Combating infections from drug-resistant bacteria: Unleashing synergistic broad-spectrum antibacterial power with high-entropy MXene/CDs.

The growing resistance of bacteria to antibiotics has posed challenges in treating associated bacterial infections, while the development of multi-model antibacterial strategies could efficient sterilization to prevent drug resistance. High-entropy MXene has emerged as a promising candidate for antibacterial synergy with inherent photothermal and photodynamic properties. Herein, a high-entropy nanomaterial of MXene/CDs was synthesized to amplify oxidative stress under near-infrared laser irradiation. Well-exfoliated MXene nanosheets have proven to show an excellent photothermal effect for sterilization. The incorporation of CDs could provide photo-generated electrons for MXene nanosheets to generate ROS, meanwhile reducing the recombination of electron-hole pairs to further accelerate the generation of photo-generated electrons. The MXene/CDs material demonstrates outstanding synergistic photothermal and photodynamic effects, possesses excellent biocompatibility and successfully eliminates drug-resistant bacteria as well as inhibits biofilm formation. While attaining a remarkable killing efficiency of up to 99.99% against drug-resistant Escherichia coli and Staphylococcus aureus, it also demonstrates outstanding antibacterial effects against four additional bacterial strains. This work not only establishes a synthesis precedent for preparing high-entropy MXene materials with CDs but also provides a potential approach for addressing the issue of drug-resistant bacterial infections.

Reduced representative methylome profiling of cell-free DNA for breast cancer detection.

BACKGROUND: Whole-genome methylation sequencing of cfDNA is not cost-effective for tumor detection. Here, we introduce reduced representative methylome profiling (RRMP), which employs restriction enzyme for depletion of AT-rich sequence to achieve enrichment and deep sequencing of CG-rich sequences. METHODS: We first verified the ability of RRMP to enrich CG-rich sequences using tumor cell genomic DNA and analyzed differential methylation regions between tumor cells and normal whole blood cells. We then analyzed cfDNA from 29 breast cancer patients and 27 non-breast cancer individuals to detect breast cancer by building machine learning models. RESULTS: RRMP captured 81.9% CpG islands and 75.2% gene promoters when sequenced to 10 billion base pairs, with an enrichment efficiency being comparable to RRBS. RRMP allowed us to assess DNA methylation changes between tumor cells and whole blood cells. Applying our approach to cfDNA from 29 breast cancer patients and 27 non-breast cancer individuals, we developed machine learning models that could discriminate between breast cancer and non-breast cancer controls (AUC = 0.85), suggesting possibilities for truly non-invasive cancer detection. CONCLUSIONS: We developed a new method to achieve reduced representative methylome profiling of cell-free DNA for tumor detection.

Microstructured Gel Polymer Electrolyte and an Interdigital Electrode-Based Iontronic Barometric Pressure Sensor with High Resolution over a Broad Range.

We present a novel iontronic barometric pressure sensor based on a gel polymer electrolyte and interdigital electrodes with a much simpler structure than that of existing devices. By introducing high-density microstructures on the gel polymer electrolyte and one side electrode arrangement configuration, the developed sensor offers high performances with an ultrahigh resolution of 10 Pa, an ultrawide barometric pressure-response range from -92 to 7 kPa, a fast response time of ∼15 ms, and excellent long-term stability. The single pressure sensor is able to detect positive and negative barometric pressures without needing any additional means and can operate as a barometric altimeter with a resolution of about one-floor height. The performances of the sensors significantly surpass those of existing barometric pressure sensors. This work provides a new strategy for making high-performance barometric pressure sensors that are highly sought for commercial applications such as altitude detection, negative pressure ambulance, and consumer electronics.

Electroacupuncture promotes neurogenesis in the dentate gyrus and improves pattern separation in an early Alzheimer's disease mouse model.

BACKGROUND: Impaired pattern separation occurs in the early stage of Alzheimer's disease (AD), and hippocampal dentate gyrus (DG) neurogenesis participates in pattern separation. Here, we investigated whether spatial memory discrimination impairment can be improved by promoting the hippocampal DG granule cell neogenesis-mediated pattern separation in the early stage of AD by electroacupuncture (EA). METHODS: Five familial AD mutations (5 × FAD) mice received EA treatment at Baihui and Shenting points for 4 weeks. During EA, mice were intraperitoneally injected with BrdU (50 mg/kg) twice a day. rAAV containing Wnt5a shRNA was injected into the bilateral DG region, and the viral efficiency was evaluated by detecting Wnt5a mRNA levels. Cognitive behavior tests were conducted to assess the impact of EA treatment on cognitive function. The hippocampal DG area Aß deposition level was detected by immunohistochemistry after the intervention; The number of BrdU+/CaR+ cells and the gene expression level of calretinin (CaR) and prospero homeobox 1(Prox1) in the DG area of the hippocampus was detected to assess neurogenesis by immunofluorescence and western blotting after the intervention; The gene expression levels of FZD2, Wnt5a, DVL2, p-DVL2, CaMKII, and p-CaMKII in the Wnt signaling pathway were detected by Western blotting after the intervention. RESULTS: Cognitive behavioral tests showed that 5 × FAD mice had impaired pattern separation (P < 0.001), which could be improved by EA (P < 0.01). Immunofluorescence and Western blot showed that the expression of Wnt5a in the hippocampus was decreased (P < 0.001), and the neurogenesis in the DG was impaired (P < 0.001) in 5 × FAD mice. EA could increase the expression level of Wnt5a (P < 0.05) and promote the neurogenesis of immature granule cells (P < 0.05) and the development of neuronal dendritic spines (P < 0.05). Interference of Wnt5a expression aggravated the damage of neurogenesis (P < 0.05), weakened the memory discrimination ability (P < 0.05), and inhibited the beneficial effect of EA (P < 0.05) in AD mice. The expression level of Wnt pathway related proteins such as FZD2, DVL2, p-DVL2, CAMKII, p-CAMKII increased after EA, but the effect of EA was inhibited after Wnt5a was knocked down. In addition, EA could reduce the deposition of Aß plaques in the DG without any impact on Wnt5a. CONCLUSION: EA can promote hippocampal DG immature granule cell neogenesis-mediated pattern separation to improve spatial memory discrimination impairment by regulating Wnt5a in 5 × FAD mice.

Proximity Effect-Induced Magnetoresistance Enhancement in a Fe3GeTe2/NbSe2/Fe3GeTe2 Magnetic Tunnel Junction.

The coupling between van der Waals-layered magnetic and superconducting materials holds the possibility of revealing novel physical mechanisms and realizing spintronic devices with new functionalities. Here, we report on the realization and investigation of a maximum ∼17-fold magnetoresistance (MR) enhancement based on a vertical magnetic tunnel junction of Fe3GeTe2 (FGT)/NbSe2/FGT near the NbSe2 layer's superconducting critical temperature (TC) of 6.8 K. This enhancement is attributed to the band splitting in the atomically thin NbSe2 spacer layer induced by the magnetic proximity effect on the material interfaces. However, the band splitting is strongly suppressed by the interlayer coupling in the thick NbSe2 layer. Correspondingly, the device with a thick NbSe2 layer displays no MR increase near TC but a current dependent on transport properties at extremely low temperatures. This work carefully investigates the mechanism of MR enhancement, paving an efficient way for the modulation of spintronics' properties and the achievement of spin-based integrated circuits.

Tunable asymmetric magnetoresistance in an Fe3GeTe2/graphite/Fe3GeTe2 lateral spin valve.

van der Waals (vdW) ferromagnetic heterojunctions, characterized by an ultraclean device interface and the absence of lattice matching, have emerged as indispensable and efficient building blocks for future spintronic devices. In this study, we present a seldom observed antisymmetric magnetoresistance (MR) behavior with three distinctive resistance states in a lateral van der Waals (vdW) structure comprising Fe3GeTe2 (FGT)/graphite/FGT. In contrast to traditional spin valves governed by the magnetization configurations of ferromagnetic electrodes (FEs), this distinct feature can be attributed to the interaction between FGT and the FGT/graphite interface, which is primarily influenced by the internal spin-momentum locking effect. Furthermore, modulation of the MR behavior is accomplished by employing the coupling between antiferromagnetic and ferromagnetic materials to adjust the coercive fields of two FEs subsequent to the in situ growth of an FGT oxide layer on FGT. This study elucidates the device physics and mechanism of property modulation in lateral spin valves and holds the potential for advancing the development of gate-tunable spintronic devices and next-generation integrated circuits.

A Machine Learning-Based Unenhanced Radiomics Approach to Distinguishing Between Benign and Malignant Breast Lesions Using T2-Weighted and Diffusion-Weighted MRI.

BACKGROUND: Breast MRI has been recommended as supplemental screening tool to mammography and breast ultrasound of breast cancer by international guidelines, but its long examination time and use of contrast material remains concerning. PURPOSE: To develop an unenhanced radiomics model with using non-gadolinium based sequences for detecting breast cancer based on T2-weighted (T2W) and diffusion-weighted (DW) MRI. STUDY TYPE: Retrospective analysis followed by retrospective and prospective cohorts study. POPULATION: 1760 patients: Of these, 1293 for model construction (n = 775 for training and 518 for validation). The remaining patients for model testing in internal retrospective (n = 167), internal prospective (n = 188), and external retrospective (n = 112) cohorts. FIELD STRENGTH/SEQUENCE: 3.0T MR scanners from two institution. T2WI, DWI, and first contrast-enhanced T1-weighted sequence. ASSESSMENT: AUCs in distinguishing breast cancer were compared between combined model with gadolinium agent sequence and unenhanced model. Subsequently, the AUCs in testing cohorts of unenhanced model was compared with two radiologists' diagnosis for this research. Finally, patient subgroup analysis in testing cohorts was performed based on clinical subgroups and different types of malignancies. STATISTICAL TESTS: Mann-Whitney U test, Kruskal-Wallis H test, chi-square test, weighted kappa test, and DeLong's test. RESULTS: The unenhanced radiomics model performed best under Gaussian process (GP) classifiers (AUC: training, 0.893; validation, 0.848) compared to support vector machine (SVM) and logistic, showing favorable prediction in testing cohorts (AUCs, 0.818-0.840). The AUCs for the unenhanced radiomics model were not statistically different in five cohorts from those of the combined radiomics model (P, 0.317-0.816), as well as the two radiologists (P, 0.181-0.918). The unenhanced radiomics model was least successful in identifying ductal carcinoma in situ, whereas did not show statistical significance in other subgroups. DATA CONCLUSION: An unenhanced radiomics model based on T2WI and DWI has comparable diagnostic accuracy to the combined model using the gadolinium agent. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.

Fabrication of Enzyme-Responsive Prodrug Self-Assembly Based on Fluazinam for Reducing Toxicity to Aquatic Organisms.

Prodrug-based nanodrug delivery systems were drug formulations by covalently conjugating drugs with inversely polar groups via a cleavable bond to self-assemble into nanoparticles for efficient drug delivery. To improve the utilization efficiency of fluazinam (FZN), enzyme-responsive prodrugs were prepared by conjugating FZN with different alkyl aliphatic acids through a nucleophilic substitution reaction and subsequently self-assembled into nanoparticles (FZNP NPs) without using any harmful adjuvant. The obtained FZNP NPs exhibited excellent efficacies against Sclerotinia sclerotiorum as a result of improved physicochemical properties, including low surface tension, high retention, and enhanced photostability. The LC50 values of FZNP NPs toward zebrafish were 3-8 times that of FZN, which illustrated that the FZNP NPs reduced the detriments of FZN to the aquatic organisms while retaining good biological activity. Therefore, prodrug self-assembly technology would offer a potential method for improving the utilization efficiency of pesticides and lowering the risks to the ecological environment.

Experimental study on the flow structures and dynamics of turbulent Rayleigh-Bénard convection in an annular cell.

We conduct an experimental study on the flow structures and dynamics of turbulent Rayleigh-Bénard convection in an annular cell with radius ratio η≃0.5 and aspect ratio Γ≃4. The working fluid is water with a Prandtl number of Pr≃5.4, and the Rayleigh number (Ra) ranges from 5.05×10^{7} to 5.05×10^{8}. The multithermal-probe method and the particle image velocimetry technique are employed to measure the temperature profiles and the velocity fields, respectively. Two distinct states with multiroll standing waves are observed, which are the quadrupole state (QS) characterized by a four-roll structure and the sextupole state (SS) by a six-roll structure. The scaling exponents of Reynolds number Re with Ra are different for the two states, which are 0.56 for QS and 0.41 for SS. In addition, the standing waves become unstable upon tilting the cell by 1^{∘} in relation to the horizontal plane, and they evolve into traveling waves. At relatively high Ra, for instance, Ra⩾2.55×10^{8}, it is observed that the traveling wave state SS undergoes a transition to the traveling wave state QS. However, the opposite transition from QS to SS is not observed in our experiments. Our findings provide insights into the flow structures and dynamics in the convection flow with rotation symmetry.

Toxicities associated with immune checkpoint inhibitors: a systematic study.

BACKGROUND: Available evidence shows that the incidence of toxicities associated with cancer immunotherapy, such as programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1)-related toxicities, is estimated to be between 0.3 and 1.3%. OBJECTIVE: This systematic review aimed to investigate cancer patients' susceptibility to toxicities associated with PD-1/PD-L1 inhibitors and establish a clinically relevant landscape of side effects of PD-1/PD-L1 inhibitors. DATA SOURCES: Relevant publications from PubMed, Embase, Cochrane Library, Web of Science, and China National Knowledge Infrastructure (CNKI) between 2014 and 2019. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: We searched randomized controlled trials (RCTs) reporting treatment-related toxicities associated with PD-1 and PD-L1 inhibitors in the treatment of cancers. The primary endpoint was to assess the difference in the incidences of toxicities between cancer patients who did and did not receive PD-1/PD-L1 inhibitors. A total of 29 RCTs, incorporating 8576 patients, met the eligibility criteria. STUDY APPRAISAL AND SYNTHESIS METHODS: We calculated the pooled relative risks and corresponding 95% CIs using a random-effects model and assessed the heterogeneity between different groups. The subgroup analyses were conducted based on cancer type, toxicity grade (severity), system and organ, treatment regimens in the intervention arm and the control arm, PD-1/PD-L1 inhibitor drug type, and cancer type. RESULTS: A total of 11 categories (e.g. endocrine toxicity), and 39 toxicity types (e.g. hyperthyroidism) were identified. For toxicities at any grade, those treated with PD-1/PD-L1 inhibitors were at lower risks for gastrointestinal toxicity, hematologic toxicity, and treatment event leading to discontinuation; and were at higher risks for respiratory toxicity (all P <0.05). Those treated with PD-1/PD-L1 inhibitors were at lower risks for fatigue, asthenia, and peripheral edema and were at higher risks for pyrexia, cough, dyspnea, pneumonitis, and pruritus. LIMITATIONS: The present research is a meta-analysis at the study level rather than at the patient level; insights on risk factors associated with the development of toxicities cannot be found in our study. There was a possible overlap in Common Terminology Criteria for Adverse Events (CTCAE) definitions which prevents understanding the true rates of specific toxicities. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: For most toxicity types based on system and organ, the incidence proportions for patients in the intervention arm were lower than those in the control arm, which suggested the general safety of PD-1/PD-L1 inhibitors against conventional chemotherapy and cytotoxic t-lymphocyte-associated protein 4 (CTLA-4) inhibitors. Future research should focus on taking effective targeted measures to decrease the risks of different toxicities for different patient populations. SYSTEMATIC REVIEW REGISTRATION NUMBER: We registered the research protocol with PROSPERO (registration number CRD42019135113).

Generating multi-focus beams with a spatial non-uniform coherence structure.

We introduce a class of structured light beams, named multi-focus beams, which exhibit self-focusing at multiple propagation distances. We show that the proposed beams not only have the ability to produce multiple longitudinal focal spots, but also that the number, intensity, and position of the foci can be controlled by adjusting the initial beam parameters. Furthermore, we demonstrate that these beams still exhibit self-focusing in the shadow of an obstacle. We have experimentally generated such beams and the results are consistent with the theoretical predictions. Our studies may find application where fine control of the longitudinal spectral density is needed, such as longitudinal optical trapping and manipulation of multiple particles, and transparent material cutting.

A high adhesion co-assembly based on myclobutanil and tannic acid for sustainable plant disease management.

BACKGROUND: Pesticides are irreplaceable inputs for protecting crops from pests and improving crop yield and quality. Self-assembly nanotechnology is a promising strategy by which to develop novel nano-formulations for pesticides. Nano-formulations improve the effective utilization of pesticides and reduce risks to the environment because of their eco-friendly preparation, high drug loading, and desirable physicochemical properties. Here, to enhance the utilization efficiency of myclobutanil (MYC) and develop a novel nano-formulation, carrier-free co-assembled nanoparticles (MT NPs) based on MYC and tannic acid (TA) were prepared by noncovalent molecular interactions using a green preparation process without any additives. RESULTS: The results showed that the prepared spherical nanoparticles had good stability in neutral and acidic aqueous solutions, low surface tension (40.53 mN m-1 ), high rainfastness, and good maximum retention values on plant leaves. Release of active ingredients from MT NPs could be regulated by altering the molar ratio of subassemblies in the co-assembly and the pH of the environment. Antifungal experiments demonstrated that MT NPs had better activities against Alternaria alternata and Fusarium graminearum [half-maximal effective concentration (EC50 ) = 6.40 and 77.08 mg/L] compared with free MYC (EC50 = 11.46 and 124.82 mg/L), TA (EC50 = 251.19 and 503.81 mg/L), and an MYC + TA mixture (EC50 = 9.62 and 136.21 mg/L). These results suggested that MYC and TA incorporated in the co-assembled nanoparticles had a synergistic antifungal activity. The results of a genotoxicity assessment indicated that MT NPs could reduce the genotoxicity of MYC to plant cells. CONCLUSION: Co-assembled MT NPs with synergistic antifungal activity have outstanding potential for the management of plant diseases. © 2023 Society of Chemical Industry.

Stable Fluorescent Nanoparticles Based on Co-assembly of Acifluorfen and Poly(salicylic acid) for Enhancing Herbicidal Activity and Reducing Environmental Risks.

Herbicides are widely used in modern agricultural production for their advantages of high efficiency, convenience, and speed. However, there have been many problems caused by herbicide formulations, such as volatilization, leaching, and rain-washing loss in the process of agricultural application. Self-assembled nanotechnology is a promising strategy to solve these existing problems due to the environmentally friendly preparation process and high delivery efficiency. In this study, the stable fluorescent nanoparticles (AP NPs) based on co-assembly of acifluorfen (ACI) and poly(salicylic acid) (PSA) are constructed by using non-covalent bond interactions. The results indicate that the obtained nanoparticles with a stable fluorescence characteristic show improved physiochemical properties, such as uniform morphology, good thermal stability, low surface tension, and high retention on plants. The co-assembly can produce singlet oxygen to enhance the herbicidal activity under irradiation of light and reduce the leaching property of ACI to minimize the adverse impact on the aquatic environment. The safety evaluation of soybean seedlings indicates that AP NPs have no damage to non-target plants. In summary, the co-assembled herbicidal nano-formulation composed of ACI and PSA has high bioactivity and low environmental risks, which can be widely used in agricultural production.

CENPF knockdown inhibits adriamycin chemoresistance in triple-negative breast cancer via the Rb-E2F1 axis.

Drug resistance occurs frequently in triple-negative breast cancer (TNBC) and leads to early relapse and short survival. Targeting the DNA damage response (DDR) has become an effective strategy for overcoming TNBC chemoresistance. CENPF (centromere protein) is a key regulator of cell cycle progression, but its role in TNBC chemotherapy resistance remains unclear. Here, we found that CENPF, which is highly expressed in TNBC, is associated with a poor prognosis in patients receiving chemotherapy. In addition, in vitro CENPF knockdown significantly increased adriamycin (ADR)-induced cytotoxicity in MDA-MB-231 cells and ADR-resistant cells (MDA-MB-231/ADR). Then, we demonstrated that CENPF targets Chk1-mediated G2/M phase arrest and binds to Rb to compete with E2F1 in TNBC. Considering the crucial role of E2F1 in the DNA damage response and DNA repair, a novel mechanism by which CENPF regulates the Rb-E2F1 axis will provide new horizons to overcome chemotherapy resistance in TNBC.

Activation of Hedgehog signaling by the oncogenic RELA fusion reveals a primary cilia-dependent vulnerability in supratentorial ependymoma.

BACKGROUND: Supratentorial RELA fusion (ST-RELA) ependymomas (EPNs) are resistant tumors without an approved chemotherapeutic treatment. Unfortunately, the molecular mechanisms that lead to chemoresistance traits of ST-RELA remain elusive. The aim of this study was to assess RELA fusion-dependent signaling modules, specifically the role of the Hedgehog (Hh) pathway as a novel targetable vulnerability in ST-RELA. METHODS: Gene expression was analyzed in EPN from patient cohorts, by microarray, RNA-seq, qRT-PCR, and scRNA-seq. Inhibitors against Smoothened (SMO) (Sonidegib) and Aurora kinase A (AURKA) (Alisertib) were evaluated. Protein expression, primary cilia formation, and drug effects were assessed by immunoblot, immunofluorescence, and immunohistochemistry. RESULTS: Hh components were selectively overexpressed in EPNs induced by the RELA fusion. Single-cell analysis showed that the Hh signature was primarily confined to undifferentiated, stem-like cell subpopulations. Sonidegib exhibited potent growth-inhibitory effects on ST-RELA cells, suggesting a key role in active Hh signaling; importantly, the effect of Sonidegib was reversed by primary cilia loss. We, thus, tested the effect of AURKA inhibition by Alisertib, to induce cilia stabilization/reassembly. Strikingly, Alisertib rescued ciliogenesis and synergized with Sonidegib in killing ST-RELA cells. Using a xenograft model, we show that cilia loss is a mechanism for acquiring resistance to the inhibitory effect of Sonidegib. However, Alisertib fails to rescue cilia and highlights the need for other strategies to promote cilia reassembly, for treating ST-RELA tumors. CONCLUSION: Our study reveals a crucial role for the Hh pathway in ST-RELA tumor growth, and suggests that rescue of primary cilia represents a vulnerability of the ST-RELA EPNs.

Risk stratification for 1- to 2-cm gastric gastrointestinal stromal tumors: visual assessment of CT and EUS high-risk features versus CT radiomics analysis.

OBJECTIVES: To investigate the ability of CT and endoscopic sonography (EUS) in predicting the malignant risk of 1-2-cm gastric gastrointestinal stromal tumors (gGISTs) and to clarify whether radiomics could be applied for risk stratification. METHODS: A total of 151 pathologically confirmed 1-2-cm gGISTs from seven institutions were identified by contrast-enhanced CT scans between January 2010 and March 2021. A detailed description of EUS morphological features was available for 73 gGISTs. The association between EUS or CT high-risk features and pathological malignant potential was evaluated. gGISTs were randomly divided into three groups to build the radiomics model, including 74 in the training cohort, 37 in validation cohort, and 40 in testing cohort. The ROIs covering the whole tumor volume were delineated on the CT images of the portal venous phase. The Pearson test and least absolute shrinkage and selection operator (LASSO) algorithm were used for feature selection, and the ROC curves were used to evaluate the model performance. RESULTS: The presence of EUS- and CT-based morphological high-risk features, including calcification, necrosis, intratumoral heterogeneity, irregular border, or surface ulceration, did not differ between very-low and intermediate risk 1-2-cm gGISTs (p > 0.05). The radiomics model consisting of five radiomics features showed favorable performance in discrimination of malignant 1-2-cm gGISTs, with the AUC of the training, validation, and testing cohort as 0.866, 0.812, and 0.766, respectively. CONCLUSIONS: Instead of CT- and EUS-based morphological high-risk features, the CT radiomics model could potentially be applied for preoperative risk stratification of 1-2-cm gGISTs. KEY POINTS: • The presence of EUS- and CT-based morphological high-risk factors, including calcification, necrosis, intratumoral heterogeneity, irregular border, or surface ulceration, did not correlate with the pathological malignant potential of 1-2-cm gGISTs. • The CT radiomics model could potentially be applied for preoperative risk stratification of 1-2-cm gGISTs.

The Pharmacokinetics and Pharmacodynamics of A Novel Recombinant Activated Human Factor VII, GEN-0828, in Hemophilia B Mice.

GEN-0828, a proposed clinical candidate for hemophilia and trauma hemorrhage treatment, is a novel recombinant activated human factor VII (rFVIIa). The purpose of this paper is to compare the pharmacokinetics and pharmacodynamics of GEN-0828 in hemophilia B mice with those of NovoSeven®, the only marketed rFVIIa product worldwide., GEN-0828 and NovoSeven® showed similar affinity bioactivity to recombinant tissue factor (rTF) in vitro. Pharmacodynamics data indicated a generally similar hemostatic efficacy (ED50) of GEN-0828 (10.91 KIU·kg-1) and NovoSeven® (18.91 KIU·kg-1) at the doses studied in hemophilia B mice, while GEN-0828 represented a lower initial effective dosage compared with that of NovoSeven® in terms of both blood loss and APTT. GEN-0828 exhibited linear pharmacokinetic profiles in hemophilia B mice at the 30-338 KIU·kg-1 dose range, the comparative pharmacokinetic study with NovoSeven® indicated better characteristics than NovoSeven® in terms of the appropriate higher maximal concentration (Cmax) and area under the plasma concentration-time curve (AUClast) and longer mean residence time (MRT). In conclusion, GEN-0828 was a promising new type of rFVIIa compound with favourable pharmacokinetic and pharmacodynamic profiles.

Nitrogen-doped cyan-emissive carbon quantum dots for fluorescence tetracycline detection and lysosome imaging.

Tetracyclines (TCs) prevent the growth of peptide chains and the synthesis of proteins, and they are widely used to inhibit Gram-positive and -negative bacteria. For the detection of tetracyclines in cell and in vitro, a convenient and simple detection system based on nitrogen-doped cyan carbon quantum dots (C-CQDs) was developed. C-CQDs have excellent excitation-independent properties, the best optimal excitation peak is 360 nm and the best emission peak is 480 nm. Based on the inner filter effect (IFE), the fluorescence intensity of C-CQDs in solution decreases with the increase of tetracyclines. In the range of 0-100 µM, C-CQDs present a good linear relationship with three tetracyclines (CTC, TET, OCT), with R 2 all greater than 0.999. C-CQDs can detect tetracycline in milk samples with recovery in the range of 98.2-103.6%, which demonstrates their potential and broad application in real samples. Furthermore, C-CQDs exhibit excellent lysosomal targeting, as indicated by a Pearson's coefficient of 0.914 and an overlap of 0.985. The internalisation of C-CQDs was mainly affected by lipid raft-mediated endocytosis in endocytic pathway experiments. These experiments indicate that C-CQDs can be effectively used to detect TC content and target lysosomes as an alternative to commercial dyes.

Effect of Roxadustat versus erythropoietin (EPO) for treating anemia in patients with diabetic kidney disease: a retrospective cohort study.

Background: Renal anemia of diabetic kidney disease (DKD) shows higher incidence rate, earlier onset and higher severity than other chronic kidney disease (CKD). Roxadustat, an oral hypoxia-inducible factor-prolyl hydroxylase inhibitor, improves CKD anemia. This retrospective cohort study evaluates if Roxadustat could effectively treat DKD anemia. Methods: DKD anemia patients treated with either Roxadustat or erythropoietin (EPO) for 3 months in two hospitals were enrolled. EPO group were matched 1:1 to Roxadustat group based on age, gender and baseline Hb. Baseline data include age, sex, dialysis, height, weight, hemoglobin (Hb), hematocrit (Hct), serum albumin (ALB), serum creatinine (Scr), eGFR, C-reactive protein (CRP), and intact parathyroid hormone (iPTH). Primary and secondary outcomes were change of Hb (ΔHb) and Hct (ΔHct), Hb response rate and Hb qualified rate. Sensitivity analyses were performed and the effect size were calculated. Results: No significant differences were observed in body mass index (BMI), Scr, eGFR, Hct, CRP, and dialysis between the 2 groups (61 subjects each). ALB, iPTH, and DKD stage differed between the 2 groups. After 3-month treatment, Roxadustat significantly increased patients' Hb and Hct. Although ΔHb and ΔHct of the Roxadustat group was higher than those of EPO group, difference in the least-square mean changes (95% CI) were 4.9 (-2.4, 12.1) and 1.2 (-1.1, 3.4), while Cohen's d were 0.18 and 0.14, suggesting that Roxadustat's ability to increase Hb within 3-month was similar to EPO. 78.7% and 54.1% of the patients responded to anti-anemia therapy in the Roxadustat and EPO group, respectively. Logistic regression analysis showed the Hb response rate of Roxadustat was 3.30 (1.20, 9.94) times higher than that of EPO. Subgroup analysis suggested that Roxadustat might have better efficacy in treating patients in the advanced stage, with high CRP and iPTH, and low ALB levels. Conclusions: In DKD patients, Roxadustat improves renal anemia. Effect of Roxadustat is similar to that of EPO.

Evaluation of the metabolism of PEP06, an endostatin-RGDRGD 30-amino-acid polypeptide and a promising novel drug for targeting tumor cells.

PEP06 is a novel endostatin-Arg-Gly-Asp-Arg-Gly-Asp (RGDRGD) 30-amino-acid polypeptide featuring a terminally fused RGDRGD hexapeptide at the N terminus. The active endostatin fragment of PEP06 directly targets tumor cells and exerts an antitumoral effect. However, little is known about the kinetics and degradation products of PEP06 in vitro or in vivo. In this study, we investigated the in vitro metabolic stability of PEP06 after it was incubated with living cells obtained from animals of different species; we further identified the degradation characteristics of its cleavage products. PEP06 underwent rapid enzymatic degradation in multiple types of living cells, and the liver, kidney, and blood play important roles in the metabolism and clearance of the peptides resulting from the molecular degradation of PEP06. We identified metabolites of PEP06 using full-scan mass spectrometry (MS) and tandem MS (MS2), wherein 43 metabolites were characterized and identified as the degradation metabolites from the parent peptide, formed by successive losses of amino acids. The metabolites were C and N terminal truncated products of PEP06. The structures of 11 metabolites (M6, M7, M16, M17, M21, M25, M33, M34, M39, M40, and M42) were further confirmed by comparing the retention times of similar full MS spectrum and MS2 spectrum information with reference standards for the synthesized metabolites. We have demonstrated the metabolic stability of PEP06 in vitro and identified a series of potentially bioactive downstream metabolites of PEP06, which can support further drug research.