Caffeic Acid Reduces Ferroptosis to Dampen Inflammation of Keratinocytes in Psoriasis by Inhibiting EGR1-induced Transcription Activation of CHAC1.

BACKGROUND: Ferroptosis of keratinocytes is closely associated with amplification of skin inflammation in psoriasis. This study focuses on unlocking the role of caffeic acid (CA), a polyphenol compound, in keratinocyte ferroptosis and understanding the underlying mechanistic basis. METHODS: The interaction between early growth response protein 1 (EGR1) and chac glutathione specific γ­glutamylcyclotransferase 1 (CHAC1) was predicted by bioinformatics and validated via chromatin immunoprecipitation and dual-luciferase reported assays. Their expressions in primary human epidermal keratinocytes were altered by transfection of EGR1/CHAC1 overexpression or knockdown plasmids, and then keratinocytes were followed by CA treatment and Erastin (ferroptosis inducer). Keratinocyte viability was determined by CCK-8 assay, and the ferroptotic effect was evaluated using colorimetric assay and flow cytometry. Proinflammatory cytokine secretion by keratinocytes was detected via ELISA. Expressions of EGR1 and CHAC1 in keratinocytes were analyzed by qRT-PCR or Western blot. RESULTS: Increased expressions of EGR1 and CHAC1 were detected in keratinocytes with Erastin treatment. CA (100 µM) antagonized Erastin (10 µM)-induced decrease in viability, increases in EGR1 and CHAC1 expressions, upregulation of MDA, ROS, and Fe2+, downregulation of GSH and SOD, and secretion of proinflammatory cytokines from keratinocytes. EGR1 overexpression potentiated Erastin-induced effects. Moreover, EGR1 overexpression and CA mutually counteracted their effects on Erastin-induced keratinocytes. EGR1 transcriptionally activated and positively regulated CHAC1. The above Erastin-induced effects were neutralized by EGR1 knockdown but potentiated by CHAC1 overexpression. Moreover, EGR1 knockdown and CHAC1 overexpression reversed each other's effects. CONCLUSION: CA reduces ferroptosis by inhibiting EGR1-induced activation of CHAC1 to dampen inflammation of keratinocytes in psoriasis. This study providing new compounds and candidate targets for the clinical treatment of psoriasis.

lncRNA CASC7 contributes to the progression of LPS-induced liver injury by targeting miRNA-217/TLR4 axis

It has been reported that long non-coding RNAs (lncRNAs) are involved in sepsis-induced liver injury, while the role of cancer susceptibility candidate 7 (CASC7) in liver injury induced by sepsis remains elusive. In our study, 62 patients and 55 healthy controls were enrolled from our hospital, from whom CASC7 and microRNA-217 (miR-217) in serum samples were detected by quantitative real-time PCR (qRT-PCR). Then the sepsis-induced liver injury mice model was established by lipopolysaccharide (LPS). The effect of CASC7 on liver injury induced by sepsis was confirmed by hematoxylin and eosin (HE) staining, ELISA assay, TUNEL assay, Annexin V-FITC apoptosis assay and cell counting kit-8 (CCK-8) assay, respectively. Besides, RNA pull-down, luciferase reporter gene assay, qRT-PCR, and western blot were used to evaluate the underlying mechanisms. In this study, lncRNA CASC7 was significantly increased while miR-217 was significantly decreased in patients with sepsis-induced liver injury compared with that in healthy controls. There was a negative association of CASC7 and miR-217 in serum samples from patients with sepsis-induced liver injury and healthy controls. CASC7 was upregulated in a time-dependent manner in liver tissues of LPS-treated mice. It was found that knockdown of CASC7 reduced the liver injury induced by LPS in mice. In vitro, LPS treatment enhanced cell apoptosis, while knockdown of CASC7 inhibited the role of LPS in cell apoptosis. Moreover, knockdown of CASC7 suppressed the LPS-enhanced tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1ß) expression. In addition, miR-217 was found to be a target of CASC7, and miR-217 mimic could reverse CASC7-promoted liver injury. Furthermore, toll-like receptor 4 (TLR4) was identified as the target of miR-217, and both CASC7 and miR-217 could downregulate the mRNA and protein level of TLR4. Additionally, TLR4 overexpression could reverse miR-217-inhibited or CASC7-promoted liver injury. Taken together, CASC7 contributes to the progression of LPS-induced liver injury via the miR-217/TLR4 axis.

The risk of asthma in singletons conceived by ART: a retrospective cohort study.

STUDY QUESTION: Do singleton children conceived by ART have a higher asthma risk than naturally conceived (NC) singletons? SUMMARY ANSWER: The asthma risk was similar for ART-conceived singletons and NC singletons, and there were no clear differences between the various types of ART. WHAT IS KNOWN ALREADY: Whether ART increases asthma risk in offspring is questionable. The evidence is inconsistent and limited by ethnicity, geographic distribution, inadequate confounder adjustment, unsatisfactory control groups, and specific methods of ART. Furthermore, the mediating effects of obstetric and neonatal outcomes on the association between ART and asthma remain unclear. STUDY DESIGN SIZE DURATION: This observational, single-centre study was conducted at a reproductive centre of an affiliated university hospital between September 2009 and April 2023. A total of 3227 singletons aged 3-6 years conceived by IVF versus ICSI or fresh versus frozen embryo transfer were retrospectively enrolled, and a total of 1206 NC singletons of the same age were subsequently recruited. PARTICIPANTS/MATERIALS SETTING METHODS: Asthma was defined as a self-reported physician diagnosis or wheezing in the past 12 months. We performed multivariable logistic regression analyses to examine associations between asthma in offspring and ART use, adjusting for parental characteristics (age, education level, occupation type, BMI, asthma), smoking exposure, residence type, child sex, child age, and year of follow-up. Mediating effects were explored using longitudinal mediation structural equation modelling. MAIN RESULTS AND THE ROLE OF CHANCE: Asthma was reported for 51 (4.2%) of the 1206 NC singletons (median [interquartile range] age 5 [4-5] years; 48.1% females) and 169 (5.2%) of the 3227 ART-conceived singletons (5 [5-5] years; 47.6% females). We found that risks of childhood asthma in singletons conceived by ART were, overall, similar to those of NC singletons before (odds ratio [OR], 1.25 [95% CI, 0.92-1.74]; P = 0.170) and after adjustment (adjusted OR [aOR], 0.66 [95% CI, 0.44-1.03]; P = 0.126). The results were similar in multiple sensitivity analyses, and there were no clear differences in asthma risks according to the method of ART. Mediation analysis revealed a significant positive indirect effect of neonatal intensive care unit (NICU) admission (standard path coefficient, b = 0.025, P < 0.05) and a negative indirect effect of breastfeeding (b = -0.012, P < 0.05) on the association between ART and asthma in singleton offspring. LIMITATIONS REASONS FOR CAUTION: This study is limited to singletons only and cannot be generalized. The study is also limited by its retrospective observational single-centre nature and sample size. Mediation analyses were exploratory. Therefore, the findings need to be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: These findings can help infertile couples undergoing ART be reassured about the risk of childhood asthma in singleton offspring. Breastfeeding is recommended as a potentially feasible intervention to reduce the asthma risks in ART-conceived children who are at increased potential risk of asthma, such as those with NICU admissions. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Key Research and Development Program of Zhejiang Province (2021C03100), the National Key Research and Development Program of China (2021YFC2700603), and the Program for Key Subjects of Zhejiang Province in Medicine and Hygiene to Y. Z., the Zhejiang Province Natural Science Foundation (No. LQ22H040006) and the National Natural Science Foundation of China (No.82101759) to M.T., and the National Natural Science Foundation of China (No. 82201860) to J.Y. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: ChiCTR2300069906.

Association between maternal polycystic ovarian syndrome undergoing assisted reproductive technology and pregnancy complications and neonatal outcomes: a systematic review and meta-analysis.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is recognized as the most prevalent endocrine disorder among women of reproductive age. While the utilization of assisted reproductive technology (ART) has resulted in favorable outcomes for infertility treatment in PCOS patients, the inherent pathophysiological features of the condition give rise to complications and consequences during pregnancy and delivery for both the mother and offspring. This study was to assess the correlation between maternal PCOS and various pregnancy complications and neonatal outcomes undergone ART. METHODS: A systematic search was conducted on PubMed, EmBase, and the Cochrane Library to identify observational studies that investigated the association between PCOS and the risk of various pregnancy complications and neonatal outcomes, including gestational diabetes mellitus (GDM), hypertension in pregnancy (PIH), preeclampsia (PE), preterm birth, abortion, congenital malformations (CA), small for gestational age (SGA), large for gestational age (LGA), low birth weight (LBW), macrosomia, neonatal intensive care unit (NICU) admission and birth weight. Eligible studies were selected based on predetermined inclusion and exclusion criteria. The meta-analysis was conducted using Review Manager and Stata software, with odds ratios (ORs) or mean difference (MD), confidence intervals (CIs), and heterogeneity (I2) being calculated. The search was conducted up to March 2023. RESULTS: A total of 33 studies with a combined sample size of 92,810 participants were identified. The findings indicate that PCOS is significantly associated with an increased risk of GDM (OR 1.51, 95% CI:1.17-1.94), PIH (OR 1.72, 95% CI:1.25-2.39), PE (OR 2.12, 95% CI:1.49-3.02), preterm birth (OR 1.29, 95% CI:1.21-1.39), and LBW (OR 1.29, 95% CI:1.14-1.47). In subgroup analyses, the risks of GDM (OR 1.80, 95% CI:1.23-2.62) and abortion (OR 1.41, 95% CI:1.08-1.84) were elevated in fresh embryo transferred (ET) subgroup, whereas elevated risk of PE (OR 1.82, 95% CI:1.17-2.83) and preterm birth (OR 1.31, 95% CI:1.21-1.42) was identified in frozen ET subgroup. Whatever with or without hyperandrogenism, patients with PCOS had a higher risk in preterm birth (OR 1.69, 95% CI: 1.31-2.18; OR 1.24, 95% CI:1.02-1.50) and abortion (OR 1.38, 95% CI:1.12-1.71; OR 1.23, 95% CI:1.06-1.43). CONCLUSION: Our findings suggest that individuals with PCOS undergone ART are at a notably elevated risk for experiencing pregnancy complications and unfavorable neonatal outcomes. Nevertheless, to establish a definitive association between PCOS and pregnancy-related outcomes, it is necessary to conduct extensive prospective, blinded cohort studies and effectively control for confounding variables.

Isoforskolin modulates AQP4-SPP1-PIK3C3 related pathway for chronic obstructive pulmonary disease via cAMP signaling.

BACKGROUND: Cyclic adenosine monophosphate (cAMP) levels are directly activated by adenylate cyclase (AC) and play an anti-inflammatory role in chronic obstructive pulmonary disease (COPD). Previously, we have shown that isoforskolin (ISOF) can effectively activate AC1 and AC2 in vitro, improve pulmonary ventilation and reduce the inflammatory response in COPD model rats, supporting that ISOF may be a potential drug for the prevention and treatment of COPD, but the mechanism has not been explored in detail. METHODS: The potential pharmacological mechanisms of ISOF against COPD were analyzed by network pharmacology and multi-omics based on pharmacodynamic study. To use specific agonists, inhibitors and/or SiRNA for gene regulation function studies, combined qPCR, WB were applied to detect changes in mRNA and protein expression of important targets PIK3C3, AKT, mTOR, SPP1 and AQP4 which related to ISOF effect on COPD. And the key inflammatory factors detected by ELISA. RESULTS: Bioinformatics suggested that the anti-COPD pharmacological mechanism of ISOF was related to PI3K-AKT signaling pathway, and suggested target protein like PIK3C3, AQP4, SPP1, AKT, mTOR. Using the AQP4 inhibitor,or inhibiting SPP1 expression by siRNA-SPP1 could block the PIK3C3-AKT-mTOR pathway and ameliorate chronic inflammation. ISOF showed cAMP-promoting effect then suppressed AQP4 expression, together with decreased level of IL-1ß, IL-6, and IL-8. CONCLUSIONS: These findings demonstrate ISOF controlled the cAMP-regulated PIK3C3-AKT-mTOR pathway, thereby alleviating inflammatory development in COPD. The cAMP/AQP4/PIK3C3 axis also modulate Th17/Treg differentiation, revealed potential therapeutic targets for this disease.

Integrated bioinformatics analysis elucidates granulosa cell whole-transcriptome landscape of PCOS in China.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common reproductive, neuroendocrine, and metabolic disorder in women of reproductive age that affects up to 5-10% of women of reproductive age. The aetiology of follicle development arrest and critical issues regarding the abnormal follicular development in PCOS remain unclear. The present study aims to systematically evaluate granulosa cell whole-transcriptome sequencing data to gain more insights into the transcriptomic landscape and molecular mechanism of PCOS in China. METHODS: In the present study, the microarray datasets GSE138518, GSE168404, GSE193123, GSE138572, GSE95728, and GSE145296 were downloaded from the Gene Expression Omnibus (GEO) database. Subsequently, differential expression analysis was performed on the PCOS and control groups, followed by functional interaction prediction analysis to investigate gene-regulatory circuits in PCOS. Finally, hub genes and their associated ncRNAs were validated by qPCR in human-luteinized granulosa (hGL) cells and were correlated with the clinical characteristics of the patients. RESULTS: A total of 200 differentially expressed mRNAs, 3 differentially expressed miRNAs, 52 differentially expressed lncRNAs, and 66 differentially expressed circRNAs were found in PCOS samples compared with controls. GO and KEGG enrichment analyses indicated that the DEGs were mostly enriched in phospholipid metabolic processes, steroid biosynthesis and inflammation related pathways. In addition, the upregulated miRNA hsa-miR-205-5p was significantly enriched in the ceRNA network, and two hub genes, MVD and PNPLA3, were regulated by hsa-miR-205-5p, which means that hsa-miR-205-5p may play a fundamental role in the pathogenesis of PCOS. We also found that MVD and PNPLA3 were related to metabolic processes and ovarian steroidogenesis, which may be the cause of the follicle development arrest in PCOS patients. CONCLUSIONS: In summary, we systematically constructed a ceRNA network depicting the interactions between the ncRNAs and the hub genes in PCOS and control subjects and correlated the hub genes with the clinical characteristics of the patients, which provides valuable insights into the granulosa cell whole-transcriptome landscape of PCOS in China.

Amorphous mixed-valent Mn-containing nanozyme with cocklebur-like morphology for specific colorimetric detection of cancer cells via Velcro effects.

Designing nanozymes with excellent catalytic activity through valence state engineering and defect engineering is a widely applicable strategy. However, their development is hindered by the complexity of the design strategies. In this work, we employed a simple calcination method to regulate the valence of manganese and crystalline states in manganese oxide nanozymes. The oxidase-like activity of the nanozymes was found to benefit from a mixed valence state dominated by Mn (III). And the amorphous structure with more active defect sites significantly enhanced the catalytic efficiency. Moreover, we demonstrated that amorphous mixed-valent Mn-containing (amvMn) nanozymes with unique cocklebur-like biomimetic morphology achieved specific binding to cancer cells through the Velcro effects. Subsequently, the nanozymes mediated TMB coloration through their oxidase-like activity, enabling the colorimetric detection of cancer cells. This work not only provides guidance for optimizing nanozyme performance, but also inspire the development of equipment-free visual detection methods for cancer cells.

[Prevalence, risk factors and characteristics of delirium in intensive care unit patients: a prospective observational study].

OBJECTIVE: To investigate the prevalence, risk factors, duration and outcome of delirium in intensive care unit (ICU) patients. METHODS: A prospective observational study was conducted for critically ill patients admitted to the department of critical care medicine, the Affiliated Hospital of Guizhou Medical University from September to November 2021. Delirium assessments were performed twice daily using the Richmond agitation-sedation scale (RASS) and confusion assessment method of ICU (CAM-ICU) for patients who met the inclusions and exclusion criteria. Patient's age, gender, body mass index (BMI), underlying disease, acute physiologic assessment and chronic health evaluation (APACHE) at ICU admission, sequential organ failure assessment (SOFA) at ICU admission, oxygenation index (PaO2/FiO2), diagnosis, type of delirium, duration of delirium, outcome, etc. were recorded. Patients were divided into delirium and non-delirium groups according to whether delirium occurred during the study period. The clinical characteristics of the patients in the two groups were compared, and risk factors for the development of delirium were screened using univariate analysis and multivariate Logistic regression analysis. RESULTS: A total of 347 ICU patients were included, and delirium occurred in 57.6% (200/347) patients. The most common type was hypoactive delirium (73.0% of the total). Univariate analysis showed statistically significant differences in age, APACHE score and SOFA score at ICU admission, history of smoking, hypertension, history of cerebral infarction, immunosuppression, neurological disease, sepsis, shock, glucose (Glu), PaO2/FiO2 at ICU admission, length of ICU stay, and duration of mechanical ventilation between the two groups. Multivariate Logistic regression analysis showed that age [odds ratio (OR) = 1.045, 95% confidence interval (95%CI) was 1.027-1.063, P < 0.001], APACHE score at ICU admission (OR = 1.049, 95%CI was 1.008-1.091, P = 0.018), neurological disease (OR = 5.275, 95%CI was 1.825-15.248, P = 0.002), sepsis (OR = 1.941, 95%CI was 1.117-3.374, P = 0.019), and duration of mechanical ventilation (OR = 1.005, 95%CI was 1.001-1.009, P = 0.012) were all independent risk factors for the development of delirium in ICU patients. The median duration of delirium in ICU patients was 2 (1, 3) days. Delirium was still present in 52% patients when they discharged from the ICU. CONCLUSIONS: The prevalence of delirium in ICU patients is over 50%, with hypoactive delirium being the most common. Age, APACHE score at ICU admission, neurological disease, sepsis and duration of mechanical ventilation were all independent risk factors for the development of delirium in ICU patients. More than half of patients with delirium were still delirious when they discharged from the ICU.

Relationship between anxiety and depressive trajectories of women who conceived through assisted reproductive technology and their children's emotional and behavioral problems: A prospective cohort study.

OBJECTIVE: This study aimed to examine the relationship between the anxiety and depressive trajectory of women conceived through assisted reproductive technology (ART) and their children's emotional and behavioral problems. METHODS: This prospective cohort study including 18,711 women, was conducted between July 2014 and December 2017. Self-rating scales for anxiety and depression were used before treatment, during the first trimester, and two to three years postpartum. A latent class growth analysis identified their maternal anxiety and depressive symptom trajectories. Multiple comparison and linear regression models were performed to assess the relationships between maternal trajectories and their offspring's emotional and behavioral problems. RESULTS: Three longitudinal heterogeneous trajectories of maternal anxiety and depressive symptoms were identified: resilient, recurrent, and emergent. After adjusting for covariates, children with mothers in the recurrent and emergent trajectory groups had higher Child Behavior Checklist/2-3 scores. Additionally, the participants with a recurrent trajectory had lower education and employment levels and younger maternal age at delivery. They also had a history of ovarian surgery, primipara, secondary infertility, polycystic ovary syndrome, and more embryo transferred cycles, including intracytoplasmic sperm injections. Those with resilient trajectories had higher antral follicle counts and GnRH antagonist protocol. Finally, the participants with emergent trajectories had a lower monthly income, primipara, ectopic pregnancy, and fresh embryo transfers. CONCLUSIONS: Infertile women's psychological stress was not alleviated by the ART-sociodemographic, infertility-related and treatment-related characteristics determined three mental health trajectories. Children with mothers in recurrent and emergent trajectories showed higher odds of experiencing emotional and behavioral problems.

Machine learning links different gene patterns of viral infection to immunosuppression and immune-related biomarkers in severe burns.

Introduction: Viral infection, typically disregarded, has a significant role in burns. However, there is still a lack of biomarkers and immunotherapy targets related to viral infections in burns. Methods: Virus-related genes (VRGs) that were extracted from Gene Oncology (GO) database were included as hallmarks. Through unsupervised consensus clustering, we divided patients into two VRGs molecular patterns (VRGMPs). Weighted gene co-expression network analysis (WGCNA) was performed to study the relationship between burns and VRGs. Random forest (RF), least absolute shrinkage and selection operator (LASSO) regression, and logistic regression were used to select key genes, which were utilized to construct prognostic signatures by multivariate logistic regression. The risk score of the nomogram defined high- and low-risk groups. We compared immune cells, immune checkpoint-related genes, and prognosis between the two groups. Finally, we used network analysis and molecular docking to predict drugs targeting CD69 and SATB1. Expression of CD69 and SATB1 was validated by qPCR and microarray with the blood sample from the burn patient. Results: We established two VRGMPs, which differed in monocytes, neutrophils, dendritic cells, and T cells. In WGCNA, genes were divided into 14 modules, and the black module was correlated with VRGMPs. A total of 65 genes were selected by WGCNA, STRING, and differential expression analysis. The results of GO enrichment analysis were enriched in Th1 and Th2 cell differentiation, B cell receptor signaling pathway, alpha-beta T cell activation, and alpha-beta T cell differentiation. Then the 2-gene signature was constructed by RF, LASSO, and LOGISTIC regression. The signature was an independent prognostic factor and performed well in ROC, calibration, and decision curves. Further, the expression of immune cells and checkpoint genes differed between high- and low-risk groups. CD69 and SATB1 were differentially expressed in burns. Discussion: This is the first VRG-based signature (including 2 key genes validated by qPCR) for predicting survival, and it could provide vital guidance to achieve optimized immunotherapy for immunosuppression in burns.

Structural insights into a shared mechanism of human STING activation by a potent agonist and an autoimmune disease-associated mutation.

Stimulator of interferon gene (STING) is increasingly exploited for the potential in cancer immunotherapy, yet its mechanism of activation remains not fully understood. Herein, we designed a novel STING agonist, designated as HB3089 that exhibits robust and durable anti-tumor activity in tumor models across various cancer types. Cryo-EM analysis reveals that HB3089-bound human STING has structural changes similar to that of the STING mutant V147L, a constitutively activated mutant identified in patients with STING-associated vasculopathy with onset in infancy (SAVI). Both structures highlight the conformational changes of the transmembrane domain (TMD), but without the 180°-rotation of the ligand binding domain (LBD) previously shown to be required for STING activation. Further structure-based functional analysis confirmed a new STING activation mode shared by the agonist and the SAVI-related mutation, in which the connector linking the LBD and the TMD senses the activation signal and controls the conformational changes of the LBD and the TMD for STING activation. Together, our findings lead to a new working model for STING activation and open a new avenue for the rationale design of STING-targeted therapies either for cancer or autoimmune disorders.

PENet: Prior evidence deep neural network for bladder cancer staging.

Bladder cancer is a heterogeneous, complicated, and widespread illness with high rates of morbidity, death, and expense if not treated adequately. The accurate and exact stage of bladder cancer is fundamental for treatment choices and prognostic forecasts, as indicated by convincing evidence from randomized trials. The extraordinary capability of Deep Convolutional Neural Networks (DCNNs) to extract features is one of the primary advantages offered by these types of networks. DCNNs work well in numerous real clinical medical applications as it demands costly large-scale data annotation. However, a lack of background information hinders its effectiveness and interpretability. Clinicians identify the stage of a tumor by evaluating whether the tumor is muscle-invasive, as shown in images by the tumor's infiltration of the bladder wall. Incorporating this clinical knowledge in DCNN has the ability to enhance the performance of bladder cancer staging and bring the prediction into accordance with medical principles. Therefore, we introduce PENet, an innovative prior evidence deep neural network, for classifying MR images of bladder cancer staging in line with clinical knowledge. To do this, first, the degree to which the tumor has penetrated the bladder wall is measured to get prior distribution parameters of class probability called prior evidence. Second, we formulate the posterior distribution of class probability according to Bayesian Theorem. Last, we modify the loss function based on posterior distribution of class probability which parameters include both prior evidence and prediction evidence in the learning procedure. Our investigation reveals that the prediction error and the variance of PENet may be reduced by giving the network prior evidence that is consistent with the ground truth. Using MR image datasets, experiments show that PENet performs better than image-based DCNN algorithms for bladder cancer staging.

Blockage of PD-L1 by FERMT3-mediated Wnt/ß-catenin signalling regulates chemoresistance and immune evasion of colorectal cancer cells.

Colorectal cancer (CRC) constitutes a major public health problem because of the high rate of morbidity and mortality. Chemotherapy and immunotherapy are the major and promising strategies for cancer patients including CRC; nevertheless, chemoresistance and immune escape limit the final efficacy of the above approaches. FERMT3 has proven to exert a critical role in the immune system and has contradictive effects on cancer progression. In this study, bioinformatics database analysis and clinical specimen detection both corroborated the downregulation of FERMT3 in CRC tissues and cells. Of interest, overexpression of FERMT3 suppressed CRC cell invasion and sensitized cells to 5-fluorouracil (5-FU) by reducing cell viability and increasing cell apoptosis and caspase 3 activity. Noticeably, FERMT3 upregulation enhanced natural killer (NK) cells activation by increasing secretions of interferon γ (IFN-γ) and tumour necrosis factor α (TNF-α) when NK cells were co-cultured with CRC cells. Importantly, upregulation of FERMT3 promoted NK cell-mediated killing of CRC cells. Mechanically, FERMT3 inhibited the aberrant activation of Wnt/ß-catenin signalling and the subsequent programmed death-ligand 1 (PD-L1) expression in CRC cells. Moreover, knockdown of PD-L1 suppressed CRC cell invasion, 5-FU resistance and NK cells-mediated tumour killing. Additionally, reactivating the Wnt/ß-catenin signalling with a specific WNT agonist CAS 853220-52-7 overturned the efficacy of FERMT3 overexpression against CRC cell invasion, 5-FU chemoresistance and cell susceptibility to NK cell-mediated cytotoxicity. Therefore, the current findings substantiate that FERMT3 elevation may attenuate CRC cell chemoresistance and NK cell-mediated immune response to tumour cells by inhibiting Wnt/ß-catenin-PD-L1 signalling. Therefore, FERMT3 elevation may be a promising therapeutic approach to overcome chemoresistance and immune evasion in CRC.

Kindlin-2 haploinsufficiency protects against fatty liver by targeting Foxo1 in mice.

Nonalcoholic fatty liver disease (NAFLD) affects a large population with incompletely defined mechanism(s). Here we report that Kindlin-2 is dramatically up-regulated in livers in obese mice and patients with NAFLD. Kindlin-2 haploinsufficiency in hepatocytes ameliorates high-fat diet (HFD)-induced NAFLD and glucose intolerance without affecting energy metabolism in mice. In contrast, Kindlin-2 overexpression in liver exacerbates NAFLD and promotes lipid metabolism disorder and inflammation in hepatocytes. A C-terminal region (aa 570-680) of Kindlin-2 binds to and stabilizes Foxo1 by inhibiting its ubiquitination and degradation through the Skp2 E3 ligase. Kindlin-2 deficiency increases Foxo1 phosphorylation at Ser256, which favors its ubiquitination by Skp2. Thus, Kindllin-2 loss down-regulates Foxo1 protein in hepatocytes. Foxo1 overexpression in liver abrogates the ameliorating effect of Kindlin-2 haploinsufficiency on NAFLD in mice. Finally, AAV8-mediated shRNA knockdown of Kindlin-2 in liver alleviates NAFLD in obese mice. Collectively, we demonstrate that Kindlin-2 insufficiency protects against fatty liver by promoting Foxo1 degradation.

γ-Ray-Triggered Drug Release of Reactive Oxygen Species-Sensitive Nanomedicine for Enhanced Concurrent Chemoradiation Therapy.

Radiotherapy (RT) combined with chemotherapy remains a dominant therapeutic manner in clinical tumor treatment, which is irreplaceable in a short term. To seek an intrinsic connection of combined chemoradiation therapy and maximize the antitumor efficacy, we developed a reactive oxygen species (ROS)-sensitive nanomicelle drug delivery system based on a self-assembled amphiphilic polymer, hyaluronic acid-graft-poly-(propylene sulfide) (HA-PPS). A chemical radiosensitizer, doxorubicin (DOX), was encapsulated into the core of HA-PPS nanomicelles, constituting the DOX-loaded nanomicelles (HA-PPS@DOX NMs) with a spherical structure of around 205.10 ± 11.33 nm diameter with a narrow polydispersity index (PDI) of 0.135 ± 0.01. When combined with RT, the ROS-sensitive HA-PPS@DOX NMs disintegrated and released great drug cargos, which further enhanced cytotoxicity. Meanwhile, as a radiosensitizer, the released DOX sensitized cancer cells to radiotherapy, which has been confirmed by an enhanced sensitizer enhancement ratio (SER) value of 1.78 contributing to the increased cytotoxicity of concurrent chemoradiation tumor therapy, as evidenced by the improvement of half maximal inhibitory concentration (IC50 value) of DOX from 2.316 to 0.8235 µg/mL. Moreover, in vivo studies revealed that HA-PPS@DOX NMs exhibited prolonged circulation time and improved tumor accumulation. Particularly, the released DOX triggered by radiation strengthened radiotherapy sensitization in return. Consequently, these superiorities of HA-PPS@DOX NMs shown by the concurrent chemoradiation tumor therapy resulted in an ideal tumor inhibition rate of 70.4%, thus providing a promising ROS-sensitive nanomedicine for cancer treatment.

Anatomical deviations of vertebral artery in hemifacial spasm: a quantitative study.

PURPOSE: There exist different opinions on whether the anatomical laterality of vertebral artery (VA) is related to the unilateral onset of hemifacial spasm (HFS). In this study, we intended to qualitatively explore the potential correlation between the anatomical deviations of VA and the clinical characteristics of HFS. METHODS: Two hundred and forty patients who underwent microvascular decompression for HFS between January 2018 and December 2019 were recruited. Clinical data including medical records and preoperative MRI images were retrospectively reviewed. A score system was specially designed for VAs to illustrate their distribution, and a score-weighted cross-sectional area of VA was proposed to represent the relative thickness of VA on each side. Then, the anatomical deviations of VA were comparatively analyzed between the symptomatic side and asymptomatic side and between VA-involved cases and non-VA-involved cases. RESULTS: The score and weighted cross-sectional area (WCSA) of VA in symptomatic side were significantly greater than those in asymptomatic side (P = 0.000, P = 0.000). And in symptomatic side, the score and WCSA of VA in VA-involved cases were significantly greater than those in non-VA-involved cases (P = 0.000). Moreover, with higher score (P = 0.000) and greater WCSA (P = 0.001) on the left side, the VA-involved cases showed a preference (74%) of left HFS. CONCLUSIONS: In HFS, the symptomatic side tends to have an ipsilaterally deviated and relatively larger VA, especially in VA-involved cases. And it is the VA-involved cases that are prone to have a prevalence of left HFS, but not the non-VA-involved cases.

GPNMB silencing suppresses the proliferation and metastasis of osteosarcoma cells by blocking the PI3K/Akt/mTOR signaling pathway.

Glycoprotein non­metastatic melanoma protein B (GPNMB) is a glycoprotein that is highly expressed in various types of cancer, including osteosarcoma. However, its cellular functions and related mechanisms in osteosarcoma remain unclear. In the present study, a higher GPNMB mRNA level was observed in osteosarcoma tissues, than in adjacent non­cancerous tissues. In addition, upregulation of the GPNMB mRNA and protein level was detected in the osteosarcoma cells SaOS2, 143B, MG63 and U2OS using western blot analysis and qPCR. Following transfection with GPNMB siRNA, the proliferation, migration and invasion of MG63 and U2OS cells were assessed using MTT and Transwell assays. The knockdown of GPNMB markedly inhibited the proliferation and metastasis of MG63 and U2OS cells. GPNMB silencing inhibited the activation of PI3K/Akt/mTOR signaling in MG63 and U2OS cells. PI3K/AKT activator insulin­like growth factor­1 (IGF­1) significantly activated the PI3K/Akt/mTOR signaling and reversed the suppressive effects of GPNMB silencing. IGF­1 counteracted the inhibitory effects of GPNMB silencing on the proliferation and metastasis of the MG63 and U2OS cells. In conclusion, we provided evidence that GPNMB silencing regulated the proliferation and metastasis of osteosarcoma cells by suppressing the PI3K/Akt/mTOR signaling pathway. Thus, GPNMB may be a potential therapeutic target for osteosarcoma treatment.

Significant MRI indicators of malignancy for breast non-mass enhancement.

OBJECTIVE: To explore and evaluate new malignant predictors of breast non-mass enhancement lesions using the new BI-RADS MRI lexicon. METHODS: A dataset involving 422 consecutive women underwent breast 3.0 T MRI between January 2014 and July 2016 was assembled for this study. Each case was retrospectively reviewed by 3 radiologists. Eighty-four lesions that present non-mass enhancement in 79 patients were identified in the study. Dynamic contrast-enhanced MRI features were analyzed using univariate and multivariate analyses to identify significant indicators of malignancy. RESULTS: Of 84 non-mass enhancement lesions, 52 (61.9%) were malignant and 32 (38.1%) were benign. Segmental distribution (P = 0.015 from univariate analysis; OR = 4.739, P = 0.008 from multivariate analysis), cluster ring enhancement (P = 0.017 from univariate analysis; OR = 3.601, P = 0.032 from multivariate analysis), time-intensity curve of plateau (P = 0.002 from univariate analysis; OR = 3.525, P = 0.027 from multivariate analysis) and phase to peak (P = 0.06 from univariate analysis; OR = 6.327, P = 0.015 from multivariate analysis) were significantly different between malignant and benign lesions. CONCLUSIONS: This study demonstrated that segmental distribution, clustered ring enhancement, and short time to peak could act as new malignant predictors for breast non-mass enhancement detected on 3.0 T MRI.

Metastatic gastric carcinoma to the breast: A case report and review of the Chinese literature.

Breast metastasis is extremely unusual in gastric cancer patients worldwide. We herein report the case of a 39-year-old female Chinese patient presenting with symptoms of inflammation in the left breast. A biopsy did not reveal any evidence of malignancy. A modified radical mastectomy was performed and the postoperative pathological examination revealed infiltration by signet ring cell gastric carcinoma. A review of the Chinese literature was performed, and a total of 16 patients with breast metastasis from gastric carcinoma have been reported from 1990 onwards. This condition is associated with a poor prognosis, with a survival time of 1 month to 4 years. More studies are required to determine the optimal treatment.

Facile synthesis of soybean phospholipid-encapsulated MoS2 nanosheets for efficient in vitro and in vivo photothermal regression of breast tumor.

Two-dimensional MoS2 nanosheet has been extensively explored as a photothermal agent for tumor regression; however, its surface modification remains a great challenge. Herein, as an alternative to surface polyethylene glycol modification (PEGylation), a facile approach based on "thin-film" strategy has been proposed for the first time to produce soybean phospholipid-encapsulated MoS2 (SP-MoS2) nanosheets. By simply vacuum-treating MoS2 nanosheets/soybean phospholipid/chloroform dispersion in a rotary evaporator, SP-MoS2 nanosheet was successfully constructed. Owing to the steric hindrance of polymer chains, the surface-coated soybean phospholipid endowed MoS2 nanosheets with excellent colloidal stability. Without showing detectable in vitro and in vivo hemolysis, coagulation, and cyto-/histotoxicity, the constructed SP-MoS2 nanosheets showed good photothermal conversion performance and photothermal stability. SP-MoS2 nanosheet was shown to be a promising platform for in vitro and in vivo breast tumor photothermal therapy. The produced SP-MoS2 nanosheets featured low cost, simple fabrication, and good in vivo hemo-/histocompatibility and hold promising potential for future clinical tumor therapy.