MXene-Enhanced Bi2S3/CdIn2S4 Heterojunction Photosensitive Gate for DEHP Detection in a Signal-On OPECT Aptamer Biosensor.

Organic electrochemical transistors with signal amplification and good stability are expected to play a more important role in the detection of environmental pollutants. However, the bias voltage at the gate may have an effect on the activity of vulnerable biomolecules. In this work, a novel organic photoelectrochemical transistor (OPECT) aptamer biosensor was developed for di(2-ethylhexyl) phthalate (DEHP) detection by combining photoelectrochemical analysis with an organic electrochemical transistor, where MXene/Bi2S3/CdIn2S4 was employed as a photoactive material, target-dependent DNA hybridization chain reaction was used as a signal amplification unit, and Ru(NH3)63+ was selected as a signal enhancement molecule. The poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate)-based OPECT biosensor modulated by the MXene/Bi2S3/CdIn2S4 photosensitive material achieved a high current gain of nearly a thousand times at zero bias voltage. The developed signal-on OPECT sensing platform realized sensitive and specific detection of DEHP, with a detection range of 1-200 pM and a minimum detection limit of 0.24 pM under optimized experimental conditions, and its application to real water samples was also evaluated with satisfactory results. Hence, the construction of this OPECT biosensing platform not only provides a promising tool for the detection of DEHP but also reveals the great potential of the OPECT application for the detection of other environmental toxins.

Ascorbic Acid Induced the Improved Oxygen Vacancy Defects of Bi4O5Br2 and Its Application on Photoelectrochemical Detection of DNA Demethylase MBD2 with Improved Detection Sensitivity.

Oxygen vacancy defects (OVs) are one of the main strategies for nanomaterials modification to improve the photoactivity, but current methods for fabricating OVs are usually complicated and harsh. It is important to develop simple, rapid, safe, and mild methods to fabricate OVs. By studying the effects of different weak reducing agents, the concentration of the reducing agent and the reaction time on fabrication of OVs, it is found that L-ascorbic acid (AA) gently and rapidly induces the increase of OVs in Bi4O5Br2 at room temperature. The increased OVs not only improve the adsorption of visible light, but also enhance the photocurrent response. Based on this, the preparation of OVs in Bi4O5Br2 is employed to the development of a photoelectrochemical biosensor for the detection of DNA demethylase of methyl-CpG binding domain protein 2 (MBD2). The biosensor shows a wide linear range of 0.1-400 ng mL-1 and a detection limit as low as 0.03 ng mL-1 (3σ). In addition, the effect of plasticizers on MBD2 activity is evaluated using this sensor. This work not only provides a novel method to prepare OVs in bismuth rich materials, but also explores a new novel evaluation tool for studying the ecotoxicological effects of contaminants.

Combination of scavenger receptor-A with anti-cyclic citrullinated peptide antibody for the diagnosis of rheumatoid arthritis.

OBJECTIVES: The routine biomarkers for rheumatoid arthritis (RA), including anticyclic citrullinated peptide antibody (anti-CCP), rheumatoid factor (RF), immunoglobulin M (IgM), erythrocyte sedimentation rate (ESR), and C-reaction protein (CRP) have limited sensitivity and specificity. Scavenger receptor-A (SR-A) is a novel RA biomarker identified by our group recently, especially for seronegative RA. Here, we performed a large-scale multicentre study to further assess the diagnostic value of SR-A in combination with other biomarkers for RA. METHODS: The performance of SR-A in combination with other biomarkers for RA diagnosis was first revealed by a pilot study, and was further elucidated by a large-scale multicentre study. A total of 1129 individuals from 3 cohorts were recruited in the study, including RA patients, healthy controls, and patients with other common rheumatic diseases. Diagnostic properties were evaluated by the covariate-adjusted receiver-operating characteristic (AROC) curve, sensitivity, specificity and clinical association, respectively. RESULTS: Large-scale multicentre analysis showed that SR-A and anti-CCP dual combination was the optimal method for RA diagnosis, increasing the sensitivity of anti-CCP by 13% (87% vs 74%) while maintaining a specificity of 90%. In early RA patients, SR-A and anti-CCP dual combination also showed promising diagnostic value, increasing the sensitivity of anti-CCP by 7% (79% vs 72%) while maintaining a specificity of 94%. Moreover, SR-A and anti-CCP dual combination was correlated with ESR, IgM, and autoantibodies of RA patients, further revealing its clinical significance. CONCLUSION: SR-A and anti-CCP dual combination could potentially improve early diagnosis of RA, thus improving the prognosis and reducing mortality.

Tough Bonding of PVA Hydrogel-on-Textured Titanium Alloy with Varying Texture Densities in Swollen State.

Cartilage defects in large joints are a common occurrence in numerous degenerative diseases, especially in osteoarthritis. The hydrogel-on-metal composite has emerged as a potential candidate material, as hydrogels, to some extent, replicate the composition of human articular cartilage consisting of collagen fibers and proteoglycans. However, achieving tough bonding between the hydrogel and titanium alloy remains a significant challenge due to the swelling of the hydrogel in a liquid medium. This swelling results in reduced interfacial toughness between the hydrogel and titanium alloy, limiting its potential clinical applications. Herein, our approach aimed to achieve durable bonding between a hydrogel and a titanium alloy composite in a swollen state by modifying the surface texture of the titanium alloy. Various textures, including circular and triangular patterns, with dimple densities ranging from 10 to 40%, were created on the surface of the titanium alloy. Subsequently, poly(vinyl alcohol) (PVA) hydrogel was deposited onto the textured titanium alloy using a casting-drying method. Our findings revealed that PVA hydrogel on the textured titanium alloy with a 30% texture density exhibited the highest interfacial toughness in the swollen state, measuring at 1300 J m-2 after reaching equilibrium swelling in deionized water, which is a more than 2-fold increase compared to the hydrogel on a smooth substrate. Furthermore, we conducted an analysis of the morphologies of the detached hydrogel from the textured titanium alloy after various swelling durations. The results indicated that interfacial toughness could be enhanced through mechanical interlocking, facilitated by the expanded volume of the hydrogel protrusions as the swelling time increased. Collectively, our study demonstrates the feasibility of achieving tough bonding between a hydrogel and a metal substrate in a liquid environment. This research opens up promising avenues for designing soft/hard heterogeneous materials with strong adhesive properties.

[Effect of printing orientation on physical and mechanical properties of 3D printing prosthodontic base resin materials].

OBJECTIVE: To analyze the influence of forming direction on the surface characteristics, elastic modulus, bending strength and fracture toughness of printed parts and the relationship between forming direction and force direction, and to provide scientific basis and guidance for the clinical application of oral denture base resin materials. METHODS: The 3D printing technology was used to print denture base resin samples. The shape and size of the samples referred to the current standard for testing conventional denture base materials. The samples used for physical performance testing were cylindrical (with a diameter of 15 mm and a thickness of 1 mm) and printed at different angles along the Z axis (0°, 45°, 90°). Scanning electron microscope was used to observe the microscopic topography of the different samples. The color stability of different samples was observed by color stabilizer. The surface roughness of the samples was analyzed by using surface roughness tester. The Vickers hardness was measured to analyze the hardness of the samples. The samples used for mechanical performance testing were rectangular (elastic modulus and bending strength: A length of 64 mm, a width of 10 mm, and a height of 3.3 mm; fracture toughness: A length of 39 mm, a width of 8 mm, and a height of 4 mm), divided into two groups: W group and H group. The W group was printed from the bottom up along the Z axis with the length × width as the bottom surface parallel to the X, Y axis plane, while the H group printed from the bottom up along the Z axis with the length × height as the bottom surface parallel to the X, Y axis plane. The forming angles of both groups were equally divided into 0°, 45°, and 90°. The elastic modulus, bending strength and fracture toughness of different samples were studied through universal mechanical testing machine. SPSS 22.0 software was used for statistical analysis. RESULTS: The microscopic topography and roughness of different samples were closely related to the printing direction, with significant differences between the 0°, 45°, and 90° specimens. The 0° specimens had the smoothest surface (roughness < 1 µm). The surface of the 45° specimen was the roughest (roughness>3 µm). The microhardness of the 0° sample was the best [(196.13±0.20) MPa], with a significant difference compared with the 90° sample [(186.62±4.81) MPa, P < 0.05]. The mechanical properties of different samples were also closely related to the printing direction. The elastic modulus, bending strength, and fracture toughness of the 45° samples in the W group were the highest compared with the other groups. The results of elastic modulus showed that in the H group, the 45° specimens had the highest elastic mo-dulus, which was significantly different from the 0° and 90° specimens (P < 0.05). The elastic modulus of 0° and 45° specimens in the W group were higher than those in 90° specimens (P < 0.05). The bending strength results showed that there was no significant difference between the specimens from dif-ferent angles in the H group. The bending strength of the 90° specimens in the W group was the smallest, and there was a significant difference between 90° and the 0° and 45° specimens (P < 0.05); And the bendind strength of the 0° and 45° specimens in the W group was significantly higher than that of the 0° and 45° specimens in the H group (P < 0.05). The fracture toughness results showed that the fracture toughness of the H group specimens was lower than 1.9 MPa m1/2, which was specified in the denture base standard. The 45° samples in the W group were the highest, with significant differences compared with the 0° and 90° samples (P < 0.05). And the 90° samples of the W group specimens were lower than 1.9 MPa m1/2. And the fracture toughness of the 45° specimen in the W group was significantly higher than that of all the specimens in the H group (P < 0.05). CONCLUSION: The 0° samples had relatively better physical properties. The 45° samples had the best mechanical properties. But the fracture toughness of specimens (H group and 90° samples of W group) did not yet meet clinical requirements. That indicated that the characteristics of the 3D printing denture base resin were affected by the printing direction. Only when the performance of the printed samples in all directions met the minimum requirements of the standard, they could be used in clinical practice.

The role of TXNIP in cancer: a fine balance between redox, metabolic, and immunological tumor control.

Thioredoxin-interacting protein (TXNIP) is commonly considered a master regulator of cellular oxidation, regulating the expression and function of Thioredoxin (Trx). Recent work has identified that TXNIP has a far wider range of additional roles: from regulating glucose and lipid metabolism, to cell cycle arrest and inflammation. Its expression is increased by stressors commonly found in neoplastic cells and the wider tumor microenvironment (TME), and, as such, TXNIP has been extensively studied in cancers. In this review, we evaluate the current literature regarding the regulation and the function of TXNIP, highlighting its emerging role in modulating signaling between different cell types within the TME. We then assess current and future translational opportunities and the associated challenges in this area. An improved understanding of the functions and mechanisms of TXNIP in cancers may enhance its suitability as a therapeutic target.

Magnetic field modulated ultrafast spin dynamics at Ni80Fe20/Neodymium interface.

Ultrafast spin dynamics is crucial for the next-generation spintronic devices towards high-speed data processing. Here, we investigate the ultrafast spin dynamics of Neodymium/Ni80Fe20 (Nd/Py) bilayers by the time-resolved magneto-optical Kerr effect. The effective modulation of spin dynamics at Nd/Py interfaces is realized by an external magnetic field. The effective magnetic damping of Py increases with increasing Nd thickness, and a large spin mixing conductance (∼19.35×1015 cm-2) at Nd/Py interface is obtained, representing the robust spin pumping effect by Nd/Py interface. The tuning effects are suppressed at a high magnetic field due to the reduced antiparallel magnetic moments at Nd/Py interface. Our results contribute to understanding ultrafast spin dynamics and spin transport behavior in high-speed spintronic devices.

Sex-specific associations between cord blood lead and neurodevelopment in early life: The mother-child cohort (Shanghai, China).

The extent to which neurodevelopment is affected by prenatal lead exposure has not been conclusive. In addition, studies on the effects of sex on these relationships are inconsistent. The aim of this study was to investigate the impact of cord blood lead on neurodevelopment in children within sex subgroups. A total of 275 mother-child pairs from the Shanghai mother-child cohort were included. Umbilical cord blood lead was measured using graphite furnace atomic absorption spectrophotometry. The Bayley Scales for Infant Development-III (BSID-III) was used to measure the neurodevelopment of infants at the age of 18 ± 1.5 months. The median and interquartile range of cord blood lead levels in the total participants, male, and female children were 44.0 (24.5) µg/L, 44.0 (24.3) µg/L, and 46.0 (24.0) µg/L, respectively. According to multiple linear regression, cord blood lead concentrations showed a negative association with fine motor scores in all models associated with female children (ß = -1.5; 95%confidence interval: -2.6, -0.4). However, prenatal lead levels were not associated with any of the BSID-III scores in male children. In addition, cord serum DHA was found positively related to fine motor scores in male children. Our findings suggest that prenatal lead exposure could lead to decreased motor function, although this phenomenon was only observed in female children. And DHA may be a protective factor against lead exposure in boys. Thus, further studies are needed to investigate the associations between prenatal lead exposure and neurobehavioral development, as well as the mechanism of sex differences.

Molecular Dynamics Simulations on the Adsorbed Monolayers of N-Dodecyl Betaine at the Air-Water Interface.

Betaine is a kind of zwitterionic surfactant with both positive and negative charge groups on the polar head, showing good surface activity and aggregation behaviors. The interfacial adsorption, structures and properties of n-dodecyl betaine (NDB) at different surface coverages at the air-water interface are studied through molecular dynamics (MD) simulations. Interactions between the polar heads and water molecules, the distribution of water molecules around polar heads, the tilt angle of the NDB molecule, polar head and tail chain with respect to the surface normal, the conformations and lengths of the tail chain, and the interfacial thickness of the NDB monolayer are analyzed. The change of surface coverage hardly affects the locations and spatial distributions of the water molecules around the polar heads. As more NDB molecules are adsorbed at the air-water interface, the number of hydrogen bonds between polar heads and water molecules slightly decreases, while the lifetimes of hydrogen bonds become larger. With the increase in surface coverage, less gauche defects along the alkyl chain and longer NDB chain are obtained. The thickness of the NDB monolayer also increases. At large surface coverages, tilted angles of the polar head, tail chain and whole NDB molecule show little change with the increase in surface area. Surface coverages can change the tendency of polar heads and the tail chain for the surface normal.

Photoelectrochemical Biosensor for Histone Deacetylase Sirt1 Detection Based on Polyaspartic Acid-Engaged and Triggered Redox Cycling Amplification and Enhanced Photoactivity of BiVO4 by Gold Nanoparticles and SnS2.

A photoelectrochemical (PEC) biosensor was established for histone deacetylase Sirt1 detection based on the polyaspartic acid (PASP)-mediated redox cycling amplification and Sirt1 catalysis deacetylation-triggered recognition of the deacetylated substrate peptide, using PASP as the recognition reagent. After BiVO4 was composited with gold nanoparticles and SnS2, the photoactivity of the composite was greatly enhanced due to the matched energy band structure. Under the catalysis of Sirt1 enzyme, the acetylated substrate peptide was deacetylated to obtain a positive peptide, which was recognized by negative PASP. In addition to the recognition function, PASP also played other triple roles. First, PASP interacted with the positive peptide to form a double-stranded structure, which led to the electrode interface changing from irregular to regular, resulting in an improved PEC response. Second, PASP was involved into redox cycle amplification due to its reduction to dehydroascorbic acid. Further, it was used for repeated preparation of ascorbic acid to provide electron donors. This process enhanced the PEC response. Third, based on the matched energy band with BiVO4, PASP effectively improved the photoactivity of BiVO4. With multiplex signal amplification, the PEC biosensor showed a wide linear range (1.83-1830 pM) and high detection sensitivity with a low detection limit of 0.732 pM (S/N = 3). The applicability of this method was evaluated by studying the effects of a known inhibitor of nicotinamide and the heavy metal ions of Cd2+ and Pb2+ on Sirt1 enzyme activity, and the results showed that this method not only provided a new platform for screening Sirt1 enzyme inhibitors but also provided new biomarkers for evaluating the ecotoxicological effects of environmental pollutants.

CTRP4 acts as an anti-inflammatory factor in macrophages and protects against endotoxic shock.

Despite the availability of antibiotics, current therapies to treat sepsis are still ineffective and many clinical trials aimed at neutralizing specific inflammatory cytokines have failed, suggesting the urgent need for new treatments. Using two models of LPS-induced endotoxemia and cecal ligation and puncture (CLP)-induced sepsis, we investigated the effects of C1q/TNF-related protein 4(CTRP4) on septic lethality and sepsis-induced inflammation. The effects of CTRP4 on survival, inflammation, organ damage, and bacterial clearance were assessed. Here, we found that CTRP4 decreased the mortalities of mice and alleviated pathological lung injury in mice model. In vivo depletion and adoptive transfer studies showed CTRP4-expressing macrophages as the key cell type inhibiting LPS-induced septic shock. The mechanism associated with the CTRP4 deficiency involved promoting of TLR4 internalization and activation of downstream pathways that resulted in a lethal, prolonged proinflammatory cytokine storm. Treatment of macrophages with exogenous CTRP4 abrogated proinflammatory cytokine production. Our results showed CTRP4 regulates inflammatory response and could be a promising strategy to treat septic shock.

Effects of prenatal exposure to persistent organic pollutants on neonatal Outcomes:A mother-child cohort (Shanghai, China).

Persistent organic pollutants (POPs), known as common environmental pollutants, which have adverse effects on neurobehavioral development, are widely applied in industry and agriculture. However, evidence about neurodevelopmental toxicity of POPs in humans is limited. This study aimed to explore the relationship between prenatal exposure to POPs and birth outcome of the newborn including birth length, weight, and head circumference. In this study, 1522 mother-child pairs were included in this study and cord blood samples were collected, which were detected to determine exposure level of 37 POPs in total. After delivery, the neonatal anthropometric indices detection (birth length, weight, and head circumference) was performed. According to the multivariate linear regression, the newborn with high detection rates (≥75 percentile) of hexachlorobenzene (HCB), beta-hexachlorocyclohexane (ß-HCH), p,p'-dichlorodiphenyl dichloroethylene (p,p'-DDE) in the umbilical cord blood were demonstrated negative relationship with birth head circumference after adjusting for confounding factors, but not related with birth length and weight. After confirming that there was a nonlinear relationship between HCB and birth head circumference based on sex stratification through the generalized additive model (GAM), further two-piecewise linear regression model was conducted to explore the saturation threshold effect between HCB and birth head circumference, which showed cord serum HCB concentration greater than 0.5 µg/L was negatively associated with birth head circumference in girls. Our study provided evidence for the adverse influence of HCB, ß-HCH and p,p'-DDE exposure during pregnancy on the birth head circumference of offspring. Although HCB induced reduction of birth head circumference was found in girls, the mechanism of gender difference remained unclear. Further studies are needed to explore the effect of POPs on the growth and development of offspring based on in vivo or in vitro experimental models.

Neutrophil CD64 index for diagnosis of infectious disease in the pediatric ICU: a single-center prospective study.

BACKGROUND: Infection is a major cause of death in children, and it is particularly important to identify biological indicators of early infection. Previous studies showed that the neutrophil CD64 (nCD64) index may be a useful biomarker for infection. The purpose of this study was to investigate use of the nCD64 index to identify infection in children from a pediatric ICU (PICU) in China. METHODS: This prospective observational study enrolled 201 children who were admitted to our PICU and were divided into an infection group and a non-infection group. In each patient, C-reactive protein (CRP), nCD64 index, procalcitonin (PCT), and white blood cell count were measured during the first 24 h after admission. Receiver operating characteristic (ROC) analyses were used to determine the sensitivity, specificity, and diagnostic value of the nCD64 index for infection. RESULTS: Among all 201 children, the infection group had greater levels of CRP, nCD64 index, and PCT (all p < 0.05). ROC analysis indicated the nCD64 index had a sensitivity of 68.8%, specificity of 90.7%, accuracy of 80.5%, and an optimal cut-off value of 0.14, which had better diagnostic value than CRP or PCT. For children with postoperative fever, the nCD64 index also distinguished systemic inflammatory response syndrome (SIRS) from infection with accuracy of 79%. CONCLUSIONS: The nCD64 index is a useful biomarker for the diagnosis of early infection in children admitted to the PICU.

Knockdown of CENPK inhibits cell growth and facilitates apoptosis via PTEN-PI3K-AKT signalling pathway in gastric cancer.

Previous studies have indicated that centromere protein K (CENPK) is upregulated in several cancers and related to tumorigenesis. Nevertheless, the potential function of CENPK in gastric cancer (GC) remains unknown. Here, we investigated the function of CENPK on oncogenicity and explored its underlying mechanisms in GC. Our results showed that CENPK was dramatically overexpressed in GC and was associated with poor prognosis through bioinformatics analysis. We demonstrated that CENPK is upregulated in GC tissues and cell lines. Moreover, knockdown of CENPK significantly inhibited proliferation in vitro and attenuated the growth of implanted GCs in vivo. In addition, CENPK silencing induced G1 phase cell cycle arrest and facilitated apoptosis of GC cells. KEGG pathway analysis indicated that the PI3K-AKT signalling pathway was considerably enriched. Knockdown of CENPK decreased the expression of PI3K, p-Akt (Ser437) and p-GSK3ß (Ser9) in GC cells, and increased the expression of PTEN. In conclusion, this study indicated that CENPK was overexpressed in GC and may promote gastric carcinogenesis through the PTEN-PI3K-AKT signalling pathway. Thus, CENPK may be a potential target for cancer therapeutics in GC.

Association between prenatal exposure to persistent organic pollutants and neurodevelopment in early life: A mother-child cohort (Shanghai, China).

As common environmental pollutants, persistent organic pollutants (POPs) that are widely applied in industry and agriculture have adverse effects on neurodevelopment. However, evidence on the neurotoxicity of POPs in neural development of offspring is limited. This study explored the relationship between prenatal exposure to POPs and neurodevelopment of 18-month-old toddlers in a mother-child cohort in Shanghai, China. In this study, we determined exposure levels of 37 POPs in cord blood serum collected at the time of delivery. The detection rate of pollutants HCB, ß-HCH, and p,p'-DDE was higher than 60%, so these will be discussed in the following analysis. From birth to approximately 18 months, we followed up infants to longitudinally explore whether POPs influenced their language, motor, and cognitive development according to a Bayley-Ⅲ assessment . Based on multivariable regression analyses, the ß-HCH concentration in cord serum was negatively related to motor development scores in children at 18 months by adjusting for the covariates, but there was no change in language and cognition. Further piecewise linear regression analysis showed that a cord serum ß-HCH concentration greater than 0.2 µg/L had a significantly negative correlation with the motor development scores. p,p'-DDE was positively associated with language development at 18 months before and after adjusting for covariates. But prenatal HCB levels were not associated with any of the Bayley-Ⅲ subscales at 18 months. We concluded that prenatal exposure to ß-HCH might have adverse effects on infants' motor development. The minimum harmful concentration of ß-HCH was estimated at 0.2 µg/L in cord serum. The unexpected positive association between p,p'-DDT and language development could be due to live birth bias.

The decrease of T3 / T4 is not hypothyroidism - a new mutation of Serpina7 gene results in partial thyroglobulin deficiency.

To explore an unusual cause of the decrease of T3/T4 through a new mutation of TBG gene in a family, so as to avoid habitual thinking and reduce subsequent over treatment. TSH, free total T4, T3 and free T4, T3 were determined by automatic chemiluminescence immunoassay. The TBG mutation was identified by direct DNA sequencing. A frameshift mutation of p. l372ffs * 32 was found in the TBG gene (c.1114delc) of the patient by direct DNA sequencing, and the proband of the family was heterozygous. In vitro expression showed that the affinity of TBG for T4 decreased. Further examination of the family members showed that T3 and T4 were decreased, while FT3, FT4 and TSH were normal. If the patients with low TT4 and TT3 but normal TSH are found, the serum TBG level and related genes should be detected to determine whether it is TBG deficiency and avoid wrong treatment.

A novel protein CMTM1-v5 specifically induced human lymphoma cells apoptosis in vitro and in vivo.

Lymphoma is among the top 10 leading causes of cancer-related morbidity around the world in males, but currently, there is a lack of effective treatment strategies for this disease. Recently, we identified an alternatively spliced protein isoform, CMTM1-v5, which is significantly associated with tumor development and could serve as a potential therapeutic drug for lymphoma. Here, we showed that the overexpression of CMTM1-v5 in Raji cells or the addition of the CMTM1-v5 polypeptide to the cell culture medium induced apoptosis in vitro. During the in vivo experiments, most of the fluorescent CMTM1-v5 polypeptide converged within the tumor cells in Raji xenografts 24 h after treatment, and the injection of the polypeptide into the tail vein significantly extended survival in mice bearing Raji tumor cells. Mechanistically, the interaction between CMTM1-v5 and CAML (calcium-modulating cyclophilin ligand) negatively regulated the Ca2+ response in the ER, inducing the activation of caspases and the release of cytochrome c in mitochondria and resulting in cell apoptosis. Thus, our study provides a proof-to-concept that supports the use of CMTM1-v5 to treat lymphoma.

Endothelial cells promote triple-negative breast cancer cell metastasis via PAI-1 and CCL5 signaling.

Endothelial cells (ECs) in the tumor microenvironment have been reported to play a more active role in solid tumor growth and metastatic dissemination than simply providing the physical structure to form conduits for blood flow; however, the involvement of ECs in the process of triple-negative breast cancer (TNBC) metastasis has not been addressed. Here, we demonstrate that ECs-when mixed with TNBC cells-could increase TNBC cell metastatic potency. After treatment with TGF-ß to induce endothelial-mesenchymal transition (EMT), TNBC cells could produce plasminogen activator inhibitor-1 (PAI-1) and stimulate the expression and secretion of the chemokine, CCL5, from ECs, which then acts in a paracrine fashion on TNBC cells to enhance their migration, invasion, and metastasis. CCL5, in turn, accelerates TNBC cell secretion of PAI-1 and promotes TNBC cell metastasis, thus forming a positive feedback loop. Moreover, this enhanced metastatic ability is reversible and dependent on CCL5 signaling via the chemokine receptor, CCR5. Of importance, key features of this pathway are manifested in patients with TNBC and in The Cancer Genome Atlas database. Taken together, our results suggest that ECs enhance EMT-induced TNBC cell metastasis via PAI-1 and CCL5 signaling and illustrate the potential of developing new PAI-1- and CCL5-targeting therapy for patients with TNBC.-Zhang, W., Xu, J., Fang, H., Tang, L., Chen, W., Sun, Q., Zhang, Q., Yang, F., Sun, Z., Cao, L., Wang, Y., Guan, X. Endothelial cells promote triple-negative breast cancer cell metastasis via PAI-1 and CCL5 signaling.

S1PR3 is essential for phosphorylated fingolimod to protect astrocytes against oxygen-glucose deprivation-induced neuroinflammation via inhibiting TLR2/4-NFκB signalling.

Fingolimod (FTY720) is used as an immunosuppressant for multiple sclerosis. Numerous studies indicated its neuroprotective effects in stroke. However, the mechanism remains to be elucidated. This study was intended to investigate the mechanisms of phosphorylated FTY720 (pFTY720), which was the principle active molecule in regulating astrocyte-mediated inflammatory responses induced by oxygen-glucose deprivation (OGD). Results demonstrated that pFTY720 could protect astrocytes against OGD-induced injury and inflammatory responses. It significantly decreased pro-inflammatory cytokines, including high mobility group box 1 (HMGB1) and tumour necrosis factor-α (TNF-α). Further, studies displayed that pFTY720 could prevent up-regulation of Toll-like receptor 2 (TLR2), phosphorylation of phosphoinositide 3-kinase (PI3K) and nuclear translocation of nuclear factor kappa B (NFκB) p65 subunit caused by OGD. Sphingosine-1-phosphate receptor 3 (S1PR3) knockdown could reverse the above change. Moreover, administration of TLR2/4 blocker abolished the protective effects of pFTY720. Taken together, this study reveals that pFTY720 depends on S1PR3 to protect astrocytes against OGD-induced neuroinflammation, due to inhibiting TLR2/4-PI3K-NFκB signalling pathway.

Intratumor heterogeneity predicts metastasis of triple-negative breast cancer.

Even with the identical clinicopathological features, the ability for metastasis is vastly different among triple-negative breast cancer (TNBC) patients. Intratumor heterogeneity (ITH), which is common in breast cancer, may be a key mechanism leading to the tumor progression. In this study, we studied whether a quantitative genetic definition of ITH can predict clinical outcomes in patients with TNBC. We quantified ITH by calculating Shannon index, a measure of diversity in a population, based on Myc, epidermal growth factor receptor/centromeric probe 7 (EGFR/CEP7) and cyclin D1/centromeric probe 11 (CCND1/CEP11) copy number variations (CNVs) in 300 cells at three different locations of a tumor. Among 75 TNBC patients, those who developed metastasis had significantly higher ITH, that is Shannon indices of EGFR/CEP7 and CCND1/CEP11 CNVs. Higher Shannon indices of EGFR/CEP7 and CCND1/CEP11 CNVs were significantly associated with the development of metastasis and were predictive of significantly worse metastasis-free survival (MFS). Regional heterogeneity, defined as the difference in copy numbers of Myc, EGFR or CCND1 at different locations, was found in 52 patients. However, the presence of regional heterogeneity did not correlate with metastasis or MFS. Our findings demonstrate that higher ITH of EGFR/CEP7 and CCND1/CEP11 CNVs is predictive of metastasis and is associated with significantly worse MFS in TNBC patients, suggesting that ITH is a very promising novel prognostic factor in TNBC.