Increased blood CSF3R+ myeloid-derived suppressor cell is a predictor for breast cancer recurrence.

Early detection of cancer recurrence using specific biomarkers remains a clinically unmet need, although methodologies for monitoring tumor markers, cell-free DNA, and circulating tumor cells have been established for decades. Tumor recurrence develops in metastatic or dormant cancer cells under continuous immune surveillance. Alterations in the population and function of immune cells may contribute to cancer recurrence. Here, we utilized an animal model to imitate breast tumor recurrence after surgical resection and investigated the abundance and gene expression profiles of immune cells using NanoString analysis. Bioinformatic analysis of a published single-cell RNA sequencing database of myeloid-derived suppressor cells (MDSCs) was performed to identify common targets between the two studies. Identified biomarkers were validated using human peripheral blood mononuclear cell (PBMC) datasets. The inhibitory effect of MDSCs on T-cell proliferation was assessed in vitro. Our data demonstrated that the number of MDSCs significantly increased during recurrence. Comparison of our NanoString data with a single-cell RNA sequencing dataset of MDSCs in another spontaneous breast cancer model identified colony-stimulating factor 3 receptor (Csf3r)-positive MDSCs as a potential marker for predicting tumor relapse. We validated our findings using two previously published PBMC databases of patients with breast cancer with or without recurrence and confirmed the elevated MDSC gene signature and CSF3R expression in patients with tumor recurrence. 35 patients with breast cancer were also included in our study, that patients with higher levels of CSF3R had worse survival. In vitro experiments demonstrated that Csf3r + MDSCs exhibited enhanced reactive oxygen species (ROS) levels and robust T-cell suppression ability. We conclude that an increase in CSF3R + MDSCs is a potential biomarker for early detection of tumor recurrence in patients with breast cancer.

Discovery of Dual MER/AXL Kinase Inhibitors as Bifunctional Small Molecules for Inhibiting Tumor Growth and Enhancing Tumor Immune Microenvironment.

A series of bifunctional compounds have been discovered for their dual functionality as MER/AXL inhibitors and immune modulators. The furanopyrimidine scaffold, renowned for its suitability in kinase inhibitor discovery, offers at least three distinct pharmacophore access points. Insights from molecular modeling studies guided hit-to-lead optimization, which revealed that the 1,3-diketone side chain hybridized with furanopyrimidine scaffold that respectively combined amino-type substituent and 1H-pyrazol-4-yl substituent on the top and bottom of the aryl regions to produce 22 and 33, exhibiting potent antitumor activities in various syngeneic and xenograft models. More importantly, 33 demonstrated remarkable immune-modulating activity by upregulating the expression of total T-cells, cytotoxic CD8+ T-cells, and helper CD4+ T-cells in the spleen. These findings underscored the bifunctional capabilities of 33 (BPR5K230) with excellent oral bioavailability (F = 54.6%), inhibiting both MER and AXL while modulating the tumor microenvironment and highlighting its diverse applicability for further studies to advance its therapeutic potential.

Ophthalmic drug effects on the amyloidogenesis of a transforming growth factor ß-induced protein (TGFBIp) peptide fragment.

Drugs that can treat one disease may either be detrimental or beneficial toward another due to possible cross-interactions. Therefore, care in choosing a suitable drug for patients with multiple diseases is crucial in successful patient management. This study explores several currently available ophthalmic drugs used to treat common ocular diseases to understand how they can affect the amyloidogenesis of a transforming growth factor ß-induced protein (TGFBIp) peptide fragment found in abundance in the corneal protein aggregation deposits of lattice corneal dystrophy (LCD) patients. Results from this study provided supporting evidence that some drugs intended to treat other diseases can enhance or inhibit fibrillar aggregation of TGFBIp peptide, which may have potential implication of affecting the disease progression of LCD by either worsening or ameliorating it. Comparisons of the different properties of ophthalmic compounds explored in this study may also provide some guidance for future design of drugs geared toward the treatment of LCD.

Using silver nanoparticle-decorated whey protein isolate amyloid fibrils to modify the electrode surface used for electrochemical detection of para-nitrophenol.

Due to their organized structures, remarkable stiffness, and nice biocompatibility and biodegradability, amyloid fibrils serve as building blocks for versatile sustainable materials. Silver nanoparticles (AgNPs) are commonly used as the nano-catalysts for various electrochemical reactions. Given their large specific surface area and high surface energy, AgNPs exhibit high aggregation propensity, which hampers their electrocatalytic performance. Food protein wastes have been identified to be associated with climate change and environmental impacts, and a surplus of whey proteins in dairy industries causes high biological and chemical demands, and greenhouse gas emissions. This study is aimed at constructing sustainable electrode surface modifiers using AgNP-deposited whey protein amyloid fibrils (AgNP/WPI-AFs). AgNP/WPI-AFs were synthesized and characterized via spectroscopic techniques, electron microscopy, and X-ray diffraction. Next, the electrocatalytic performance of AgNP/WPI-AF modified electrode was assessed via para-nitrophenol (p-NP) reduction combined with various electrochemical analyses. Moreover, the reaction mechanism of p-NP electrocatalysis on the surface of AgNP/WPI-AF modified electrode was investigated. The detection range, limit of detection, sensitivity, and selectivity of the AgNP/WPI-AF modified electrode were evaluated accordingly. This work not only demonstrates an alternative for whey valorization but also highlights the feasibility of using amyloid-based hybrid materials as the electrode surface modifier for electrochemical sensing purposes.

Sudden adiabaticity signals reentrant bulk superconductivity in UTe2.

There has been a recent surge of interest in UTe2 due to its unconventional magnetic field (H)-reinforced spin-triplet superconducting phases persisting at fields far above the simple Pauli limit for H∥[010]. Magnetic fields in excess of 35 T then induce a field-polarized magnetic state via a first-order-like phase transition. More controversially, for field orientations close to H∥[011] and above 40 T, electrical resistivity measurements suggest that a further superconducting state may exist. However, no Meissner effect or thermodynamic evidence exists to date for this phase making it difficult to exclude alternative scenarios. In this paper, we describe a study using thermal, electrical, and magnetic probes in magnetic fields of up to 55 T applied between the [010] (b) and [001] (c) directions. Our MHz conductivity data reveal the field-induced state of low or vanishing electrical resistance; our simultaneous magnetocaloric effect measurements (i.e. changes in sample temperature due to changing magnetic field) show the first definitive evidence for adiabaticity and thermal behavior characteristic of bulk field-induced superconductivity.

Breakthrough Curve Modeling and Analysis for Lysozyme Adsorption by Tris(hydroxymethyl)aminomethane Affinity Nanofiber Membrane.

In this study, a polyacrylonitrile nanofiber membrane was first hydrolyzed and then functionalized with tris(hydroxymethyl)aminomethane (P-Tris), then used as an affinity nanofiber membrane for lysozyme adsorption in membrane chromatography. The dynamic adsorption behavior of lysozyme was investigated in a flow system under various operating parameters, including adsorption pHs, initial feed lysozyme concentration, loading flow rate, and the number of stacked membrane layers. Four different kinetic models, pseudo-first-order, pseudo-second-order, Elovich, and intraparticle diffusion kinetic models, were applied to experimental data from breakthrough curves of lysozyme. The results showed that the dynamic adsorption results were fitted well with the pseudo-second-order kinetic model. The breakthrough curve experimental results show significant differences in the breakthrough time, the dynamic binding capacity, the length of the mass transfer zone, and the utilization rate of the membrane bed under different operating parameters. Four dynamic adsorption models (i.e., Bohart-Adams, Thomas, Yoon-Nelson, and BDST models) were used to analyze the breakthrough curve characteristics of the dynamic adsorption experiments. Among them, the Yoon-Nelson model was the best model to fit the breakthrough curve. However, some of the theoretical results based on the Thomas and Bohart-Adams model analyses of the breakthrough curve fit well with the experimental data, with an error percentage of <5%. The Bohart-Adams model has the largest difference from the experimental results; hence it is not suitable for breakthrough curve analysis. These results significantly impact dynamic kinetics studies and breakthrough curve characteristic analysis in membrane bed chromatography.

Developing targeted drug delivery carriers for breast cancer using glutathione-sensitive doxorubicin-coupled glycated bovine serum albumin nanoparticles.

Incorporation of the nano-based carriers into drug delivery provides a promising alternative to overcome the limitations of the conventional chemotherapy. Doxorubicin (DOXO) is an effective chemotherapeutic drug widely used in chemotherapy for breast cancer treatment. A globular protein bovine serum albumin (BSA) holds great potential as carriers in pharmaceutical applications. This work is aimed at developing the DOXO-coupled glycated BSA nanoparticles via desolvation method for improving the capability of targeting the GLUT5 transporters over-expressed on breast cancer cells. Fructosamine assay and Fourier transform infrared spectroscopy were employed to determine the content of fructosamine structure and structural changes on the surfaces of nanoparticles, respectively. Additionally, the synthesized BSA nanoparticles were further characterized by electron microscopy and dynamic light scattering. Results revealed that the DOXO-coupled glycated BSA nanoparticles were spherically shaped with a hydrodynamic diameter of ~60.74 nm and a ζ-potential of ~ - 42.20 mV. Moreover, the DOXO release behavior of as-synthesized DOXO-coupled glycated BSA nanoparticles was examined under different conditions. Finally, the DOXO-coupled glycated BSA nanoparticles were found to exhibit cytotoxicity toward both MCF-7 and MDA-MB-231 cells. Our findings evidently suggested that the drug-coupled glycated BSA nanoparticles serve as the potential candidates for targeted drug delivery platform used in breast cancer therapy.

Measuring poststroke fatigue: The psychometric properties of the Chinese version of multidimensional fatigue inventory.

OBJECTIVE: Poststroke fatigue (PSF) is a common and debilitating problem among stroke patients. Multidimensional fatigue inventory (MFI) has been recommended to assess fatigue related to acquired brain injury. This study aimed to examine the psychometric properties of the Chinese version of MFI among stroke patients. METHODS: The study recruited 252 stroke patients in China. The internal consistency of the Chinese-version MFI was evaluated using Cronbach's α coefficients. The test-retest reliability was measured over a 5-day interval with intraclass correlation coefficient. Exploratory factor analysis was conducted to analyze the construct validity. The concurrent validity of MFI was examined by calculating the Pearson's correlation coefficient between the scores of MFI and the fatigue assessment scale (FAS). RESULTS: The exploratory factor analysis of the Chinese-version of MFI showed that it captured three dimensions of PSF, namely, physical fatigue, mental fatigue, and level of activity. The Chinese-version MFI demonstrated satisfactory internal consistency with Cronbach's α ranging from 0.83 (mental fatigue) to 0.91 (total scale). The Chinese-version MFI showed adequate test-retest reliability with intraclass correlation coefficients of 0.70 for the total scale, 0.69 for physical fatigue, 0.66 for mental fatigue, and 0.62 for level of activity. The concurrent validity of the Chinese-version MFI was demonstrated by a significant positive correlation (r=0.49, p <0.001) with FAS. CONCLUSION: This study findings showed that Chinese-version MFI has adequate internal consistency and test-retest reliability, and demonstrated its concurrent validity with FAS. The findings provide preliminary evidence of the three-factor structure of Chinese-version MFI by exploratory factor analysis.

Application of Amyloid-Based Hybrid Membranes in Drug Delivery.

The properties of amyloid fibrils, e.g., unique structural characteristics and superior biocompatibility, make them a promising vehicle for drug delivery. Here, carboxymethyl cellulose (CMC) and whey protein isolate amyloid fibril (WPI-AF) were used to synthesize amyloid-based hybrid membranes as vehicles for the delivery of cationic and hydrophobic drugs (e.g., methylene blue (MB) and riboflavin (RF)). The CMC/WPI-AF membranes were synthesized via chemical crosslinking coupled with phase inversion. The zeta potential and scanning electron microscopy results revealed a negative charge and a pleated surface microstructure with a high content of WPI-AF. FTIR analysis showed that the CMC and WPI-AF were cross-linked via glutaraldehyde and the interacting forces between membrane and MB or RF was found to be electrostatic interaction and hydrogen bonding, respectively. Next, the in vitro drug release from membranes was monitored using UV-vis spectrophotometry. Additionally, two empirical models were used to analyze the drug release data and relevant rate constant and parameters were determined accordingly. Moreover, our results indicated that in vitro drug release rates depended on the drug-matrix interactions and transport mechanism, which could be controlled by altering the WPI-AF content in membrane. This research provides an excellent example of utilizing two-dimensional amyloid-based materials for drug delivery.

Isolation and stereospecific synthesis of indole alkaloids with lipid-lowering effects from the marine-derived fungus Colletotrichum gloeosporioides BB4.

Seven undescribed compounds, colletotrichindoles A-E, colletotrichaniline A, and colletotrichdiol A, as well as three known compounds, (-)-isoalternatine A, (+)-alternatine A and 3-hydroxybutan-2-yl 2-phenylacetate were isolated from the marine-derived fungus Colletotrichu gloeosporioides BB4. The racemic mixtures colletotrichindole A，colletotrichindole C, and colletotrichdiol A were further separated by chiral chromatography to give three pairs of enantiomers (10S,11R,13S)/(10R,11S,13R)-colletotrichindole A, (10R,11R,13S)/(10S,11S,13R)-colletotrichindole C, and (9S,10S)/(9R,10R)-colletotrichdiol A, respectively. The chemical structures of seven undescribed compounds and the known compounds, (-)-isoalternatine A, and (+)-alternatine A were determined using a combination of NMR, MS, X-ray diffraction, ECD calculations, and/or chemical synthesis. All possible enantiomers of colletotrichindoles A-E were synthesized and used to determine the absolute configurations of the natural products by comparing their spectroscopic data and HPLC retention times on a chiral column. In addition, the X-ray crystal structures of the known compounds (-)-isoalternatine A and (+)-alternatine A were also obtained to confirm their absolute configurations. (10S,11R,13S)-Colletotrichindole A, colletotrichindole B, and (+)-alternatine A significantly reduced triglyceride levels in 3T3-L1 cells with EC50 values of 5.8, 9.0, and 1.3 µM, respectively.

Arabidopsis histone H3 lysine 9 methyltransferases KYP/SUVH5/6 are involved in leaf development by interacting with AS1-AS2 to repress KNAT1 and KNAT2.

The Arabidopsis H3K9 methyltransferases KRYPTONITE/SUPPRESSOR OF VARIEGATION 3-9 HOMOLOG 4 (KYP/SUVH4), SUVH5 and SUVH6 are redundantly involved in silencing of transposable elements (TEs). Our recent study indicated that KYP/SUVH5/6 can directly interact with the histone deacetylase HDA6 to synergistically regulate TE expression. However, the function of KYP/SUVH5/6 in plant development is still unclear. The transcriptional factors ASYMMETRIC LEAVES1 (AS1) and AS2 form a transcription complex, which is involved in leaf development by repressing the homeobox genes KNOTTED-LIKE FROM ARABIDOPSIS THALIANA 1 (KNAT1) and KNAT2. In this study, we found that KYP and SUVH5/6 directly interact with AS1-AS2 to repress KNAT1 and KNAT2 by altering histone H3 acetylation and H3K9 dimethylation levels. In addition, KYP can directly target the promoters of KNAT1 and KNAT2, and the binding of KYP depends on AS1. Furthermore, the genome-wide occupancy profile of KYP indicated that KYP is enriched in the promoter regions of coding genes, and the binding of KYP is positively correlated with that of AS1 and HDA6. Together, these results indicate that Arabidopsis H3K9 methyltransferases KYP/SUVH5/6 are involved in leaf development by interacting with AS1-AS2 to alter histone H3 acetylation and H3K9 dimethylation from KNAT1 and KNAT2 loci.

Reactive Green 19 dye-ligand immobilized on the aminated nanofiber membranes for efficient adsorption of lysozyme: Process development and optimization in batch and flow systems.

The performance of lysozyme adsorption by the aminated nanofiber membrane immobilized with Reactive Green 19 (RG19) dyes was evaluated in batch and flow systems. The physicochemical properties of the dye-immobilized nanofiber membrane were characterized. The parameters of batch-mode adsorption of lysozyme (e.g., pH, initial dye concentration, and lysozyme concentration) were optimized using the Taguchi method. In a flow process, the factors influencing the dynamic binding performance for lysozyme adsorption in the chicken egg white (CEW) solution include immobilized dye concentration, adsorption pH value, feed flow rate, and feed CEW concentration. The impact of these operating conditions on the lysozyme purification process was investigated. Under optimal conditions, the recovery yield and purification factor of lysozyme achieved from the one-step adsorption process were 98.52% and 143 folds, respectively. The dye-affinity nanofiber membrane also did not exhibit any significant loss in its binding capacity and purification performance after five consecutive uses.

The effect of chronoradiotherapy on cervical cancer patients: A multicenter randomized controlled study.

Objectives: To investigate the short-term efficacy and radiotoxicity 3.543of chronoradiotherapy in patients with cervical cancer. We also examined the overall symptom score and quality of life (QOL) of patients who underwent morning radiotherapy and evening radiotherapy. Methods: We conducted a multicenter randomized controlled trial to compare the effects of morning radiotherapy (9:00-11:00 AM) with evening radiotherapy (7:00-9:00 PM) in cervical cancer patients receiving radiotherapy. From November 2021 to June 2022, 114 cervical cancer patients admitted to eight cancer center hospitals in Tianjin, Chongqing, Hubei, Shanxi, Shandong, Shaanxi, Hebei, and Cangzhou were randomly divided into the morning radiotherapy group (MG; N = 61) and the evening radiotherapy group (EG; N = 53). The short-term efficacy of radiotherapy on cervical cancer patients at different time points and the occurrence of radiotoxicity were explored after patients had undergone radiotherapy. Results: The total effective response (partial remission [PR] + complete remission [CR]) rate was similar across the two groups (93.5% vs. 96.3%, p > 0.05). However, the incidence of bone marrow suppression and intestinal reaction in the two groups were significantly different (p < 0.05). The patients in the MG had significantly higher Anderson symptom scores than patients in the EG (21.64 ± 7.916 vs. 18.53 ± 4.098, p < 0.05). In terms of physical activity, functional status, and overall QOL, the MG had significantly lower scores than the EG (p < 0.05). No other measures showed a significant difference between the groups. Conclusion: The radiotherapy effect of the MG was consistent with that of the EG. The incidence of radiation enteritis and radiation diarrhea in the MG was significantly higher than that in the EG; however, bone marrow suppression and blood toxicity in the EG were more serious than in the MG. Because of the small sample size of the study, we only examined the short-term efficacy of radiotherapy. Therefore, further clinical trials are needed to verify the efficacy and side effects of chronoradiotherapy. Clinical Trial Registration: http://www.chictr.org.cn/searchproj.aspx, Registration Number: ChiCTR2100047140.

Oligo-Fucoidan supplementation enhances the effect of Olaparib on preventing metastasis and recurrence of triple-negative breast cancer in mice.

BACKGROUND: Seaweed polysaccharides have been recommended as anticancer supplements and for boosting human health; however, their benefits in the treatment of triple-negative breast cancers (TNBCs) and improving immune surveillance remain unclear. Olaparib is a first-in-class poly (ADP-ribose) polymerase inhibitor. Oligo-Fucoidan, a low-molecular-weight sulfated polysaccharide purified from brown seaweed (Laminaria japonica), exhibits significant bioactivities that may aid in disease management. METHODS: Macrophage polarity, clonogenic assays, cancer stemness properties, cancer cell trajectory, glucose metabolism, the TNBC 4T1 cells and a 4T1 syngeneic mouse model were used to inspect the therapeutic effects of olaparib and Oligo-Fucoidan supplementation on TNBC aggressiveness and microenvironment. RESULTS: Olaparib treatment increased sub-G1 cell death and G2/M arrest in TNBC cells, and these effects were enhanced when Oligo-Fucoidan was added to treat the TNBC cells. The levels of Rad51 and programmed death-ligand 1 (PD-L1) and the activation of epidermal growth factor receptor (EGFR) and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) facilitate drug resistance and TNBC metastasis. However, the combination of olaparib and Oligo-Fucoidan synergistically reduced Rad51 and PD-L1 levels, as well as the activity of EGFR and AMPK; consistently, TNBC cytotoxicity and stemness were inhibited. Oligo-Fucoidan plus olaparib better inhibited the formation of TNBC stem cell mammospheroids with decreased subpopulations of CD44high/CD24low and EpCAMhigh cells than monotherapy. Importantly, Oligo-Fucoidan plus olaparib repressed the oncogenic interleukin-6 (IL-6)/p-EGFR/PD-L1 pathway, glucose uptake and lactate production. Oligo-Fucoidan induced immunoactive and antitumoral M1 macrophages and attenuated the side effects of olaparib, such as the promotion on immunosuppressive and protumoral M2 macrophages. Furthermore, olaparib plus Oligo-Fucoidan dramatically suppressed M2 macrophage invasiveness and repolarized M2 to the M0-like (F4/80high) and M1-like (CD80high and CD86high) phenotypes. In addition, olaparib- and Oligo-Fucoidan-pretreated TNBC cells resulted in the polarization of M0 macrophages into CD80(+) M1 but not CD163(+) M2 macrophages. Importantly, olaparib supplemented with oral administration of Oligo-Fucoidan in mice inhibited postsurgical TNBC recurrence and metastasis with increased cytotoxic T cells in the lymphatic system and decreased regulatory T cells and M2 macrophages in tumors. CONCLUSION: Olaparib supplemented with natural compound Oligo-Fucoidan is a novel therapeutic strategy for reprogramming cancer stemness, metabolism and the microenvironment to prevent local postsurgical recurrence and distant metastasis. The combination therapy may advance therapeutic efficacy that prevent metastasis, chemoresistance and mortality in TNBC patients.

Electronic landscape of the f-electron intermetallics with the ThCr2Si2 structure.

Although strongly correlated f-electron systems are well known as reservoirs for quantum phenomena, a persistent challenge is to design specific states. What is often missing are simple ways to determine whether a given compound can be expected to exhibit certain behaviors and what tuning vector(s) would be useful to select the ground state. In this review, we address this question by aggregating information about Ce, Eu, Yb, and U compounds with the ThCr2Si2 structure. We construct electronic/magnetic state maps that are parameterized in terms of unit cell volumes and d-shell filling, which reveals useful trends including that (i) the magnetic and nonmagnetic examples are well separated, and (ii) the crossover regions harbor the examples with exotic states. These insights are used to propose structural/chemical regions of interest in these and related materials, with the goal of accelerating discovery of the next generation of f-electron quantum materials.

Silver nanoparticle-deposited whey protein isolate amyloid fibrils as catalysts for the reduction of methylene blue.

The unique structural characteristics and superior biocompatibility make the protein nanofibers promising immobilization platforms/substrates for catalysts/enzymes. Metal nanoparticles have been employed as the catalysts in industries due to their excellent catalytic activity and stability, whereas their high surface energy leads to nanoparticle aggregation, thereby hampering their catalytic performance. Here, amyloid fibril (AF) derived from whey protein isolate (WPI) was chosen as the support of silver nanoparticles (AgNP) and utilized for the catalytic reduction of methylene blue (MB). The one-dimensional amyloid-based hybrid materials (AgNP/WPI-AF) were first synthesized via chemical or photochemical route. The characterization of AgNP/WPI-AF by UV-vis spectrophotometry and electron microscopy revealed that the sizes of AgNP on WPI-AF's surface ranged from 2 to 30 nm. Next, the catalytic performances of AgNP/WPI-AF prepared by various routes for MB degradation were investigated. Additionally, the kinetic data were analyzed using two different models and the apparent rate constants and thermodynamic parameters were further determined accordingly. Moreover, the reusability of AgNP/WPI-AF was assessed by monitoring the percentage removal of MB over consecutive filtering cycles. Our results indicated that Langmuir-Hinshelwood-type mechanism better described the catalytic MB reduction using AgNP/WPI-AF. This work provides a nice example of application of nanoparticle-amyloid fibril composite materials for catalysis.

Electrospinning of Quaternized Chitosan-Poly(vinyl alcohol) Composite Nanofiber Membrane: Processing Optimization and Antibacterial Efficacy.

N-(2-hydroxy) propyl-3-trimethylammonium chitosan chloride (HTCC) is a type of quaternary ammonium chitosan derivative with an antibacterial activity superior to the pristine chitosan, but its electrospinnability is limited. In this study, polyvinyl alcohol (PVA) was blended with HTCC to improve the electrospinnability of nanofibers. The electrospinning of PVA-HTCC nanofiber membranes was optimized in terms of structural stability and antimicrobial performance. Based on scanning electron microscopic analysis, the morphology and diameter of the produced nanofibers were influenced by the applied voltage, flow rate of the feed solution, and weight ratio of the polymer blend. An increase in the HTCC content decreased the average nanofiber diameter. The maximum water solubility of the PVA-HTCC nanofibers reached the maximum value of 70.92% at 12 h and 25 °C. The antibacterial activity of PVA-HTCC nanofiber membranes against Escherichia coli was ~90%, which is significantly higher than that of PVA-chitosan nanofiber membrane. Moreover, the antibacterial efficiency of PVA-HTCC nanofiber membranes remained unaffected after 5 cycles of antibacterial treatment. The good antibacterial performance and biocompatibility of PVA-HTCC nanofiber membrane makes them attractive for biomedical and biochemical applications that necessitate sterile conditions.

Halophilic archaea and their extracellular polymeric compounds in the treatment of high salt wastewater containing phenol.

Phenol is one of the major organic pollutants in high salt industrial wastewaters. The biological treatment of such waste using microorganisms is considered to be a cost-effective and eco-friendly method. However, in this process, salt tolerance of microorganisms is one of the main limiting factors. Halophilic microorganisms, especially halophilic archaea are thought to be appropriate for such treatment. To develop a novel effective biological method for high salt phenol wastewater treatment, the influence of phenol in high salt phenol wastewater on halophilic archaea and their extracellular polymeric substances (EPS) should be investigated. In the present study, using phenol enrichment method, 75 halophilic archaeal strains were isolated from Wuyongbulake salt lake sediment sample. The majority of the identified strains were phenol-tolerant. Six strains with high phenol tolerance were chosen, and the phenol scavenging effect was observed in the microbial suspension, supernatant, and EPS. It was noticed that the phenol degradation rate of suspensions of both strains 869-1, and 121-1 in salt water exhibited the highest rates of 83.7%, while the supernatant of strain 869-1 reached the highest rate of 78.2%. When combined with the comprehensive analysis of the artificial wastewater simulation experiment, it was discovered that in the artificial wastewater containing phenol, the phenol degradation rate of suspension of strain A387 exhibited the highest rates of 55.74% both, and supernatant of strain 630-3 reached the highest rate of 62.3%. The EPS produced by strains A00135, 558-1, 869-1, 121-1 and A387 removed 100% phenol within 96 h, and the phenol removal efficiency of EPS produced by 869-1 reached 56.1% under an artificial wastewater simulation experiment with high salt (15%NaCl) condition. The present study suggests that halophilic archaea and their EPS play an important role in phenol degradation. This approach could be potentially used for industrial high-salt wastewater treatment.

Haloterrigena gelatinilytica sp. nov., a new extremely halophilic archaeon isolated from salt-lake.

Two extremely halophilic strains, designated SYSU A558-1T and SYSU A121-1, were isolated from a saline sediment sample collected from Aiding salt-lake, China. Cells of strains SYSU A558-1T and SYSU A121-1 were Gram-stain-negative, coccoid, and non-motile. The strains were aerobic and grew at NaCl concentration of 10-30% (optimum, 20-22%), at 20-55 °C (optimum, 37-42 °C) and at pH 6.5-8.5 (optimum, 7.0-8.0). Cells lysed in distilled water. The polar lipids were phosphatidyl choline, phosphatidylglycerol phosphate methyl ester, disulfated diglycosyl diether-1 and unidentified glycolipid. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that the two strains SYSU A558-1T and SYSU A121-1 were closely related to the membranes of the genus Haloterrigena. Phylogenetic and phylogenomic trees of strains SYSU A558-1T and SYSU A121-1 demonstrated a robust clade with Haloterrigena turkmenica, Haloterrigena salifodinae and Haloterrigena salina. The genomic DNA G + C content of strains SYSU A558-1T and SYSU A121-1 were 65.8 and 65.0%, respectively. Phenotypic, phylogenetic, chemotaxonomic and genome analysis suggested that the two strains SYSU A558-1T and SYSU A121-1 represent a novel species of the genus Haloterrigena, for which the name Haloterrigena gelatinilytica sp. nov. is proposed. The type strain is SYSU A558-1T (= KCTC 4259T = CGMCC 1.15953T).

Novel FLT3/AURK multikinase inhibitor is efficacious against sorafenib-refractory and sorafenib-resistant hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and has a high mortality rate worldwide. Sorafenib is the only systemic treatment demonstrating a statistically significant but modest overall survival benefit. We previously have identified the aurora kinases (AURKs) and FMS-like tyrosine kinase 3 (FLT3) multikinase inhibitor DBPR114 exhibiting broad spectrum anti-tumor effects in both leukemia and solid tumors. The purpose of this study was to evaluate the therapeutic potential of DBPR114 in the treatment of advanced HCC. METHODS: Human HCC cell lines with histopathology/genetic background similar to human HCC tumors were used for in vitro and in vivo studies. Human umbilical vein endothelial cells (HUVEC) were used to evaluate the drug effect on endothelial tube formation. Western blotting, immunohistochemical staining, and mRNA sequencing were employed to investigate the mechanisms of drug action. Xenograft models of sorafenib-refractory and sorafenib-acquired resistant HCC were used to evaluate the tumor response to DBPR114. RESULTS: DBPR114 was active against HCC tumor cell proliferation independent of p53 alteration status and tumor grade in vitro. DBPR114-mediated growth inhibition in HCC cells was associated with apoptosis induction, cell cycle arrest, and polyploidy formation. Further analysis indicated that DBPR114 reduced the phosphorylation levels of AURKs and its substrate histone H3. Moreover, the levels of several active-state receptor tyrosine kinases were downregulated by DBPR114, verifying the mechanisms of DBPR114 action as a multikinase inhibitor in HCC cells. DBPR114 also exhibited anti-angiogenic effect, as demonstrated by inhibiting tumor formation in HUVEC cells. In vivo, DBPR114 induced statistically significant tumor growth inhibition compared with the vehicle control in multiple HCC tumor xenograft models. Histologic analysis revealed that the DBPR114 treatment reduced cell proliferation, and induced apoptotic cell death and multinucleated cell formation. Consistent with the histological findings, gene expression analysis revealed that DBPR114-modulated genes were mostly related to the G2/M checkpoint and mitotic spindle assembly. DBPR114 was efficacious against sorafenib-intrinsic and -acquired resistant HCC tumors. Notably, DBPR114 significantly delayed posttreatment tumor regrowth and prolonged survival compared with the regorafenib group. CONCLUSION: Our results indicated that targeting AURK signaling could be a new effective molecular-targeted agent in the treatment of patients with HCC.