Centrosomal protein 290 is a novel prognostic indicator that modulates liver cancer cell ferroptosis via the Nrf2 pathway.

Ferroptosis is an iron-dependent form of cell death. In spite of its significance in pathogenesis and disease progression, ferroptotic signal transduction in HBV-HCC has not been fully explained. Here, four HCC open-source datasets were downloaded from the GEO repository. Cox regression and LASSO models were established to prioritize novel prognostic candidate biomarkers, and the results were verified in vitro and in vivo. We identified 633 common DEGs in both of the bulk RNA-Seq expression profiles. Next, based upon the TCGA-LIHC cohort, a prognostic signature consisting of nine genes was extracted from 633 shared DEGs, and the specificity and sensitivity of the signature were evaluated in both training and validation datasets. This signature showed that the high-risk group had a worse prognosis than the low-risk group. CEP290 was discovered among the prognostic signature genes, and its expression notably correlated with survival, AFP level, TNM stage and vascular invasion. We confirmed expression of CEP290 in eight pairs of HCC tissues and diverse liver cancer cell lines. CEP290 knockdown reduced proliferation, migration and invasion in Hep3B liver cancer cells while Fe2+ and malondialdehyde levels were elevated. Mechanically, co-immunoprecipitation showed an interaction between CEP290 and Nrf2 proteins, and biological phenotypes of Hep3B cells under CEP290 interference were rescued by Nrf2 activator. Furthermore, CEP290 silencing considerably blocked protein expression of Nrf2 pathway members. Finally, suppression of CEP290 effectively inhibited tumor growth in vivo. The above results shed light on the important role of CEP290 in ferroptosis and present an important implication for HCC progression.

Gradient cell-structured high-entropy alloy with exceptional strength and ductility.

Similar to conventional materials, most multicomponent high-entropy alloys (HEAs) lose ductility as they gain strength. In this study, we controllably introduced gradient nanoscaled dislocation cell structures in a stable single-phase HEA with face-centered cubic structure, thus resulting in enhanced strength without apparent loss of ductility. Upon application of strain, the sample-level structural gradient induces progressive formation of a high density of tiny stacking faults (SFs) and twins, nucleating from abundant low-angle dislocation cells. Furthermore, the SF-induced plasticity and the resultant refined structures, coupled with intensively accumulated dislocations, contribute to plasticity, increased strength, and work hardening. These findings offer a promising paradigm for tailoring properties with gradient dislocation cells at the nanoscale and advance our fundamental understanding of the intrinsic deformation behavior of HEAs.

Ubiquitin-Like Modifier Activating Enzyme 1 as a Novel Diagnostic and Prognostic Indicator That Correlates With Ferroptosis and the Malignant Phenotypes of Liver Cancer Cells.

PURPOSE: Ferroptosis is a type of cell death that is iron dependent, a characteristic that distinguishes it from necrosis, apoptosis, and autophagy. However, the ferroptotic mechanisms for hepatitis B virus-associated hepatocellular carcinoma (HCC) remain incompletely described. METHODS: Two hepatitis B virus-associated HCC public datasets, GSE22058 (n=192) and GSE54238 (n=23), were obtained from the NCBI Gene Expression Omnibus (GEO) database. Bioinformatics methods, including weighted gene coexpression network analysis (WGCNA), Cox regression, and LASSO analysis, were used to identify signature markers for diagnosis and prognosis. CCK8, wound healing, Transwell migration/invasion, and ferroptosis assays were employed to explore the biological function of novel candidate markers weight gene coexpression network analysis. RESULTS: In total, 926 differentially expressed genes (DEGs) were common between the GSE22058 and GSE54238 datasets. Following WGCNA, 515 DEGs derived from the MEturquoise gene module were employed to establish diagnosis and prognosis models in The Cancer Genome Atlas (TCGA) HCC RNA-Seq cohort (n=423). The score of the diagnostic model was strikingly upregulated in the TCGA HCC group (p<2.2e-16). The prognostic model exhibited high specificity and sensitivity in both training and validation (AUC=0.835 and 0.626, respectively), and the high-risk group showed dismal prognostic outcomes compared with the low-risk group (training: p=1.416e-10; validation: p=4.495e-02). Ubiquitin-like modifier activating enzyme 1 (UBA1) was identified among both diagnosis and prognosis signature genes, and its overexpression was associated with poor survival. We validated the expression level of UBA1 in eight pairs of HCC patient tissues and liver cancer cell lines. UBA1 silencing decreased proliferation, migration, and invasion in Huh7 cells while elevating the Fe2+ and malondialdehyde (MDA) levels. Additionally, these biological effects were recovered by oltipraz (an Nrf2 activator). Furthermore, blocking UBA1 strikingly repressed the protein expression levels of Nrf2, HO-1, NQO1, and FTH1 in the Nrf2 signal transduction pathway. CONCLUSION: Our findings demonstrated that UBA1 participates in the development of HCC by modulating Huh7 phenotypes and ferroptosis via the Nrf2 signal transduction pathway and might be a promising diagnostic and prognostic indicator for HCC.

Structural and functional reorganization following unilateral internal capsule infarction contribute to neurological function recovery.

PURPOSE: To investigate proliferative reorganization in the bilateral corticospinal tract (CST) and functional reorganization in the sensorimotor network (SMN) after internal capsule stroke, and to examine the significance of this reorganization. METHODS: We recruited 17 patients with first-onset acute stroke (16 male, 1 female, mean age 52 ± 10 years) and 17 age- and sex-matched healthy controls. We excluded patients aged < 18 or > 65 years and those with lesions outside the unilateral internal capsule. All subjects underwent diffusion tensor imaging and resting-state functional MRI on days 7, 30, and 90 from symptom onset. We measured fractional anisotropy (FA) in the CST, interhemispheric functional connectivity (FC) within the SMN, and pre-MRI clinical scores, including the National Institutes of Health Stroke Scale (NIHSS), Barthel Index (BI), and Fugl-Meyer (FM). Correlations among the changes in FA, FC, and clinical scores were analyzed. RESULTS: From day 7 to 90 after stroke, FA in the bilateral CST increased (ipsilesional side, Pinternal capsule = 0.009, Pcentrum semiovale = 0.001; contralesional side, Pinternal capsule = 0.006, Pcentrum semiovale = 0.017), as did FC (P < 0.05); NIHSS scores decreased (P < 0.05), while FM and BI progressively increased (P < 0.05). Increased FA in bilateral CST was negatively correlated with decreased NIHSS scores. Increased FA in only the ipsilesional side was positively correlated with increased FM. Increased FC was positively correlated only with increased BI. CONCLUSION: Proliferative reorganization in the CST and functional reorganization in the SMN support and promote neurological functional recovery after internal capsule infarction.

A clinical research on the potential pathogenesis of somatic cancer related cerebral venous sinus thrombosis.

To investigate the pathogenesis of somatic solid cancer-related cerebral venous sinus thrombosis (CVST).A total of 174 patients with CVST were recruited from the hospital between January 2006 and December 2017 and divided into two groups: (1) somatic cancer-related CVST group, defined as active somatic solid cancer patients with acute CVST; (2) cancer group (CG), defined as active somatic solid cancer patients without CVST. The cancer group patients were age and gender-matched somatic cancer-related CVST group patients. In addition, the types and amount distribution of cancer in cancer group were also matched with somatic cancer-related CVST group patients.Compared to cancer group patients, somatic cancer-related CVST group patients had more intracranial metastasis, a higher platelet count, higher plasma D-dimer, carcinoembryonic antigen (CEA) and cancer antigen (CA) 125 levels, a greater platelet to lymphocyte ratio (PLR), and a greater platelet to neutrophil ratio (PNR). The risk for CVST in somatic cancer-related CVST group patients increased independently by 0.7% (odds ratio [OR] 1.007; 95% confidence interval [CI] 1.000, 1.015; P = .047) with a 1 ng/ml increase in D-dimer levels, by 4.6% (OR 1.046; 95% CI 1.011, 1.083; P = .010) with a 1 U/ml increase in CEA, by 2.7% (OR 1.027; 95% CI 1.003, 1.051; P = .025) with a 1 U/ml increase in CA125, and by 10.6% (OR 1.106; 95% CI 1.002, 1.220; P = .045) with a 1 unit increase in PNR.It was suggested that together impacts of elevated plasma D-dimer, CA125, CEA levels, and a greater PNR may lead to hypercoagulability and to trigger the development of cancer-related CVST.

Extra strengthening and work hardening in gradient nanotwinned metals.

Gradient structures exist ubiquitously in nature and are increasingly being introduced in engineering. However, understanding structural gradient-related mechanical behaviors in all gradient structures, including those in engineering materials, has been challenging. We explored the mechanical performance of a gradient nanotwinned structure with highly tunable structural gradients in pure copper. A large structural gradient allows for superior work hardening and strength that can exceed those of the strongest component of the gradient structure. We found through systematic experiments and atomistic simulations that this unusual behavior is afforded by a unique patterning of ultrahigh densities of dislocations in the grain interiors. These observations not only shed light on gradient structures, but may also indicate a promising route for improving the mechanical properties of materials through gradient design.

Cerebral hemorrhage as the initial manifestation in patients with systemic cancer.

BACKGROUND: Cerebral hemorrhage as well as ischemic stroke is one of the common complications among patients with cancer. Ischemic stroke could be the initial manifestation in some patients with cancer. Meanwhile, some patients with cancer also could present cerebral hemorrhage as the initial manifestation, and further studies are required to determine whether these patients have their unique clinical features. AIM: To investigate the clinical features and underlying pathogenesis of concealed systemic cancer patients with cerebral hemorrhage as the initial manifestation. METHODS: The clinical data of patients with concealed systemic cancer who presented cerebral hemorrhage as the initial manifestation registered at the First Affiliated Hospital of Guangxi Medical University from January 2010 to December 2015 were prospectively collected and analyzed. RESULTS: Seventeen systemic cancer patients with cerebral hemorrhage as the initial manifestation (0.02%) were ultimately enrolled from 8,326 patients with cerebral hemorrhage. Three patients had traditional risk factors, but the other 14 patients did not. The common subtypes of malignancy were lung cancer, liver cancer, gastric carcinoma, rectal cancer and melanoma. Most patients (11/17, 64.7%) had elevated plasma levels of cancer biochemical markers, including cancer antigen (CA)125, CA153 and CA199, carcino-embryonic antigen, and alpha fetal protein. Coagulopathy was observed in 15 patients. CONCLUSION: The concealed systemic cancer patients with cerebral hemorrhage as the initial manifestation may lack conventional vascular risk factors but did present coagulopathy and elevated plasma levels of cancer biochemical markers. Coagulopathy might be responsible for the cerebral hemorrhage.

History-independent cyclic response of nanotwinned metals.

Nearly 90 per cent of service failures of metallic components and structures are caused by fatigue at cyclic stress amplitudes much lower than the tensile strength of the materials involved. Metals typically suffer from large amounts of cumulative, irreversible damage to microstructure during cyclic deformation, leading to cyclic responses that are unstable (hardening or softening) and history-dependent. Existing rules for fatigue life prediction, such as the linear cumulative damage rule, cannot account for the effect of loading history, and engineering components are often loaded by complex cyclic stresses with variable amplitudes, mean values and frequencies, such as aircraft wings in turbulent air. It is therefore usually extremely challenging to predict cyclic behaviour and fatigue life under a realistic load spectrum. Here, through both atomistic simulations and variable-strain-amplitude cyclic loading experiments at stress amplitudes lower than the tensile strength of the metal, we report a history-independent and stable cyclic response in bulk copper samples that contain highly oriented nanoscale twins. We demonstrate that this unusual cyclic behaviour is governed by a type of correlated 'necklace' dislocation consisting of multiple short component dislocations in adjacent twins, connected like the links of a necklace. Such dislocations are formed in the highly oriented nanotwinned structure under cyclic loading and help to maintain the stability of twin boundaries and the reversible damage, provided that the nanotwins are tilted within about 15 degrees of the loading axis. This cyclic deformation mechanism is distinct from the conventional strain localizing mechanisms associated with irreversible microstructural damage in single-crystal, coarse-grained, ultrafine-grained and nanograined metals.

Potential Pathogenesis and Biomarkers of Kidney Cancer-Related Stroke.

BACKGROUND Stroke risk and stroke recurrence are increased in cancer patients, but the pathogenesis and biomarkers of kidney cancer-related stroke (KCS) are generally unclear. The aim of the present research was to investigate the pathogenesis and plasma biomarkers of kidney cancer-related stroke. MATERIAL AND METHODS A retrospective review was conducted on acute stroke patients with kidney cancer (KC) who were admitted to the hospital between January 2006 and December 2015. A total of 106 patients with KCS (active KC patients with acute stroke but without conventional vascular risks) were identified. In addition, 106 age- and sex-matched patients with KC alone were recruited. RESULTS KCS patients had higher plasma D-dimer, cancer antigen (CA) 125, and CEA levels and greater proteinuria levels than did KC patients. Multiple logistic regression analysis showed that the risk of stroke in patients with KC increased independently by 0.8% (odds ratio [OR] 1.008; 95% confidence interval [CI] 1.002, 1.013; p=0.004) with a 1 ng/mL increase in D-dimer levels, by 1.2% (OR 1.012; 95% CI 1.007, 1.018; p=0.000) with a 1 U/mL increase in CA125, by 2.5% (OR 1.025; 95% CI 1.012, 1.038; p=0.000) with a 1 U/mL increase in CEA by 1.4% (OR 1.014; 95% CI 1.005, 1.024; p=0.004) with a 1 mg increase in urine protein in 24 hours. CONCLUSIONS Elevated plasma D-dimer, CA125 and CEA levels, and increased urine protein levels might lead to hypercoagulability and then KCS; however, they may also be biomarkers of KCS.

Clinical Features of Liver Cancer with Cerebral Hemorrhage.

BACKGROUND Cerebral hemorrhage is common in patients with cancer, but the clinical features and pathogenesis of liver cancer patients with cerebral hemorrhage are not well known. MATERIAL AND METHODS Liver cancer patients who developed cerebral hemorrhage were recruited from the First Affiliated Hospital of Guangxi Medical University between January 2003 and December 2014. We retrospectively analyzed clinical presentations, results of laboratory tests, and imaging examinations. The clinical features and pathogenesis were summarized. RESULTS Among 11133 patients with liver cancer, 9 patients (0.08%), including 3 females and 6 males met the inclusion criteria. The age range was 48-73 years and the average age was 61.67±8.97 years. Five patients did not have traditional hemorrhage risk factors and 4s had the risk factors; however, all had developed hepatocellular carcinoma, and 3 had developed metastasis. All 9 patients showed elevated tumor markers: an increased AFP level was detected in 6 patients, coagulation dysfunctions in 8 patients, and abnormal liver functions in 6 patients. Five patients had developed cerebral hemorrhagic lesions in the lobes of their brains, while hemorrhagic lesions in the basal ganglia occurred in 3 patients and in the brainstem in only 1 patient. Four patients had clear consciousness, while 5 patients were in coma and showed poor prognosis. CONCLUSIONS Patients who have liver cancer complicated with cerebral hemorrhage usually lack traditional risk factors of cerebral hemorrhage. The site of cerebral hemorrhage is often detected in the lobes of the brain. Coagulation dysfunctions might be the main pathogenesis of liver cancer complicated with cerebral hemorrhage.

[Clinical characteristics of acute cerebral hemorrhage in patients with systemic malignancy].

OBJECTIVE: To investigate the clinical features of systemic malignancy patients with acute cerebral hemorrhage as well as its underlying mechanism. METHODS: The clinical data, including presentation, lab tests and neurological images, of systemic malignancy patients with acute cerebral hemorrhage at the First Affiliated Hospital of Guangxi Medical University between January 2003 and December 2014 were collected and analyzed. RESULTS: Among 61 326 systemic malignancy patients, 25 patients(0.04%)were found with acute cerebral hemorrhage and were enrolled. Out of these 25 patients, age ranged from 31 to 77 years old, with an average age of 61 years, 18 patients were males. The clinical features of the systemic malignancy patients with acute cerebral hemorrhage were found that most patients (14/25, 54.0%) lacked traditional risk factors, with sudden symptom onset and some degree of neurologic deficiency in all patients, and most hemorrhagic lesions (19/25, 76.0%) involved the hemicerebrum, for most patients (16/25, 60.0%) cerebral hemorrhage occurred after 3 days to 3 years of the malignancy diagnosis, and some malignancy patients (8/25, 32.0%) presented with cerebral hemorrhage as the first presentation. The common subtypes of malignancy found were lung cancer (8/25, 32.0%), liver cancer (7/25, 28.0%), and then gastric carcinoma (6/25, 24.0%). Most patients (22/25, 88.0%) had elevated plasma level of cancer biochemical marks (including one or more than one of cancer antigen 125, 153 and 199, carcino-embryonic antigen, and alpha fetal protein), most patients (16/25, 64.0%) were found to have coagulation disorder. CONCLUSIONS: The unique clinical features of the systemic malignancy patients with acute cerebral hemorrhage are most patients lacking traditional risk factors, with coagulation disorder and with hemorrhagic lesions in hemicerebrum. And coagulation disorder might be responsible for the cerebral hemorrhage.

Contribution of three ionic types of polysaccharides to the thermal gelling properties of chicken breast myosin.

The effects of anionic (κ-carrageenan, KCG), neutral (locust bean gum, LBG), and cationic polysaccharides (water-soluble chitosan, WSC) on the water-holding capacity (WHC) and hardness of chicken myosin gels were investigated at 0-1.0% addition levels. The changes of gel properties were explained using different instrumental techniques. The results revealed that KCG and LBG at 0.5-1.0% could respectively cause significant increases of both WHC and hardness of corresponding heat-induced myosin-polysaccharide gels (P < 0.05). These increases could be ascribed to a slower relaxation, reinforced cross-linked extent, enhanced hydrogen bonding, and a fine-stranded gel network, according to the analysis of low-field nuclear magnetic resonance, dynamic rheology, Fourier transform infrared spectroscopy, and scanning electron microscopy measurements. However, the weak molecular interaction within myosin-WSC gels induced an insignificant change of the WHC and hardness (P > 0.05). Therefore, it is interesting to search for the anionic polysaccharide and neutral polysaccharide for use as fat substitutes in the development of low-fat meat products.

One-pot synthesis of (Au nanorod)-(metal sulfide) core-shell nanostructures with enhanced gas-sensing property.

(Au nanorod)-(metal sulfide) core-shell structures are synthesized by employing Au nanorods as the starting reactants and metal thiobenzoates as the metal sulfide precursors in the presence of Ag(+) ions. The gas-sensing property of the prepared (Au nanorod)-CdS sensor exhibit a significantly enhanced response and higher sensitivity in comparison with a CdS sensor.