 + 36) and discovered that metabolic pathways are disordered in PC. Co-expression network modules of MEs were constructed using weighted gene co-expression network analysis (WGCNA), which identified two key modules. Both modules revealed that the glutathione signaling pathway is disordered in PC and correlated with PC stages. Notably, glutathione peroxidase 2 ( GPX2 ), an important gene involved in glutathione signaling pathway, is a hub gene of the key modules. Analysis of immune microenvironment components reveals that PC stage is associated with M2 macrophages, the marker gene of which is significantly correlated with GPX2 . The results indicated that GPX2 is associated with PC progression, providing new insights for future targeted therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wu, Yu, Yang, Hu, Tang, Zhang, Abudourousuli, Li, Li, Liao, Xu, Li, Chen, Qian, Feng, Li and Li.)

Bone metastasis is one of the most common distant metastasis of breast cancer, which could cause serious skeletal disease and increased cancer-related death. Therefore, identification of novel target(s) to develop therapeutics would improve patient outcomes. The role of NKX2-8 in modulation of bone remodeling was determined using osteoclastogenesis and micro-CT assays. The expression of NKX2-8 was examined via immunohistochemistry analysis in 344 breast cancer tissues. The mechanism underlying NKX2-8-mediated PTHrP downregulation was investigated using biotinylated deactivated Cas9 capture analysis, chromatin immunoprecipitation, co-immunoprecipitation assays. A bone-metastatic mouse model was used to examine the effect of NKX2-8 dysregulation on breast cancer bone metastasis and the impact of three PTHrP inhibitor on prevention of breast cancer bone metastasis. The downregulated expression of NKX2-8 was significantly correlated with breast cancer bone metastasis. In vivo bone-metastatic mouse model indicated that silencing NKX2-8 promoted, but overexpressing NKX2-8 inhibited, breast cancer osteolytic bone metastasis and osteoclastogenesis. Mechanistically, NKX2-8 directly interacted with HDAC1 on the PTHrP promoter, which resulted in a reduction of histone H3K27 acetylation, consequently transcriptionally downregulated PTHrP expression in breast cancer cells. Furthermore, targeting PTHrP effectively inhibited NKX2-8-downregulation-mediated breast cancer bone metastasis. Taken together, our results uncover a novel mechanism underlying NKX2-8 downregulation-mediated breast cancer bone metastasis and represent that the targeting PTHrP might be a tailored treatment for NKX2-8 silencing-induced breast cancer bone metastasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Abudourousuli, Chen, Hu, Qian, Liao, Xu, Song, Zhang and Li.)

Root cap not only protects root meristem, but also detects and transduces the signals of environmental changes to affect root development. The symplastic communication is an important way for plants to transduce signals to coordinate the development and physiology in response to the changing enviroments. However, it is unclear how the symplastic communication between root cap cells affects root growth. Here we exploit an inducible system to specifically block the symplastic communication in the root cap. Transient blockage of plasmodesmata (PD) in differentiated collumella cells severely impairs the root development in Arabidopsis, in particular in the stem cell niche and the proximal meristem. The neighboring stem cell niche is the region that is most sensitive to the disrupted symplastic communication and responds rapidly via the alteration of auxin distribution. In the later stage, the cell division in proximal meristem is inhibited, presumably due to the reduced auxin level in the root cap. Our results reveal the essential role of the differentiated collumella cells in the root cap mediated signaling system that directs root development., (© 2022 Institute of Botany, Chinese Academy of Sciences.)

This paper investigates the influence of board network centrality on corporate social responsibility (CSR) decoupling. CSR decoupling refers to the gap between corporate internal and external actions in CSR practices. Specifically, we measure CSR decoupling as the difference between corporate social disclosure (CSD) and corporate social performance (CSP). This paper uses a sample of Chinese A-share listed firms during 2009-2018, takes the technical dimension score (T-score) and content dimension score (C-score) of RKS ratings as proxies of CSD and CSP, and obtains CSR decoupling as the difference between CSD and CSP. Our results show that (1) board network centrality is positively related to over-decoupling in the pre-adoption period (2009-2014) of the new environmental law but negatively related to over-decoupling in the post-adoption period (2015-2018) and (2) centrality is not related to under-decoupling in the pre-adoption period but a significantly positive related in the post-adoption period. Our finding reveals a complex role of the board network in CSR practices in China., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Zhong, Liao, Ye and Deng.)

Nano-enabled phytoremediation is an emerging remediation strategy for soils that are moderately contaminated with persistent organic contaminants, and there is a significant need for increased mechanistic understanding and for case studies. Herein, we evaluated the remediation of PCB28-contaminated soil using combined alfalfa and Fe-based materials, including zero-valent iron at 20 nm, 100 nm, and 5 µm, and also iron oxide nanomaterials including α-Fe 2 O 3 , γ-Fe 2 O 3 , and Fe 3 O 4 around 20-30 nm. Compared with alfalfa remediation alone (63.2%), Fe-based nanomaterials increased PCB28 removal values to 72.4-93.5% in planted soil, with α-Fe 2 O 3 treatment promoting the most effective pollutant removal. Mechanistically, the crystalline Fe-based nanoparticles were transformed into amorphous forms in the plant rhizosphere, resulting in greater availability and enhanced iron nutrition. This nutritional shift induced root metabolic reprogramming of amino acid and carbohydrate cycling, and related functional bacterial enrichment of Ramlibacter, Dyella, Bacillus, and Paraburkholderia in rhizosphere. A significant positive correlation between amorphous iron and root metabolites-associated microbes with PCB28 removal was evident, implying that iron supplementation selected for rhizospheric microorganisms favored PCBs degradation. Overall, this rhizoremediation promotion strategy of Fe species-metabolites-microbes highlights the potential for the hybrid application of nano-enabled phytotechnology in the remediation of soils contaminated with persistent organic xenobiotics., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Dibenzocycloheptanones containing a tricyclic 6-7-6-system are present in numerous biologically active natural molecules. However, the simple and efficient preparation of derivatives containing a dibenzocycloheptanone scaffold remains difficult to date. Herein, we report a versatile strategy for the construction of these challenging seven-membered rings using a 7- endo -trig cyclization which is initiated by a phosphorus-centered radical. This approach provides a step-economical regime for the facile assembly of a wide range of phosphorylated dibenzocycloheptanones. Remarkably, we also have devised a traceless addition/exchange strategy for the preparation of dephosphorylated products at room temperature with excellent yields. Therefore, this protocol allows for the concise synthesis of biorelevant allocochicine derivatives., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Breast cancer (BC) has a marked tendency to spread to the bone, resulting in significant skeletal complications and mortality. Recently, circular RNAs (circRNAs) have been reported to contribute to cancer initiation and progression. However, the function and mechanism of circRNAs in BC bone metastasis (BC-BM) remain largely unknown., Methods: Bone-metastatic circRNAs were screened using circRNAs deep sequencing and validated using in situ hybridization in BC tissues with or without bone metastasis. The role of circIKBKB in inducing bone pre-metastatic niche formation and bone metastasis was determined using osteoclastogenesis, immunofluorescence and bone resorption pit assays. The mechanism underlying circIKBKB-mediated activation of NF-κB/bone remodeling factors signaling and EIF4A3-induced circIKBKB were investigated using RNA pull-down, luciferase reporter, chromatin isolation by RNA purification and enzyme-linked immunosorbent assays., Results: We identified that a novel circRNA, circIKBKB, was upregulated significantly in bone-metastatic BC tissues. Overexpressing circIKBKB enhanced the capability of BC cells to induce formation of bone pre-metastatic niche dramatically by promoting osteoclastogenesis in vivo and in vitro. Mechanically, circIKBKB activated NF-κB pathway via promoting IKKβ-mediated IκBα phosphorylation, inhibiting IκBα feedback loop and facilitating NF-κB to the promoters of multiple bone remodeling factors. Moreover, EIF4A3, acted acting as a pre-mRNA splicing factor, promoted cyclization of circIKBKB by directly binding to the circIKBKB flanking region. Importantly, treatment with inhibitor eIF4A3-IN-2 reduced circIKBKB expression and inhibited breast cancer bone metastasis effectively., Conclusion: We revealed a plausible mechanism for circIKBKB-mediated NF-κB hyperactivation in bone-metastatic BC, which might represent a potential strategy to treat breast cancer bone metastasis., (© 2021. The Author(s).)

Mitochondrial dynamics play vital roles in the tumorigenicity and malignancy of various types of cancers by promoting the tumor-initiating potential of cancer cells, suggesting that targeting crucial factors that drive mitochondrial dynamics may lead to promising anticancer therapies. In the current study, we report that overexpression of mitochondrial fission factor (MFF), which is upregulated significantly in liver cancer-initiating cells (LCIC), promotes mitochondrial fission and enhances stemness and tumor-initiating capability in non-LCICs. MFF-induced mitochondrial fission evoked mitophagy and asymmetric stem cell division and promoted a metabolic shift from oxidative phosphorylation to glycolysis that decreased mitochondrial reactive oxygen species (ROS) production, which prevented ROS-mediated degradation of the pluripotency transcription factor OCT4. CRISPR affinity purification in situ of regulatory elements showed that T-box transcription factor 19 (TBX19), which is overexpressed uniquely in LCICs compared with non-LCICs and liver progenitor cells, forms a complex with PRMT1 on the MFF promoter in LCICs, eliciting epigenetic histone H4R3me2a/H3K9ac-mediated transactivation of MFF. Targeting PRMT1 using furamidine, a selective pharmacologic inhibitor, suppressed TBX19-induced mitochondrial fission, leading to a profound loss of self-renewal potential and tumor-initiating capacity of LCICs. These findings unveil a novel mechanism underlying mitochondrial fission-mediated cancer stemness and suggest that regulation of mitochondrial fission via inhibition of PRMT1 may be an attractive therapeutic option for liver cancer treatment. SIGNIFICANCE: These findings show that TBX19/PRMT1 complex-mediated upregulation of MFF promotes mitochondrial fission and tumor-initiating capacity in liver cancer cells, identifying PRMT1 as a viable therapeutic target in liver cancer., (©2021 American Association for Cancer Research.)

Avasimibe is a bioavailable acetyl-CoA acetyltransferase (ACAT) inhibitor and shows a good antitumor effect in various human solid tumors, but its therapeutic value in cholangiocarcinoma (CCA) and underlying mechanisms are largely unknown. In the study, we proved that avasimibe retard cell proliferation and tumor growth of CCAs and identified FoxM1/AKR1C1 axis as the potential novel targets of avasimibe. Aldo-keto reductase 1 family member C1 (AKR1C1) is gradually increased along with the disease progression and highly expressed in human CCAs. From survival analysis, AKR1C1 could be a vital predictor of tumor recurrence and prognostic factor. Enforced Forkhead box protein M1 (FoxM1) expression results in the upregulation of AKR1C1, whereas silencing FoxM1 do the opposite. FoxM1 directly binds to promoter of AKR1C1 and triggers its transcription, while FoxM1-binding site mutation decreases AKR1C1 promoter activity. Moreover, over-expressing exogenous FoxM1 reverses the growth retardation of CCA cells induced by avasimibe administration, while silencing AKR1C1 in FoxM1-overexpressing again retard cell growth. Furthermore, FoxM1 expression significantly correlates with the AKR1C1 expression in human CCA specimens. Our study demonstrates a novel positive regulatory between FoxM1 and AKR1C1 contributing cell growth and tumor progression of CCA and avasimibe may be an alternative therapeutic option for CCA by targeting this FoxM1/AKR1C1 signaling pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gao, Xu, Li, Xu, Pan, Liao, Qian, Hu and Yu.)

The incidence of bone metastases in hepatocellular carcinoma (HCC) has increased prominently over the past decade owing to the prolonged overall survival of HCC patients. However, the mechanisms underlying HCC bone-metastasis remain largely unknown. In the current study, HCC-secreted lectin galactoside-binding soluble 3 (LGALS3) is found to be significantly upregulated and correlates with shorter bone-metastasis-free survival of HCC patients. Overexpression of LGALS3 enhances the metastatic capability of HCC cells to bone and induces skeletal-related events by forming a bone pre-metastatic niche via promoting osteoclast fusion and podosome formation. Mechanically, ubiquitin ligaseRNF219-meidated α -catenin degradation prompts YAP1/ β -catenin complex-dependent epigenetic modifications of LGALS3 promoter, resulting in LGALS3 upregulation and metastatic bone diseases. Importantly, treatment with verteporfin, a clinical drug for macular degeneration, decreases LGALS3 expression and effectively inhibits skeletal complications of HCC. These findings unveil a plausible role for HCC-secreted LGALS3 in pre-metastatic niche and can suggest a promising strategy for clinical intervention in HCC bone-metastasis., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Published by Wiley‐VCH GmbH.)

Selective autophagy for the elimination of aberrant mitochondria, termed mitophagy, can be regulated by the kinase PINK1 and the ubiquitin ligase Parkin. The lysosome-associated membrane protein 2 (LAMP-2) plays diverse functions in non-selective autophagy, chaperone-mediated autophagy and selective autophagy for the degradation of RNA/DNA. In the present study, we investigated whether LAMP-2 plays important roles during PINK1/Parkin-mediated mitophagy. The results obtained clearly show that knockdown of LAMP-2 does not cause defects in mitophagy in HeLa cells stably expressing Parkin, indicating that LAMP-2 is dispensable for PINK1/Parkin-mediated mitophagy. The present study is the first to determine the potential role of LAMP-2 in PINK1/Parkin-mediated mitophagy, thereby providing more insight into the sophisticated process of mitophagy., (© 2019 Federation of European Biochemical Societies.)

Aims: Intraoperative blood salvage (IBS) is associated with shortened lifespan of red blood cells (RBCs). This study aims to examine how salvaged RBCs are compromised during IBS., Main Methods: Thirty patients who underwent vertebra surgery with IBS were included in the study. To examine possible mechanisms of IBS-induced injury, both fresh and salvaged RBCs from each patient were mixed with plasma, the Ca 2+ ionophore ionomycin or mannitol-adenine-phosphate (MAP) solution (n = 10 patients per condition). Binding of Fluo-3 and/or Annexin V by RBCs was measured., Key Findings: The percentage of Fluo-3-binding RBCs in salvaged samples was 2.83 ± 0.76%, which increased to 15.34 ± 5.99% after 48-h incubation in plasma. These percentages were significantly higher than those observed with fresh RBCs (P < 0.01). Ionomycin dose-dependently increased the percentage of Fluo-3-binding RBCs in salvaged samples, while MAP solution decreased it. Incubating salvaged RBCs in plasma for 48 h increased the percentage of Fluo-3-positive spherocytes from 0.8 ± 0.6% to 11.35 ± 3.96%, and this increase was blocked by MAP solution. Ionomycin increased the percentage of RBCs binding both Fluo-3 and Annexin V, while MAP decreased this percentage. The percentage of Annexin V-binding RBCs was also higher in salvaged samples than in fresh samples, but this percentage was unaffected by either ionomycin or MAP solution., Significance: Our results suggest that IBS induces a postponed RBC damage by inducing spherocyte formation, which likely reflects Ca 2+ entry induced by energy exhaustion, as well as by exposing phosphatidylserine on the RBC surface, which likely occurs via Ca 2+ entry and via Ca 2+ -independent pathways., (Copyright © 2019 Elsevier Inc. All rights reserved.)