Genomic evolution and diverse models of systemic metastases in colorectal cancer.

OBJECTIVE: The systemic spread of colorectal cancer (CRC) is dominated by the portal system and exhibits diverse patterns of metastasis without systematical genomic investigation. Here, we evaluated the genomic evolution of CRC with multiorgan metastases using multiregion sequencing. DESIGN: Whole-exome sequencing was performed on multiple regions (n=74) of matched primary tumour, adjacent non-cancerous mucosa, liver metastasis and lung metastasis from six patients with CRC. Phylogenetic reconstruction and evolutionary analyses were used to investigate the metastatic seeding pattern and clonal origin. Recurrent driver gene mutations were analysed across patients and validated in two independent cohorts. Metastatic assays were performed to examine the effect of the novel driver gene on the malignant behaviour of CRC cells. RESULTS: Based on the migration patterns and clonal origins, three models were revealed (sequential, branch-off and diaspora), which not only supported the anatomic assumption that CRC cells spread to lung after clonally expanding in the liver, but also illustrated the direct seeding of extrahepatic metastases from primary tumours independently. Unlike other cancer types, polyphyletic seeding occurs in CRC, which may result in late metastases with intermetastatic driver gene heterogeneity. In cases with rapid dissemination, we found recurrent trunk loss-of-function mutations in ZFP36L2, which is enriched in metastatic CRC and associated with poor overall survival. CRISPR/Cas9-mediated knockout of ZFP36L2 enhances the metastatic potential of CRC cells. CONCLUSION: Our results provide genomic evidence for metastatic evolution and indicate that biopsy/sequencing of metastases may be considered for patients with CRC with multiorgan or late postoperative metastasis.

Association of anti-TNF-α treatment with gut microbiota of patients with ankylosing spondylitis.

OBJECTIVE: Gut dysbiosis contributes to multiple autoimmune diseases, including ankylosing spondylitis, which is commonly treated with tumor necrosis factor (TNF)-α inhibitors (TNFis). Because host TNF-α levels are considered to interact with gut microbiota, we aimed to systematically investigate the microbiota profile of ankylosing spondylitis patients with anti-TNF-α-based treatment and identify potential key bacteria. METHODS: Fecal samples were collected from 11 healthy controls and 24 ankylosing spondylitis patients before/after anti-TNF-α treatment, the microbiota profiles of which were evaluated by 16S ribosomal DNA amplicon sequencing and subsequent bioinformatic analysis. RESULTS: Significantly different microbial compositions were observed in samples from ankylosing spondylitis patients compared with healthy controls, characterized by a lower abundance of short-chain fatty acid (SCFA)-producing bacteria. All patients exhibited a positive response after anti-TNF-α treatment, accompanied by a trend of restoration in the microbiota compositions and functional profile of ankylosing spondylitis patients to healthy controls. In particular, the abundance of SCFA-producing bacteria (e.g. Megamonsa and Lachnoclostridium ) was not only significantly lower in ankylosing spondylitis patients than in healthy controls and restored after anti-TNF-α treatment but also negatively correlated with disease severity (e.g. cor = -0.52, P = 8 × 10 -5 for Megamonsa ). In contrast, Bacilli and Haemophilus may contribute to ankylosing spondylitis onset and severity. CONCLUSIONS: Microbiota dysbiosis in ankylosing spondylitis patients can be restored after anti-TNF-α treatment, possibly by impacting SCFA-producing bacteria.

Erythrocyte Membrane-Coated Invisible Acoustic-Sensitive Nanoparticle for Inducing Tumor Thrombotic Infarction by Precisely Damaging Tumor Vascular Endothelium.

Selective induction of tumor thrombus infarction is a promising antitumor strategy. Non-persistent embolism due to non-compacted thrombus and activated fibrinolytic system within the tumor large blood vessels and tumor margin recurrence are the main therapeutic bottlenecks. Herein, an erythrocyte membrane-coated invisible acoustic-sensitive nanoparticle (TXA+DOX/PFH/RBCM@cRGD) is described, which can induce tumor thrombus infarction by precisely damaging tumor vascular endothelium. It is revealed that TXA+DOX/PFH/RBCM@cRGD can effectively accumulate on the endothelial surface of tumor vessels with the help of the red blood cell membrane (RBCM) stealth coating and RGD cyclic peptide (cRGD), which can be delivered in a targeted manner as nanoparticle missiles. As a kind of phase-change material, perfluorohexane (PFH) nanodroplets possess excellent acoustic responsiveness. Acoustic-sensitive missiles can undergo an acoustic phase transition and intense cavitation with response to low-intensity focused ultrasound (LIFU), damaging the tumor vascular endothelium, rapidly initiating the coagulation cascade, and forming thromboembolism in the tumor vessels. The drugs loaded in the inner water phase are released explosively. Tranexamic acid (TXA) inhibits the fibrinolytic system, and doxorubicin (DOX) eliminates the margin survival. In summary, a stealthy and acoustically responsive multifunctional nanoparticle delivery platform is successfully developed for inducing thrombus infarction by precisely damaging tumor vascular endothelium.

Denatured bovine serum albumin hydrogel-based electrochemical biosensors for detection of IgG.

An antifouling sensing surface was constructed by crosslinking two-dimensional nanomaterial MXene with bovine serum albumin (BSA) denatured by urea previously. The immunoglobulin G (IgG) capture peptide was then modified to the surface to construct a highly selective antifouling electrochemical biosensor. Due to the large specific surface area and good electrical conductivity of MXene, the sensitivity of the biosensor is significantly enhanced. The biosensor at a working potential of around - 0.18 V (vs. Ag/AgCl) provides a wide linear detection range (0.1 ng/mL to 10 µg/mL) for IgG with a limit of detection of 23 pg/mL (3σ/k). The result is consistent with that obtained from the commercial enzyme-linked immunosorbent kit. Compared with BSA, which is usually used as a passivator or blocker for biosensing platforms, the hydrogel formed through the peptide chain obtained from BSA with good hydrophilicity can provide a better antifouling sensing surface to resist nonspecific adsorption. The prepared biosensor can quantitatively detect the concentration of IgG in complex human serum with high sensitivity. Thus, the antifouling sensing surface constructed without expensive antifouling materials and complex process is expected to develop as a variety of electrochemical biosensors and used for the clinical testing of biomarkers. Graphical abstract An antifouling sensing surface was constructed by crosslinking two-dimensional nanomaterial MXene with bovine serum albumin (BSA) denatured by urea previously. The immunoglobulin G (IgG) capture peptide was then modified to the surface to construct a highly selective antifouling electrochemical biosensor.

Flexible Polypropylene-Supported ZIF-8 Membranes for Highly Efficient Propene/Propane Separation.

Metal-organic framework (MOF) membranes have enormous potential in separation applications. There are several MOF membranes grown on polymer substrates aimed for scale-up, but their brittleness hampers any industrial application. Herein, intergrown continuous polypropylene (PP)-supported ZIF-8 membranes have been successfully synthesized via fast current-driven synthesis (FCDS) within 1 h. The PP-supported ZIF-8 membranes exhibit a promising separation factor of 122 ± 13 for binary C3H6-C3H8 mixtures combined with excellent flexibility behavior. The C3H6/C3H8 separation performance of the PP-supported ZIF-8 membrane was found to be constant after bending the supported ZIF-8 film with a curvature of 92 m-1. This outstanding mechanical property is crucial for practical applications. Moreover, we further synthesized ZIF-8 membranes on various polymer substrates and even polymer hollow fibers to demonstrate the production scalability.

Balancing the Grain Boundary Structure and the Framework Flexibility through Bimetallic Metal-Organic Framework (MOF) Membranes for Gas Separation.

Separation is one of the most energy-intensive processes in the chemical industry, and membrane-based separation technology helps to reduce the energy consumption dramatically. Supported metal-organic framework (MOF) layers hold great promise as a molecular sieve membrane, yet only a few MOF membranes showed the expected separation performance. The main reasons include e.g. nonselective grain boundary transport or the flexible MOF framework, especially the inevitable linker rotation. Here, we propose a crystal engineering strategy that balances the grain boundary structure and framework flexibility in Co-Zn bimetallic zeolitic imidazolate framework (ZIF) membranes and exploit their contributions to the improvement of membrane quality and separation performance. It reveals that a good balance between the two trade-off factors enabled a "sweet spot" that offers the best C3H6/C3H8 separation factor up to 200.

Biomimetic Design of Peptide Neutralizer of Ebola Virus with Molecular Simulation.

Ebola virus (EBOV) belongs to the Filoviridae family, which can cause severe hemorrhagic fever in humans and nonprimates. The neutralization of EBOV by monoclonal antibody (mAb) ADI-15946 was reported recently. In the present study, the molecular interactions between the receptor GPcl of EBOV and ADI-15946 were studied by molecular dynamics (MD) simulation and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) analysis. Hydrophobic interaction was identified as the main driving force for the binding of ADI-15946 on EBOV. Moreover, the contribution of each amino acid residue for the binding was evaluated. Then, an affinity binding model (ABM) was constructed using the residues favorable for the binding, including Y107, F108, D109, W110, and R113. The biomimetic design of neutralizer against EBOV according to the ABM of ADI-15946 was then performed, followed by screening using docking, structural similarity. Two neutralizers YFDWHMR and YFDWRYR were obtained, which were proven to be capable of strong binding on GPcl and then neutralizing GPcl. These results would be helpful for the development of neutralizers for Ebola virus.

Novel aryltriazole acyclic C-azanucleosides as anticancer candidates.

Nucleoside analogues represent an important class of drug candidates. With the aim of searching for novel bioactive nucleosides, we developed an efficient synthetic way to construct a series of aryl 1,2,3-triazole acyclic C-azanucleosides via Huisgen 1,3-dipolar cycloaddition. The aryl 1,2,3-triazole motifs within these azanucleosides showed coplanar features, suggesting they could act as surrogates for large planar aromatic systems or nucleobases. Moreover, several aryltriazole acyclic C-azanucleosides bearing long alkyl chains exhibited potent antiproliferative activity against various cancer cell lines via induction of apoptosis. Most interestingly, the lead compound significantly down-regulated the key proteins involved in the heat shock response pathway, representing the first anticancer acyclic azanucleoside with such a mode of action. These novel aryl 1,2,3-triazole cyclic C-azanucleosides therefore serve as promising paradigms for further exploring anticancer drug candidates.

Rational Discovery of Response Biomarkers: Candidate Prognostic Factors and Biomarkers for Checkpoint Inhibitor-Based Immunotherapy.

Immunotherapy with checkpoint inhibitor has been successfully applied in treatment for multiple cancer types, especially for patients at advanced stage. However, response rate of this promising therapy is low, thus requiring biomarkers for precise medication to reduce the ineffective treatment. With multiple retrospective clinical studies, more and more candidate prognostic factors have been identified with possible mechanic explanation, including the basic clinical characteristics (e.g., age and gender), molecular features (e.g., PD-L1 expression and tumor mutation burden). After validation in independent patient cohorts with large sample size, several markers have been approved as companion biomarkers. However, validation and combinations of all the possible candidate biomarkers are still challenging to predict the treatment outcomes. In this chapter, we will summarize and introduce the prognostic factors and biomarkers for checkpoint inhibitor-based immunotherapy.

Ultra-Tuning of the Aperture Size in Stiffened ZIF-8_Cm Frameworks with Mixed-Linker Strategy for Enhanced CO2 /CH4 Separation.

ZIF-8 membrane has the potential for CO2 /CH4 separation based on size exclusion. But if traditionally prepared by solvothermal methods, it shows only negligible selectivity due to the linker mobility. Here, ≈500 nm-thin hybrid ZIF-7x -8 membranes with suppressed linker mobility and narrowed window aperture are prepared by a fast current-driven synthesis (FCDS) within 20 min. The in situ electric field during FCDS allows the formation of stiffened ZIF-8_Cm as parent skeleton and the mixed-linker strategy is applied to narrow the aperture size simultaneously. The ZIF-722 -8 membrane shows significantly sharpened molecular sieving for CO2 /CH4 with a separation factor above 25, which soared tenfold compared with other unmodified ZIF-8 membranes. Additionally, the membrane shows exceptional separation performance for H2 /CH4 and CO2 /N2 , with separation factors of 71 and 20, respectively. After 180 h temperature swing operation, it still maintains the excellent separation performance.

Dynamic changes of bacterial community under bioremediation with Sphingobium sp. LY-6 in buprofezin-contaminated soil.

Buprofezin is a commonly used chemical with satisfactory biological activity against sucking insect pests, but its disposal can cause serious environmental problems. To study the feasibility of remedying contamination by buprofezin, microcosm experiments were carried out to study the effects of various concentrations of buprofezin and Sphingobium sp. LY-6 on soil bacterial communities in soils collected from vegetable fields. In this experiment, the results showed that buprofezin was effectively degraded by Sphingobium sp. LY-6 in incubation soils. Comparing to non-incubated soils, the cumulative degradation ratio of buprofezin was significantly increased, up to the extent of 85 and 51%, in the initial concentration of 10 and 100 mg kg(-1). The abundance and community structure of the bacterial communities were analysed by real-time PCR (qPCR) and terminal-restriction fragment length polymorphism (T-RFLP). The findings suggest that buprofezin had a negative effect on soil bacterial community, and decreases in bacterial abundance were observed in the later part of the incubation period. The bacterial community structure and diversity shifted significantly at each sampling time. In conclusion, the buprofezin-degrading strain LY-6 played a major role in the bioremediation of the buprofezin-contaminated soil and influenced the dynamics and structure of the bacterial community, demonstrating the great potential of exogenous microorganisms for soil remediation.

QM/MM studies of the mechanism of unusual bifunctional fructose-1,6-bisphosphate aldolase/phosphatase.

Archaeal fructose-1,6-bisphosphate aldolase/phosphatase (FBPA/P) is a newly identified unusual bifunctional enzyme (Nature, 2010, 464, 1077), which contains one single catalytic domain but catalyzes two chemically distinct reactions of gluconeogenesis. It is different from the ordinary enzymes whose active sites are responsible for a specific reaction. To explore the catalytic characteristic of FBPA/P, the aldol condensation mechanism of bifunctional FBPA/P has been investigated using quantum mechanics/molecular mechanics (QM/MM) method. The whole reaction process can be divided into two half-reactions involving seven elementary steps. A Schiff base intermediate is theoretically confirmed, agreeing well with the recently resolved crystal structures (Nature, 2011, 478, 538). The free energy barrier of the rate-limiting step is calculated to be 22.2 kcal mol(-1), which is a concerted process of a nucleophilic attack by the enolic carbon to the ketonic carbon and a proton transfer from Tyr229 to the ketonic oxygen. Lys232 plays an important role in forming a Schiff base intermediate with the substrate (DHAP). Tyr229 functions as a proton shuttle during the catalysis. This is the first theoretical study on the aldol condensation mechanism of FBPA/P, which may provide useful information for understanding bifunctional enzymes.

RETRACTED: Chen et al. A Novel Drug Self-Delivery System from Fatty Alcohol Esters of Tranexamic Acid for Venous Malformation Sclerotherapy. Pharmaceutics 2022, 14, 343.

The Pharmaceutics Editorial Office retracts the article, "A Novel Drug Self-Delivery System from Fatty Alcohol Esters of Tranexamic Acid for Venous Malformation Sclerotherapy" [...].

[Effect of different kinds of gingival retraction agents on the polymerization inhibition of polyvinyl siloxane impression materials].

PURPOSE: To evaluate the effect of different kinds of gingival retraction agents after directly contacted with polyvinyl siloxane impression materials on polymerization inhibition and the inhibition degree. METHODS: Five kinds of gingival retraction agents (0.1% epinephrine hydrochloride, 0.05% oxymetazoline, 15.5% ferric sulfate, 25% aluminum chloride and 5% aluminum chloride) were chosen, normal saline was as control group, and two kinds of polyvinyl siloxane impression materials (ExpressTM, ImprintTM Ⅱ) were combined into 12 groups. There were 12 specimens in each group and 144 specimens in total. Silicone rubber impression materials were mixed by the same operator using a dispensing gun into the acrylic mold, so that they could directly contact the gingival retraction agents on the densely woven cotton fabrics. The samples were removed when the polymerization time arrived according to the manufactures' recommendations and then placed under a stereomicroscope with a magnification of 10 times to observe whether polymerization inhibition occurred, the degree of inhibition was compared afterwards. SPSS 22.0 software package was used for statistical analysis. RESULTS: The polymerization inhibition of two kinds of silicone rubber impression materials occurred in 15.5% ferric sulfate group and 25% aluminum chloride group, and the inhibition occurrence rate was 100%, the difference was statistically significant (P＜0.05) compared with normal saline group. Inhibition was not found in 0.1% epinephrine hydrochloride group, 0.05% oxymetazoline group and 5% aluminum chloride. The effect of 15.5% ferric sulfate and 25% aluminum chloride on polymerization inhibition degree of ImprintTM Ⅱ was greater than ExpressTM, and the difference was statistically significant(P＜0.05). CONCLUSIONS: When silicone rubber impression material is used during impression procedure, attention should be paid to the effect of the gingival retraction agent containing 15.5% ferric sulfate and 25% aluminum chloride on its polymerization. The gingival retraction agent should be washed before impression to avoid the residue directly contacting the silicone rubber to prevent polymerization.

Antifouling Electrochemiluminescence Biosensor Based on Bovine Serum Albumin Hydrogel for the Accurate Detection of p53 Gene in Human Serum.

To detect biomarkers in complex samples, it is fundamental to avoid the nonspecific adsorption of impurities to improve the selectivity of biosensors. In this study, a sensitive antifouling electrochemiluminescence biosensor was proposed based on bovine serum albumin (BSA)- and exonuclease III (Exo III)-mediated nucleic acid cycle signal amplification strategy. Ti3C2Tx-NH4, which has a large surface area and high metal conductivity, was crosslinked with BSA to improve the conductivity of the sensing interface, which shows antifouling performance excellently due to the electrical neutrality and good hydrophilicity of BSA hydrogel. The cyclic amplification strategy based on Exo III and DNA hybridization chain reaction significantly amplified the electrochemiluminescence signal and improved the sensitivity of p53 gene detection. The linear range of the biosensor is 1 fM-1 nM with a detection limit of 0.26 fM. More importantly, the sensor showed excellent selectivity when it was used to detect the p53 gene in real samples, such as serum. Thus, this unique antifouling sensing interface is expected to construct various electrochemical biosensors in clinical diagnosis and biopathological analysis.

Unravelling the pseudocapacitive origin of graphene oxide-based aerogels by comparative insights.

We reveal the intrinsic pseudocapacitive center of graphene-oxide-based aerogels by investigating different modified graphene skeletons from various approaches. A high proportion of carbonyl groups in carbon networks is shown to optimize the construction of rational pseudocapacitive sites by triggering reversible proton-induced surface reactions, leading to satisfactory electrochemical performance.

Characterization of immature ovarian teratomas through single-cell transcriptome.

Introduction: Immature ovarian teratomas are a type of malignant germ cell tumor composed of complicated cell types and are characterized by pathological features of immature neuroectodermal tubules/rosettes. However, there is a lack of understanding of patient-derived immature ovarian teratomas (PDT) at the single cell level. Moreover, whether stem cell lines derived from immature teratomas (CDT) can be used as models for research on PDT remains to be elucidated. Methods: Single-cell RNA sequencing (scRNA-seq) and subsequent bioinformatic analysis was performed on three patient-derived immature ovarian teratomas (PDT) samples to reveal the heterogeneity, evolution trajectory, and cell communication within the tumor microenvironment of PDT. Validations were conducted in additional seven samples through multiplex immunofluorescence. Result: A total of qualified 22,153 cells were obtained and divided into 28 clusters, which can match to the scRNA-seq annotation of CDT as well as human fetal Cell Atlas, but with higher heterogeneity and more prolific cell-cell crosstalk. Radial glia cells (tagged by SOX2) and immature neuron (tagged by DCX) exhibited mutually exclusive expression and differentiated along distinct evolutionary trajectory from cycling neural progenitors. Proportions of these neuroectodermal cell subtypes may play important roles in PDT through contributing to the internal heterogeneity of PDTs. Moreover, the immune cells in PDTs were infiltrated rather than teratoma-derived, with more abundant macrophage in immature neuron than those in radial glia cells, and the infiltrated macrophage subtypes (i.e., M1 and M2) were significantly correlated to clinical grade. Overall, suppressed evolution process and transcriptome regulation in neuroectodermal cells, reduced cell-cell crosstalk, higher M1/M2 proportion ratio, and enhanced T cell effects in tumor microenvironment are enriched in patients with favorable prognosis. Discussion: This study provides a comprehensive profile of PDT at the single cell level, shedding light on the heterogeneity and evolution of neuroectodermal cells within PDTs and the role of immune cells within the tumor microenvironment. Also, our findings highlight the potential usage of CDTs as a model for research on PDT.

Dry deposition velocity of total suspended particles and meteorological influence in four locations in Guangzhou, China.

Dry deposition velocity of total suspended particles (TSP) is an effective parameter that describes the speed of atmospheric particulate matter deposit to the natural surface. It is also an important indicator to the capacity of atmosphere self-depuration. However, the spatial and temporal variations in dry deposition velocity of TSP at different urban landscapes and the relationship between dry deposition velocity and the meteorological parameters are subject to large uncertainties. We concurrently investigated this relationship at four different landscapes of Guangzhou, from October to December of 2009. The result of the average dry deposition velocity is (1.49 +/- 0.77), (1.44 +/- 0.77), (1.13 +/- 0.53) and (1.82 +/- 0.82) cm/sec for urban commercial landscape, urban forest landscape, urban residential landscape and country landscape, respectively. This spatial variation can be explained by the difference of both particle size composition of TSP and meteorological parameters of sampling sites. Dry deposition velocity of TSP has a positive correlation with wind speed, and a negative correlation with temperature and relative humidity. Wind speed is the strongest factor that affects the magnitude of TSP dry deposition velocity, and the temperature is another considerable strong meteorological factor. We also find out that the relative humidity brings less impact, especially during the dry season. It is thus implied that the current global warming and urban heat island effect may lead to correlative changes in TSP dry deposition velocity, especially in the urban areas.

Magnetic antifouling material based ratiometric electrochemical biosensor for the accurate detection of CEA in clinical serum.

A novel ratio electrochemical biosensor based on multi-functional nanocomposite was developed. Fe3O4 was synthesized in situ on carboxyl functionalized 2D nanomaterial MXene, and then covalently bonded with [Ru(NH3)6]3+ to obtain nanocomposites MXC-Fe3O4-Ru. Fe3O4 and [Ru(NH3)6]3+ can neutralize the electronegativity of the MXene to make the nanocomposites electrically neutral. Combine with the good hydrophilicity and conductivity of MXene, the nanocomposites can be utilized to construct antifouling electrochemical biosensors without modifying with specific antifouling materials. Moreover, Fe3O4 can endow the nanocomposites with magnetism, and [Ru(NH3)6]3+ is used as an internal standard molecule. The strong magnetic MXC-Fe3O4-Ru can be easily separated and firmly modified on the magnetic gold electrode (MGE). DNA double-stranded (dsDNA) containing an ferrocene (Fc)-modified carcinoembryonic antigen (CEA) aptamer can be specifically captured to the surface of the electrode by amido bond. In the presence of CEA, CEA binds to the aptamer and leaves the electrode surface, the electrochemical signal of Fc decreases, while the electrochemical signal of [Ru(NH3)6]3+ is fixed on the electrode surface remains basically unchanged. The ratio of the electrochemical signals of Fc and [Ru(NH3)6]3+ is proportional to the CEA concentration. The linear range of the sensor is 1 pg/mL to 1 µg/mL with a detection limit of 0.62 pg/mL. With the excellent antifouling performance, good conductivity of the nanocomposite, and the application of the ratiometric strategy, the biosensor can achieve high selectivity, accuracy, and sensitivity for the detection of targets even in complex samples, such as FBS and clinical serum.