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Leijuan Gan,* Shaohua Ren,* Mengran Lang,* Guangtao Li, Feng Fang, Lu Chen, Yayue Liu, Ruyu Han, Kangwei Zhu, Tianqiang Song Liver Cancer Center, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tianqiang Song, Liver Cancer Center, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China, Email songtianqiangtj@163.comPurpose: This study aimed to explore the relationship between the tumor marker score (TMS) and the postoperative recurrence of single small hepatocellular carcinoma (HCC).Patients and Methods: A total of 409 patients with one resectable HCC with a diameter of 3 cm or less who visited Tianjin Medical University Cancer Institute & Hospital from January 2010 to December 2014 were included in this study. Their alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) levels were classified into low and high groups using X-tile software. Each patients’ TMS was calculated as the sum of each tumor marker (low = 0; high = 1).Results: A total of 142 patients were classified as TMS0, 171 as TMS1, and 96 as TMS2. Kaplan–Meier analysis illustrated that TMS could divide the patients into groups with remarkably different prognoses, and the patients with high TMS had worse recurrence-free survival (RFS) than those with low TMS. Multivariate analysis showed that TMS, age, and HBeAg positive were the independent predictors of RFS rate. Subgroup analysis revealed that high TMS was a stable risk factor relative to TMS0. Receiver operating curves showed that the 1-, 3-, and 5-year area under curve (AUC) values of TMS were 0.698, 0.662, and 0.673, respectively. The AUC of TMS was higher than that of other common prognostic models in time-dependent receiver operating curve.Conclusion: TMS was an independent prognostic factor for the postoperative recurrence of a single small HCC and can provide a well-discriminated risk stratification, thus contributing to prognostic prediction and adjuvant therapeutic development.Keywords: hepatocellular carcinoma, recurrence-free survival, tumor marker score, alpha-fetoprotein, carcinoembryonic antigen, carbohydrate antigen 19-9

One of the central aims of synthetic biology and metabolic engineering is to mimic the integrality of eukaryotic cells to construct a multifunctional compartment system to perform multistep incompatible cascade reactions in a one-pot, controlled, and selective fashion. The key challenge is how to address the coexistence of antagonistic reagents and to incorporate these functionalities into an integrated system in a smart and efficient way. A novel strategy called "iterative etching-grafting" is proposed here based on monodispersed photonic spheres (PSs) prepared by microfluidics, which constructs a universal platform for incompatible cascade reactions. As a proof of concept, we spatiotemporally regulated the degree of etching of PSs, then grafted precursory groups of acid and base onto PSs, and incorporated a photocleavage method, which were capable of compartmentalizing the acid and base inside PSs. Utilizing the band-gap offsets of PSs could track the progress of cascade reactions in situ, and grafting various charged polymers on the surface of the pores by surface-initiated atom transfer radical polymerization (SI-ATRP) achieved the selectivity of the substrates, which flexibly constructed a multifunctional and integrated acid-base photonic multicompartment system (PMCS). The created PMCS shows excellent catalytic performance, convenient monitoring, and efficient substrate selectivity in the deacetalization-Knoevenagel cascade reaction. Furthermore, two types of electrophile/nucleophile PMCSs have also been accessibly constructed, demonstrating the facile generation of other incompatible systems with the versatility as well as the advancement and extensibility of the developed strategy.

The formation and properties of liquid-ordered (Lo) lipid domains (rafts) in the plasma membrane are still poorly understood. This limits our ability to manipulate ordered lipid domain-dependent biological functions. Giant plasma membrane vesicles (GPMVs) undergo large-scale phase separations into coexisting Lo and liquid-disordered lipid domains. However, large-scale phase separation in GPMVs detected by light microscopy is observed only at low temperatures. Comparing Forster resonance energy transfer-detected versus light microscopy-detected domain formation, we found that nanodomains, domains of nanometer size, persist at temperatures up to 20°C higher than large-scale phases, up to physiologic temperature. The persistence of nanodomains at higher temperatures is consistent with previously reported theoretical calculations. To investigate the sensitivity of nanodomains to lipid composition, GPMVs were prepared from mammalian cells in which sterol, phospholipid, or sphingolipid composition in the plasma membrane outer leaflet had been altered by cyclodextrin-catalyzed lipid exchange. Lipid substitutions that stabilize or destabilize ordered domain formation in artificial lipid vesicles had a similar effect on the thermal stability of nanodomains and large-scale phase separation in GPMVs, with nanodomains persisting at higher temperatures than large-scale phases for a wide range of lipid compositions. This indicates that it is likely that plasma membrane nanodomains can form under physiologic conditions more readily than large-scale phase separation. We also conclude that membrane lipid substitutions carried out in intact cells are able to modulate the propensity of plasma membranes to form ordered domains. This implies lipid substitutions can be used to alter biological processes dependent upon ordered domains.

Nanoporous membranes prepared by supramolecular assembly of block copolymers have attracted increasing attention for their well-defined nanostructure, adjustable pore size, and large-scale manufact...

Based on block copolymer assisted topochemical polymerization, a new strategy for facilely producing robust nanoporous membranes with controlled incorporation of functional groups onto nanopores is developed. As exemplified by preparing nanoporous polypyrrole decorated with amino acids, this strategy exhibits a high degree of freedom for tailoring the surface functionality in the created pores.

The aim of the present study was to explore the anti-cancer effects of total flavonoids (TF) on lung cancer and to investigate the underlying mechanism. The inhibitory effect of TF on the proliferation of A549 cells in vitro was measured using an MTT assay. The apoptotic rate of TF-treated A549 cells was analyzed using flow cytometry and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling. Migration and invasion assays were performed to investigate the anti-migration effect of TF on A549 cells. Reverse-transcription quantitative PCR was used to analyze BCL2-like 2, BCL2, Bax, Bad, cyclooxygenase 2 (COX-2), Wnt and β-catenin mRNA expression levels in A549 cells. The in vivo anti-cancer effect of TF was investigated in a subcutaneous xenograft model of lung cancer in BALB/c nude mice. The results obtained in the present study revealed that TF exerted a significant inhibitory effect on the proliferation of A549 cells in a dose-dependent manner (P

544 Background: The combination of bevacizumab and immune checkpoint inhibitors (ICI) has demonstrated promising efficacy and safety in the first-line treatment of advanced hepatocellular carcinoma (HCC). However, this combination has not been examined in patients with previous first-line treatment of ICI and tyrosine kinase inhibitor. This study aimed to investigate the effectiveness and safety of bevacizumab combined with atezolizumab or sintilimab as second-line treatment in patients with advanced HCC. Methods: The retrospective study included patients with advanced HCC who received combined therapy of bevacizumab and atezolizumab or sintilimab after failure of lenvatinib plus ICI between July 28, 2020 and March 7, 2022. Baseline patient characteristics were collected. Treatment response, overall response rate (ORR) and disease control rate (DCR) were evaluated according to response evaluation criteria in solid tumors (RECIST) version 1.1. Overall survival (OS) and progression-free survival (PFS) were analyzed by the Kaplan-Meier method. Treatment-related adverse events were graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Results: A total of 20 patients with advanced HCC were included, with a median follow-up time of 11.05 (5.03-20.63) months. Eleven patients died by the last follow-up on August 12, 2022. There were 18 males (90%) and two females (10%). The average age was 59.9±12.08 years. Seven patients (35%) had distant metastasis, and nine (45%) had vascular invasion. Liver function was classified as Child-Pugh grade A in 17 patients (85%) and grade B in three (15%). Patients with Barcelona Clinic Liver Cancer (BCLC) stages B, C and D were 1 (5%), 16 (80%) and 3 (15%), respectively. Eighteen patients (90%) had previous topical therapy. Of all patients previously administered lenvatinib plus ICI as first-line treatment, 14 (70%) had PFS longer than three months. ORR and DCR were 15% (95% confidence interval [CI], 3.2-37.9) and 55% (95% CI, 31.5-76.9), respectively. Median OS was 8.00 months (95% CI, 0.00-16.66), while median PFS was 3.80 months (95% CI, 2.41-5.19). Adverse events were observed in 14 patients (70%). Adverse events of grade 3 or worse occurred in six patients (30%). Conclusions: The combination of bevacizumab with atezolizumab or sintilimab had tolerable safety profile but poor response in the second-line treatment of HCC. Despite the satisfying efficacy as first-line therapy, this combination is not a cost-effective recommendation for advanced HCC cases who failed the first-line treatment of lenvatinib plus ICI. [Table: see text]

Evolutionarily conserved heat shock proteins are involved in the heat shock response of cells in response to changes in the external environment. In normal tissues, heat shock proteins can help cells survive in a rapidly changing environment. Likewise, in malignant tumors heat shock proteins may help tumor cells cope with external stresses as well as the stress of treatment. In this way they become accomplices of malignant tumors. Here we demonstrated for the first time that high expression of DNAJC24 (a heat shock protein) shortens survival in patients with HCC by immunohistochemical staining of 167 paired hepatocellular carcinomas and paraneoplastic tissues as well as data from public databases. In vitro experiments demonstrated that stimuli such as hypoxia, starvation and heat could upregulate DNAJC24 expression in HCC cells through transcriptional regulation of HSF2, and high expression of DNAJC24 in HCC cells could promote the proliferation and motility of HCC cells. In addition, we also verified that targeting DNAJC24 under normal culture conditions can affect the proliferation and autophagy of HCC cells by interfering with ammonia metabolism, thereby inhibiting the malignant progression of HCC. Overall, we suggested that DNAJC24 may become a new target for the treatment of HCC.

Cryptococcus neoformans is a fungal pathogen that causes life-threatening meningoencephalitis in lymphopenic patients. Pulmonary macrophages comprise the first line of host defense upon inhalation of fungal spores, whereby macrophages either aid in clearance or serve as a niche for its dissemination. Given that macrophages play a key role in the outcome of a cryptococcal infection, it is crucial to understand factors that mediate phagocytosis of C. neoformans. Since lipid rafts (high order plasma membrane domains enriched in cholesterol and sphingomyelin) have been implicated in facilitating phagocytosis, we evaluated whether these ordered domains govern macrophages’ ability to phagocytose C. neoformans. We found that cholesterol or sphingomyelin depletion resulted in significantly deficient IgG-mediated phagocytosis of the fungus. Moreover, repletion of macrophage cells with a raft-promoting sterol (7-dehydrocholesterol) rescued this phagocytic deficiency while a raft-inhibiting sterol (coprostanol) significantly decreased IgG-mediated phagocytosis of C. neoformans. Using a photoswitchable sphingomyelin (AzoSM), we observed that the raft-promoting conformation (trans-AzoSM) resulted in efficient phagocytosis whereas raft-inhibiting conformation (cis-AzoSM) significantly blunted phagocytosis in a reversible manner. We observed that the effect on phagocytosis may be mediated by facilitating Fcγ receptor (FcγR) function, whereby IgG immune complexes cross-link to FcγRIII, resulting in tyrosine phosphorylation of FcR γ-subunit (FcRγ), an important accessory protein in the FcγR signaling cascade. Correspondingly, cholesterol or sphingomyelin depletion resulted in decreased FcRγ phosphorylation. Repletion with 7-dehydrocholesterol restored phosphorylation, whereas repletion with coprostanol showed FcRγ phosphorylation comparable to unstimulated cells. Together, these data suggest that lipid rafts are critical for facilitating FcγRIII-mediated phagocytosis of C. neoformans.

COVID-19 vaccines are of great importance in reducing SARS-CoV-2 infection and severe cases. Patients with autoimmune inflammatory rheumatic diseases (AIIRDs) have been strongly recommended to be vaccinated according to the novel guidance because they are more vulnerable to SARS-CoV-2 infection.1 However, patients with AIIRDs were largely excluded from vaccine trials, leading to very limited data on the safety of COVID-19 vaccines. Notably, previous studies mainly focused on mRNA and adenovirus vector vaccines; however, little is known about inactivated COVID-19 vaccines that also have been authorised by WHO and widely used in several most populated countries, for instance, China, Brazil, Turkey and Indonesia.2 A large randomised clinical trial consisting of 40 382 participants has demonstrated two inactivated COVID-19 vaccines significantly reduced the risk of symptomatic COVID-19.3 We conducted a real-world survey to evaluate the safety profiles and disease flare in patients with AIIRDs who received any dose of inactivated COVID-19 vaccines in China. From 1 Aug 2021 to 15 Oct 2021, eligible participants completed a predefined 25-question-based questionnaire by invitation on social media or visiting the outpatient department. There was no restriction on the time interval from vaccination to completing the survey. In total, 1507 adults patients with AIIRDs who received inactivated COVID-19 vaccine participated in this study (flow diagram …

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) which preferentially infiltrates into subcutaneous adipose tissue is rare, however may mimic autoimmune diseases from the aspect of clinical manifestations. Here, we describe a 16-year-old young man, who initially presented with eyelid erythema and swelling, accompanied by fever and muscle and bone marrow involvement. He was preliminarily considered as a patient with classical dermatomyositis (DM), but finally diagnosed as SPTCL concomitant with paraneoplastic inflammatory myositis, confirmed by in total 8 times repeated biopsies at different sites. After systematically reviewing the literatures, we summarized the main features of SPTCL mimicking DM with eyelid edema as the presenting manifestation. The cautionary tale reminds rheumatologists of considering mimickers in patients with atypical autoimmune-like manifestations. Suitable biopsy is critical for diagnosis and improving prognosis.

Multicompartment assemblies attract much attention for their wide applications. However, the fabrication of multicompartment assemblies usually requires elaborately designed building blocks and careful controlling. The emergence of droplet networks has provided a facile way to construct multiple droplet architectures, which can further be converted to multicompartment assemblies. Herein, the bind motif-free building blocks are presented, which consist of the hydrophobic Tf2 N- -based ionic liquid (IL) dissolving LiTf2 N salt, that can conjugate via arrested coalescence in confined-space templates to form IL droplet networks. Subsequent ultraviolent polymerization generates robust free-standing multicompartment assemblies. The conjugation of building blocks relies not on the peripheral bind motif but on the interfacial instability-induced arrested coalescence, avoiding tedious surface modification and assembly process. By tuning structures of templates and building blocks, multicompartment assemblies with 0D, 1D, 2D, and 3D structures are prepared in a facile and high-throughput way. Importantly, the bottom-up construction enables modular control over the compositions and spatial positions of individual building blocks. Combining with the excellent solvency of ILs, this system can serve as a general platform towards versatile multicompartment architectures. As demonstrations, by tailoring the chambers the multicompartment assemblies can spatiotemporally sense and report the chemical cues and perform various modes of motion.

Tumor-targeting peptides have profound clinical implications in early detection and delineation of microscopic lesions for surgical resection, and also delivery of therapeutics with reduced systemic toxicity. Here, we demonstrate that a peptide (RS), evolved from a previously reported hepatocellular carcinoma (HCC)-targeting peptide P47, enables improved HCC micrometastasis discrimination and delineation from noncancerous tissues in murine orthotopic mice and patient biopsies, with up to 21-fold contrast. Importantly, RS targets non-small cell lung (NSCLC) and colon cancers in mice and patient biopsies, with higher selectivity for highly proliferative tumor nodules. Moreover, RS localizes to cell nucleoli of HCC, NSCLC, breast, colon and cervical cancer cells and induces nucleolar stress when conjugated with chemotherapeutic Oxaliplatin (OXA) (RS-OXA), demonstrating both cellular and subcellular targeting. RS-delivered OXA elicits significant tumor retardation in orthotopic HCC mice with markedly reduced systemic toxicity compared to OXA alone. Injection of fluorescence-labeled RS enables dynamic visualization of tumor growth in RS-OXA-treated subcutaneous HCC mice. Our study demonstrates that RS targets a spectrum of tumors and localizes to cell nucleolus, thus enabling functional imaging and targeted delivery of OXA in HCC mice, and consequently provides a versatile tool for tumor imaging and targeted therapeutics.

Objective To investigate the frequency and determinants of achieving the lupus low disease activity state (LLDAS), and the effect of LLDAS attainment on disease flare and damage accrual in a prospective, single-center cohort of Chinese lupus patients. Methods Baseline and follow-up data from consecutive patients at the Peking University First Hospital were collected from January 2017 to June 2020. Results A total of 185 patients were enrolled, with median (range) disease duration at enrolment of 2.3 (0.8–7.7) years, and median follow-up of 2.2 (1.0–2.9) years. By the end of the study, 139 (75.1%) patients had achieved LLDAS at least once; 82 (44.3%) patients achieved LLDAS for ≥ 50% of observations. Multivariable logistic regression analysis showed that 24-h urinary total protein (UTP; per g) (OR = 0.447, 95%CI [0.207–0.968], p = 0.041), serum creatinine (Scr; per 10 µmol/L) (OR = 0.72, 95%CI [0.52–0.99], p = 0.040), and C3 level (per 100 mg/L) (OR = 1.60, 95%CI [1.18–2.17], p = 0.003) at recruitment had independent negative associations with achieving LLDAS for ≥ 50% of observations. Kaplan–Meier analyses showed a significant reduction in flare rate with increased proportion of time in LLDAS. Attainment of LLDAS in at least 50% of observations was an independent protective factor for damage accrual (OR = 0.19, 95%CI [0.04–0.99], p = 0.049). Conclusions In this prospective Chinese cohort, LLDAS was an attainable goal in clinical practice. Nephritis-related markers (UTP and Scr) and C3 level at recruitment negatively influenced achievement of LLDAS. LLDAS achievement was significantly protective from flare and damage accrual. Key points • Low disease activity status (LLDAS) is an achievable target during SLE treatment in China. Urine protein, serum creatinine, and C3 level at recruitment independently affect LLDAS achievement in this group of Chinese lupus patients. • As a treatment target, LLDAS achievement has a highly protective effect for preventing flare and damage accrual, especially in case of achieving LLDAS for ≥ 50% of observations. • The present results further highlight the practical significance of treat-to-target principle in SLE management (T2T/SLE) and the needs for promoting the application of T2T/SLE in clinical practice as well as exploring the concrete implement strategy.

Plasmonic dimers not only provide a unique platform for studying fundamental plasmonic behavior and effects but also are functional materials for numerous applications. The efficient creation of well-defined dimers with flexible control of structure parameters and thus tunable optical property is the prerequisite for fully exploiting the potential of this nanostructure. Herein, based on a polymer-assisted self-assembly approach in conjugation with molecular cage chemistry, a strategy was demonstrated for constructing cage-bridged plasmonic dimers with controlled sizes, compositions, shape, symmetry, and interparticle gap separation in a modular and high-yield manner. With a high degree of freedom and controllability, this strategy allows facilely accessing various symmetrical/asymmetrical dimers with sub-5 nm gap distance and tailored optical properties. Importantly, as the linkage of the two constituent elements, the molecular cages embedded in the junction endow the assembled dimers with the ability to precisely and reversibly host rich guest molecules in hotspot regions, offering great potential for creating various plasmon-mediated applications.

Tandem cold rolling mills are comprehensive dynamic systems coupling with structure and rolling technology. A frequent problem is mill chatter, often occurring when rolling hard, thin materials at high speed and affecting the quality of the strip. In this paper, a dynamic increment model for chatter in a Universal Crown Control mill (UCM mill) is proposed with the considering of strip hardening, elastic deformation of the work roll, non-linear friction, transfer delay of the strip, and dynamic coupling effect of tension between adjacent stands. Mathematically, this model is based on the Taylor series expansion of the Bland-Ford-Hill rolling force equation. The comparative results of both simulation and experimental data show that this chatter model has a high accuracy. A novel, time-varying stability criterion is proposed to evaluate mill stability. Further study is provided on the optimal friction coefficient and reduction ratio required to increase the critical rolling speed and vibration stability in a tandem cold rolling mill. This mathematical criterion is validated by comparing the actual rolling speed with the calculated critical rolling speed. The present work provides a more accurate prediction of mill chatter and a basis for optimal design of rolling conditions.

The three most important redox couples, including cysteine (Cys)/cystine (Cyss), homocysteine (Hcys)/homocystine (Hcyss), and reduced glutathione (GSH)/glutathione disulfide (GSSG), are closely associated with human aging and many diseases. Thus, it is highly important to determine their redox statuses at the following two levels: (i) the redox identity in different thiols/disulfides and (ii) the redox ratio in a mixture of a specific couple. Herein, by using one single AIE-doped (AIE, aggregation-induced emission) photonic-structured poly(ionic liquid) (PIL) sphere as a virtual sensor array, we realize a direct determination of the redox status without a reducing pretreatment of disulfides, which will greatly promote the development of high-throughput and simple procedures. The pattern-recognition method uses the multiple noncovalent interactions of imidazolium-based PILs with these redox species to produce differential responses in both the photonic crystal and fluorescence dual channels. On the one hand, a single sphere enables the direct and simultaneous discrimination of the redox identities of Cys, Cyss, Hcys, Hcyss, GSH, and GSSG under the interference of other five commonly occurring thiols. On the other hand, this sphere also allows for not only a direct quantification of the GSH/GSSG ratios without previously determining the individual concentrations of GSH and GSSG but also the accurate prediction of the ratios in unknown redox samples. To further demonstrate applications of this method, redox mixtures in a biological sample are differentiated. Additionally, quantum calculations further support our assignments for interactions between the imidazolium-based PILs and these redox species.

In this work, two kinds of GeS2–Ga2S3–CsI chalcogenide glasses had been fabricated in conventional meltquenching method, and these glasses express excellent transmittance (0.52–10.5 µm), low refractive index difference, high Raman gain and good thermal stability against crystallization. We designed a highly nonlinear step-index fibre consisting of a 72GeS2–18Ga2S3–10CsI core and a 73GeS2–15Ga2S3–12CsI cladding with the zero dispersion wavelength in near-infrared (

We reported a highly coherent broadband supercontinuum (SC) generation in As–S chalcogenide tapered fibers pumped at 3.75 μm. The fiber preforms based on As–S glasses with a core/cladding diameter ratio of 1:25 were fabricated via isolated stacked extrusion. The waist diameters of tapered fibers can be changed by controlling the parameter of homemade tapering platform to realize all-normal dispersion characteristic. A broadband SC generation spanning from 1.5 to 8.3 μm was obtained in a 15-cm-long tapered fiber with waist core diameter of 4.8 μm. And high coherence property of the generated SC spectrum was investigated and verified by the simulation. The effect of different waist core diameters on SC spectra coherence properties was also investigated by numerical simulation.

Background Numerous preclinical studies have revealed a critical role of cysteine-rich 61 (Cyr61) in the pathogenesis of rheumatoid arthritis (RA). But there is little literature discussing the clinical value of circulation Cyr61 in RA patients. The aim of our study is to investigate the serum Cyr61 level and its association with disease activity in RA patients. Methods A training cohort was derived from consecutive RA patients who visited our clinic from Jun 2014 to Nov 2018. Serum samples were obtained at the enrollment time. To further confirm discovery, an independent validation cohort was set up based on a registered clinical trial. Paired serum samples of active RA patients were respectively collected at baseline and 12 weeks after uniformed treatment. Serum Cyr61 concentration was detected by enzyme-linked immunosorbent assay. The comparison of Cyr61 between RA patients and controls, the correlation between Cyr61 levels with disease activity, and the change of Cyr61 after treatment were analyzed by appropriate statistical analyses. Results A total of 177 definite RA patients and 50 age- and gender-matched healthy controls were enrolled in the training cohort. Significantly elevated serum Cyr61 concentration was found in RA patients, demonstrating excellent diagnostic ability to discriminate RA from healthy controls (area under the curve (AUC) = 0.98, P

Mill chatter in tandem cold rolling mill is a major rejection to the quality and production of the strips. In most mill vibration models, either the roll mass is usually limited to vibrate in vertical direction and vertical-horizontal directions, or the multiple rolls system is simplified to a single mass system. However, the torsional chatter is also a typical type of mill chatter, and the presence of intermediate roll and backup roll will affect the overall vibration of the mill structure system. In this paper, a newly cold rolling mill vibration model coupled with the dynamic rolling processing model and nonlinear vibration model is proposed with the consideration of dynamic coupling and nonlinear characteristics of the rolling process, multiroll equilibrium, and roll movement in both vertical-horizontal-torsional directions. By using Hopf bifurcation theorem and Routh–Hurwitz determinant, the existence of the Hopf bifurcation point of the mill vibration system and bifurcation characteristics are analyzed. At last, the influence of different rolling conditions on the stability of the coupled mill system is investigated, and these results can also be used to design an optimum rolling schedule and determine the appearance of mill chatter under certain rolling conditions.

Creating hotspots with significantly enhanced electromagnetic (EF) field, efficiently placing target molecules in hotspot region, and achieving uniform and reproducible Raman signals are three critical issues for developing high-performance SERS substrates. In this work, large area gold nanoparticle cluster pillar array with a gold mirror at bottom was facilely fabricated by combined use of nanosphere lithography and self-assembly approach. It is both theoretically and experimentally found that through multiple coupling interactions, the electromagnetic fields at interparticle gaps within the gold clusters were significantly enhanced in our three-dimentional (3D) pillar array substrates, which can result in one order of magnitude stronger as compared with random gold clusters on a two-dimentional planar case. Due to the periodic stucture, our substrates also possess the capbility of producing highly uniform and reproducible SERS signals. Attractively, in our case, a photoresponsive polymer was used for the formation of pillar array structure. Its unique photoinduced deformation makes it possible to reversibly open and close the gaps of the closely packed Au NP array, thus enabling efficient placement or entrapment of probe molecules into hotspot sites between adjacent nanoparticles.

One-pot cascade reactions can simplify the synthetic route and reduce the use of solvents and energy. The critical part of the completion of the cascade reaction is the preparation of multifunctional catalysts. In this work, a novel and simple pathway was developed to construct multifunctional catalysts with acidic, basic, and magnetic properties at the same time. Mesoporous silica materials modified with different metal oxides were used as catalytic elements. Microspheres that assembled with catalytic components have a diameter of 150 μm and a specific surface area larger than 400 m2 g–1 and can be used as catalysts for cascade reactions. The yield of the final product in the deacetalization–Knoevenagel reaction is 92%. Microspheres integrated with Fe3O4 nanoparticles have a magnetic susceptibility of 7.2 emu g–1 and can be easily removed from the reaction system by applying an external magnetic field. This multimodule assembly method fully reflects the enormous power of complexity resulting from simplicity. This method provides a reference and practical technical support for the preparation of other multifunctional materials.

2D semiconductors, such as MoS

In some cases lipids in one leaflet of an asymmetric artificial lipid vesicle can suppress formation of ordered lipid domains (rafts) in the opposing leaflet. Whether suppression of domain formation might occur in plasma membranes was studied using plasma membrane vesicles (PMVs) from RBL-2H3 cells. Membrane domain formation and order was assessed by FRET and fluorescence anisotropy. Ordered domains in PMV prepared from cells by N-ethyl maleimide (NEM) treatment formed up to ~37°C, while ordered domains in symmetric vesicles formed from extracted PMV lipids were stable to 55°C, indicating that stability of ordered domains was substantially less in intact PMV. This behavior paralleled lesser ordered domain stability in artificial asymmetric lipid vesicles relative to the corresponding symmetric vesicles, suggesting that intact PMV have some degree of lipid asymmetry. This was confirmed by annexin binding showing that NEM PMV are much more asymmetric than PMV formed by dithiothreitol/paraformaldehyde treatment. Stabilization of ordered domain formation, and increased membrane order at low temperature was also observed after detergent solubilization of PMV followed by membrane reconstitution via dilution from detergent, which also should destroy asymmetry, even though membrane proteins remained associated with the reconstituted vesicles. Similar changes in domain formation and membrane order were observed after detergent reconstitution of artificial asymmetric lipid vesicles. PMV ordered domain stability was not increased by digesting peripheral domains of PMV proteins with proteinase K. We conclude loss of PMV lipid asymmetry can induce ordered domain formation. Dynamic control of asymmetry may regulate ordered domain formation in plasma membranes.

Background Some studies have reported that the activated ribosomes are positively associated with malignant tumors, especially in hepatocellular carcinoma (HCC). The RNA-binding protein PNO1, as a critical ribosome has been rarely reported in human tumors. Thus, the roles of PNO1 in HCC should be explored. Methods We collected 150 formalin-fixed and paraffin-embedded (FFPE) samples and 8 fresh samples to explore the expression and prognosis of PNO1 in HCC by immunohistochemistry, Western Blotting and RT-PCR. Public databases (TCGA and GEO) were used to verify the expression and prognosis. The functions of PNO1 in HCC was verified by in vitro and in vivo experiments. The underlying molecular mechanisms of PNO1 were examined by RNA-seq analysis and a series of functional experiments. Results PNO1 expression was considerably higher in HCC tissues and the higher expression of PNO1 was associated with poor prognosis of HCC patients. In vitro experiments indicated that PNO1 overexpression promoted proliferation and depressed apoptosis of HCC cells. In addition, high expression of PNO1 increased autophagy of HCC cells. Consistent results were also observed in vivo experiments. The results of the RNA-seq analysis indicted that PNO1 as an oncogene promoted HCC progression through the MAPK signaling pathway. The results were also verified by in vivo experiments. Conclusions PNO1 was overexpressed in HCC, promoted autophagy and inhibited apoptosis of HCC cells via the MAPK signaling pathway.

ObjectivesImmune checkpoint inhibitors (ICIs) have brought impressive benefits to cancer patients, however often accompanied with immune-related adverse events (irAEs). We aimed to investigate the association of irAEs with efficacy and overall survival in cancer patients treated by ICIs, and further quantify the association by stratifying subgroups.MethodsPubMed, EMBASE and Cochrane library from database inception to 29 August 2019 were systematically searched. Articles reporting association of objective response rate (ORR), progression-free survival (PFS), overall survival (OS) with irAEs in cancer patients treated with approved ICIs were included. Adjusted odds ratios (OR) with 95% confidential intervals (CIs) were calculated for ORR, and hazard ratios (HR) were used for PFS and OS.ResultsA total of 52 articles comprising 9,156 patients were included. Pooled data demonstrated a statistically significant greater probability of achieving objective tumor response for patients with irAEs compared to those without (OR 3.91, 95% CI 3.05–5.02). In overall meta-analysis, patients who developed irAEs presented a prolonged PFS (HR 0.54; 95% CI 0.46–0.62) and OS (HR 0.51; 95% CI 0.41–0.59). More specifically, irAEs in certain cancer types (NSCLC and melanoma) and organs (skin and endocrine) were robustly associated with better clinical outcomes, while this association needs further verification regarding other tumors. High grade toxicities (G3–5) were not associated with a significantly favorable PFS or OS. Additionally, the association between irAEs and clinical benefit seemed to be more definite in patients receiving PD-(L)1 blockade than CTLA-4 blockade. Pooled data from landmark analyses displayed consistent results.ConclusionsThe occurrence of irAEs predicted improved tumor response and better survival in overall cancer patients treated with ICIs. Notably, the association stayed robust in certain cancer types (NSCLC and melanoma) and organ-specific irAEs (skin and endocrine).

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by vascular remodeling and chronic inflammation. Macrophages are the key orchestrators of inflammatory and repair responses, and have been demonstrated to be vital in the pathogenesis of PAH. However, specific phenotype of macrophage polarization (M1 & M2 macrophage) in the development of PAH and the underlying mechanisms how they work are still largely unclear. A rat model of monocrotaline (MCT) induced PAH was used. Hemodynamic analysis and histopathological experiments were conducted at day 3, 7, 14, 21 and 28, respectively. In PAH rat lung tissue, confocal microscopic images showed that CD68+NOS2+ M1-like macrophages were remarkably infiltrated on early stage, but dramatically decreased in mid-late stage. Meanwhile, CD68+CD206+ M2-like macrophages in lung tissue accumulated gradually since day 7 to day 28, and the relative ratio of M2/M1 macrophage increased over time. Results detected by western blot and immunohistochemistry were consistent. Further vitro functional studies revealed the possible mechanism involved in this pathophysiological process. By using Transwell co-culture system, it was found that M1 macrophages induced endothelial cell apoptosis, while M2 macrophages significantly promoted proliferation of both endothelial cell and smooth muscle cell. These data preliminarily demonstrated a temporal dynamic change of macrophage M1/M2 polarization status in the development of experimental PAH. M1 macrophages participated in the initial stage of inflammation by accelerating apoptosis of endothelial cell, while M2 macrophages predominated in the reparative stage of inflammation and the followed stage of aberrant tissue remodeling.

In this work, a unique molten salt-assisted carbothermal strategy was proposed to fabricate carbon-encapsulated Prussian blue material. In this strategy, Fe/C composite was firstly synthesized by employing molten sodium chloride as a floating template that carried iron nuclei through the holes in the carbon matrix, and thereafter ensured uniform growth and distribution of iron crystals. Then this Fe/C intermediate was transformed into carbon-encapsulated Prussian blue material via its impregnation into potassium hexacyanoferrate solution. Since this strategy was not unique to the system demonstrated, it should provide general guidance as to the fabrication of carbon-encapsulated Prussian blue analogs. The carbon-encapsulated Prussian blue material was characterized by XRD, Raman, TG, DSC, XPS, XANES, SEM, TEM and HRTEM measurements. Also, it was tested as a potential anode material for potassium-ion storage both in half and full cells through galvanostatic test, rate performance test, cyclic voltammetry and electrochemical impedance spectroscopy.

ObjectiveTo investigate the frequency and determinants of flare in Chinese patients with lupus, focusing on the effect of glucocorticoid (GC) tapering on flare in patients who achieved low disease activity or remission.MethodsWe collected baseline and follow-up data from all consecutive patients in a prospective lupus cohort between January 2017 and December 2020. We defined low disease activity using the lupus low disease activity status (LLDAS), applied the DORIS (Definitions of Remission in SLE) for remission criteria and then assessed flare using the SELENA-SLEDAI Flare Index.ResultsAmong a total of 185 patients enrolled, 139 exhibited low disease activity or remission with a median follow-up of 29.8 (21.2–35.2) months. The flare rates after achievement of LLDAS, clinical remission and complete remission on treatment were 0.23, 0.12 and 0.1 per patient-year, respectively. In contrast, the flare rate of patients who never achieved remission or LLDAS was 0.49 per patient-year. In patients with LLDAS or remission achievement, multivariate Cox regression analysis showed that lower C3 level at the time of first achieving LLDAS or clinical remission was an independent predictive factor for subsequent flares. Kaplan-Meier curves showed a significantly lower flare-free survival during the subsequent follow-up in patients with GC withdrawal compared with those maintained on a low dose of prednisone (≤7.5 mg/day) (HR=6.94, 95% CI 1.86 to 25.86, p=0.004). However, no significant differences in flare were observed in patients maintained on different low doses of prednisone (>5 mg/day and ≤7.5 mg/day vs >2.5 mg/day and ≤5 mg/day vs >0 mg/day and ≤2.5 mg/day) (p=0.200).ConclusionsTarget achievement significantly lowered the rate of subsequent flare, from the perspective of both stricter targets and longer period in targets. C3 level was a strong predictor of flare in patients who have achieved treatment targets. Although GC tapering to minimal doses was feasible, its withdrawal may accelerate the risk of recurrence.

Nanoparticle-hydrogel hybrid composites have a great potential for a broad range of applications, such as antibacterial materials, stimuli-responsive materials and catalysis. A novel supramolecular hydrogel system was developed using an amino acid based amphiphile containing a terminal pyrrole moiety as a gelator. The pyrrole moiety could serve as both reducing agent and monomer, and a variety of metal precursors penetrating into the hydrogel could be reduced in situ into metal nanoparticles while the pyrrole moieties preorganized in hydrogel were oxidized into polyprroles, affording metal-nanoparticle-decorated covalent conductive networks. This strategy allows the facile fabrication of diverse mono- or multimetallic nanoparticle-polymer networks from one hydrogel by a simple reaction-diffusion approach. More importantly, besides homogeneous composites, unique multisegment heterogeneous systems with spatiotemporal control were also easily accessible. Furthermore, based on the same multifunctional molecule, the fabrication of hierarchically pore-structured metal-nanoparticles-polymers as well as metal-nanoparticles-carbon structures was also realized.

To investigate the effect of different maintenance to target on radiologic outcomes in patients with rheumatoid arthritis (RA) in real-world setting. RA patients enrolled were screened from a longitudinal cohort. The radiographies were evaluated at baseline, after 1–2 years and thereafter every 2 years. An increase of mTSS > 3 from baseline was taken as the primary outcome and accelerated annual radiological progression as the secondary outcome of radiological progression. The maintenance rate (MR) to target was calculated as the proportion of the year fulfilling preset criteria of target over the whole follow-up period. COX regression and logistic analysis were used to determine the effect of variables on radiological outcomes. Two hundred forty-three patients were enrolled, with median follow-up of 2 years (3.00). Radiological progression was observed in 43 (17.7%) patients, with annual increase of mTSS 0.20 (1.33). In multivariate analysis, MR was the only independent protective factor of both primary and secondary radiological outcomes in two models [HR 0.09, 95% CI (0.04, 0.22), p < 0.001, model 1; OR 0.21, 95% CI (0.09, 0.49), p < 0.001, model 2]. ACPA positivity was another independent risk factor of secondary outcome [OR 2.96, 95% CI (1.27, 6.86), p = 0.012]. Higher MR was also associated with less radiological progression in established RA patients. Partial MR was not inferior to full maintenance within 4 years in terms of halting radiological progression. Low MR and ACPA positivity were independent risk factors of poor radiological outcomes in RA patients. No significant difference in radiological progression could be detected between partial and full maintenance group within 4 years in daily practice. • The first study showing that maintenance to target is beneficial to bone protection in established RA patients in real-world setting • No difference in radiological outcomes between partial and full maintenance group within 4 years

Molecular imprinting is an important tool for generating synthetic receptors with specific recognition sites. The resulting artificial receptor has been extensively used in areas that require molecular recognition. Nevertheless, various imprinted materials synthesized using conventional imprinting protocols have low binding capacities and slow binding kinetics because of difficulty in extracting the original templates and high resistance to mass transfer. The combination of molecular imprinting and nanostructured materials is expected to overcome such difficulties. In this work, template molecules were attached onto the electrospun fibers and by using electrospun nanofibers and attached molecules as sacrificial templates, surface molecularly imprinted membranes with bi-, tri- or tetramodal pore structures were fabricated in the absence or presence of SiO2 nanoparticles in the molecular imprinting precursor. As a demonstration, bovine serum albumin (BSA) and hemoglobin from bovine blood (bHb) were chosen as template molecules and imprinted electrospun affinity membranes with multimodal pore structures were successfully fabricated for protein separation. Compared with the membrane with a bi- or trimodal pore structure, the tetramodal membrane, which consisted of tubule channels, imprinted nanocavities on the inner surface of tube wall, gaps between tubes and pores in the tube wall left by SiO2 nanoparticles, exhibited a very favorable recognition property and efficient separation toward the template protein molecules in aqueous medium. In a two-protein system, the tetramodal membrane has also shown a very high specific recognition for the template proteins over the non-template proteins. Dynamic binding tests and reusability tests further revealed that tetramodal porous membranes had excellent selectivity, faster binding kinetics and good regenerability. These results indicate that in conjugation with the surface molecular imprinting technique the use of electrospun fibers as sacrificial templates could be used as an efficient strategy for development of high performance affinity membrane materials.

Diffusion is one of the most critical factors which affect the performance of porous catalysts in heterogeneous reactions. Hollow spheres with a hierarchical structure could significantly improve the mass transfer in the spherical catalyst. Therefore, preparation of such kind of microspheres is an important work in the field of inorganic synthesis. Herein, we combine microfluidic technology and electroless deposition to prepare hollow Cu and CuO x microspheres with a hierarchically porous structure. These microspheres have a controllable diameter (100-500 μm) and shell thickness (10-60 μm). Numerical simulation and experimental results indicate that the hollow structure is beneficial for the diffusion and utilization of the catalyst in heterogeneous reactions. The Cu and CuO x microspheres were used to catalyze the hydrogenation and Fenton-like reactions in a flow reactor, respectively. The conversion of all reactants can reach more than 95%, and catalysts can maintain their reactivity in long reaction times. Thus, the strategy in the present research should apply in the construction of other porous catalysts with high performance.

Transition metal catalysts in pharmaceutical processes is widely used, but health care agencies such as the Food and Drug Administration and the European Medicines Agency highly regulate the residual level of elemental impurities in the final drug substance and drug product to avoid any adverse effect on patients. Controlling these elemental impurities requires a thorough understanding of the catalytic mechanism and the fate of each elemental impurity. Only with this knowledge in hand can a process be developed to sufficiently remove residual elemental impurities to acceptable levels. Recently, there has been tremendous progress in metal speciation directly assisted by HPLC-ICP-MS. To investigate the removal of elemental impurities from reaction process, we have utilized metal speciation data to provide critical information on the fate of each elemental impurity and a deeper understanding of the catalytic mechanism. Herein we present our recent analytical showcases on (i) how we successfully implemented a...

Many studies have shown that the hyperactivation of ribosome biogenesis plays essential roles in the initiation and progression of cancers. As a ribosome assembly factor, PNO1 plays an important role in ribosome biogenesis. However, little is known about the expression and function of PNO1 in human tumors. In our present study, we aimed to explore the functional roles and the underlying molecular mechanisms of PNO1 in human lung adenocarcinoma (LUAD). Both bioinformatics databases and tumor tissues demonstrated that the expression of PNO1 in LUAD tissues was higher than that in adjacent tissues and predicted poor survival in LUAD patients. In vitro and in vivo assays suggested that downregulation of PNO1 expression suppressed LUAD cell proliferation and invasion. Further studies found that miR-340-5p depressed PNO1 expression via direct binding to the 3′ untranslated region (UTR) of PNO1. PNO1 expression was negatively correlated with miR-340-5p expression in LUAD cells and tissue samples. Moreover, upregulation or downregulation of miR-340-5p expression reversed the effects of PNO1 inhibition and overexpression, respectively. Meanwhile, downregulation of PNO1 inhibited Notch signaling pathway which modulated epithelial mesenchymal transition (EMT). These results indicate that PNO1, negatively regulated by miR-340-5p, played an important role in LUAD progression via Notch signaling pathway. The miR-340-5p/PNO1/Notch axis might be a potential target for individualized and precise treatment of LUAD patients in the future.

Water pollution control has become significant challenges in recent years because of their extensive species diversity. It is critical to developing general-purpose materials for environmental rehabilitation. In this paper, a novel module-assembly method is developed to prepare multi-functional materials for treating pollutants in water. Building blocks are porous nanoparticles with a different function. Microspheres (MS) with a diameter of 90 μm are prepared and have a coefficient of variation of 6.8%. The modular fashion of self-assembly process in a microfluidic chip is the crucial factor in fabricating the multifunction material. The assembled microspheres with different building modules still have a specific surface area larger than 400 m2 g−1, and exhibit excellent performance in adsorbing various pollutants in water, such as heavy metal ions and organic dyes. The adsorption capacities of them to Hg2+ and orange II reach 150 mg g−1 and 333 mg g−1, respectively. The integrated fluorescence probes in microspheres can detect low concentration (9.8 ppb) of Hg2+. Microspheres integrated with Fe3O4 nanoparticles have a magnetic susceptibility of 6.01 emu g−1 and can be easily removed from wastewater by applying an external magnetic. Due to the stability of inorganic building blocks, each function in the assembled system is well performed, and multi-functional “All-in-One” materials can be easily fabricated.

We propose a new method of resin adsorption (RA) coupled with supercritical fluid elution (SFE) for removal of pesticide residue and recovery of ginsenosides from ginseng extracts. D-101-1 resin was selected as the proper adsorption resin, acetone-n-hexane (4 : 6, v : v) served as the modifier with the flow rate of 1.5 mL/min during supercritical CO2 elution of procymidone at 25 MPa, 55°C for 2 h, and absolute ethanol as the modifier at a flow rate of 1 mL/min for supercritical CO2 elution of ginsenosides at 20 MPa, 60°C and 1 h. The results showed that the content of procymidone in the final products was only 0.0089 mg/kg. Meanwhile, the recovery rate of ginsenosides reached up to 92.5%. RA-SFE procedure provides an efficient approach to remove pesticide residue traces with little loss of active ingredients. The used resin can be recycled without any additional regeneration.

A series of Ge11.5SbxSe88.5–x (x = 5, 10, 15, 20, 25, 30) chalcogenide glasses were fabricated aiming at investigating the role of structure and water peak absorption in determining femtosecond laser ablation thresholds (Fth). The results indicate that the optical band gap decreases and that the Vickers hardness increases with increasing Sb content. Meanwhile, Raman spectra were measured before the femtosecond laser ablation experiment, suggesting a rise in average bond energy in the six glass samples with increasing Sb concentration. Ablation of the sample disks in air were performed with high repetition rate ultrashort laser pulses (150 fs, 1 kHz) at different wavelengths (2.86 and 4 μm) to investigate how the water peak absorption coefficient affects ablation thresholds, which reveals the dominating role of the multiphoton ionization (MPI) progress on the ablation threshold fluence. The results will be useful for photonic devices based on Ge–Sb–Se glasses applied in high-power laser operations to preve...

Creating well-defined plasmonic hotspots with enormous field enhancements as well as the capability of selectively trapping targeted molecules into hotspots is of critical importance and a prerequisite for numerous plasmon-assisted applications, but it represents a great challenge. In this work, a robust molecular cage decorated with thioether moieties at the periphery was designed and synthesized. By using the synthesized cage as a linker, a series of molecular cage-bridged plasmonic structures with well-defined nanogaps (hotspots) were fabricated in an efficient and controllable fashion. It was found both experimentally and theoretically that the nanogaps of about 1.2 nm created by the molecular cage in the resultant plasmonic structures led to a strong plasmon coupling, thus inducing great field enhancement inside the nanogaps. More importantly, the embedded molecular cages endowed the formed hotspots with the capability of selectively trapping targeted molecules, offering huge opportunities for many emergent applications. As a demonstration, the hotspots constructed were used as a unique nanoreactor, and under mild conditions two types of plasmon-driven chemical transformation were successfully performed. All the results clearly indicate that the integration of the host–guest chemistry of the molecular cage with the plasmon-coupling effect of metal particles afforded a new class of plasmonic structures, showing great potential for facilitating a broad variety of plasmon-based applications.

Objective Adaptive rewiring of cancer energy metabolism has received increasing attention. By binding with LDLs, LDLRs make most of the circulating cholesterol available for cells to utilize. However, it remains unclear how LDLR works in HCC development by affecting cholesterol metabolism. Methods Database analyses and immunohistochemical staining were used to identify the clinical significance of LDLR in HCC. A transcriptome analysis was used to reveal the mechanism of LDLR aberration in HCC progression. A liver orthotopic transplantation model was used to evaluate the role of LDLR in HCC progression in vivo. Results Downregulation of LDLR was identified as a negative prognostic factor in human HCC. Reduced expression of LDLR in HCC cell lines impaired LDL uptake but promoted proliferation and metastasis in vitro and in vivo. Mechanistically, increasing intracellular de novo cholesterol biosynthesis was the chief contributor to malignant behaviors caused by LDLR inhibition, which could be rescued by simvastatin. Activation of the MEK/ERK pathway by LDLR downregulation partially contributed to intracellular cholesterol synthesis in HCC. Conclusions Downregulation of LDLR may elevate intracellular cholesterol synthesis to accelerate proliferation and motility through a mechanism partially attributed to stimulation of the MEK/ERK signaling pathway. Repression of intracellular cholesterol synthesis with statins may constitute a targetable liability in the context of lower LDLR expression in HCC.