Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/relapsed acute myeloid leukemia with FLT3-ITD: A multicenter phase 2 study.

BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3-internal tandem duplication (FLT3-ITD) respond infrequently to salvage chemotherapy. OBJECTIVE: To investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population. METHODS: This multicenter, single-arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3-ITD (aged 18-65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival. RESULTS: Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 17.7 months (IQR, 8.7-24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8-NR) and event-free survival was 11.4 months (95% CI, 5.6-NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment-related death occurred in two (3.9%) patients. CONCLUSIONS: The sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3-ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored. TRIAL REGISTRATION: Clinical Trials Registry: NCT04424147.

Nanoscale Structure, Interactions, and Dynamics of Centromere Nucleosomes.

Centromeres are specific segments of chromosomes comprising two types of nucleosomes: canonical nucleosomes containing an octamer of H2A, H2B, H3, and H4 histones and CENP-A nucleosomes in which H3 is replaced with its analogue CENP-A. This modification leads to a difference in DNA wrapping (∼121 bp), considerably less than 147 bp in canonical nucleosomes. We used atomic force microscopy (AFM) and high-speed AFM (HS-AFM) to characterize nanoscale features and dynamics for both types of nucleosomes. For both nucleosomes, spontaneous asymmetric unwrapping of DNA was observed, and this process occurs via a transient state with ∼100 bp DNA wrapped around the core, followed by a rapid dissociation of DNA. Additionally, HS-AFM revealed higher stability of CENP-A nucleosomes compared with H3 nucleosomes in which dissociation of the histone core occurs prior to the nucleosome dissociation. These results help elucidate the differences between these nucleosomes and the potential biological necessity for CENP-A nucleosomes.

Discovery of 4-phenyl-1H-indazole derivatives as novel small-molecule inhibitors targeting the PD-1/PD-L1 interaction.

The inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway with small molecules is a promising approach for cancer immunotherapy. Herein, novel small molecules compounds bearing various scaffolds including thiophene, thiazole, tetrahydroquinoline, benzimidazole and indazole were designed, synthesized and evaluated for their inhibitory activity against the PD-1/PD-L1 interaction. Among them, compound Z13 exhibited the most potent activity with IC50 of 189.6 nM in the homogeneous time-resolved fluorescence (HTRF) binding assay. Surface plasmon resonance (SPR) assay demonstrated that Z13 bound to PD-L1 with high affinity (KD values of 231 nM and 311 nM for hPD-L1 and mPD-L1, respectively). In the HepG2/Jurkat T co-culture cell model, Z13 decreased the viability rate of HepG2 cells in a concentration-dependent manner. In addition, Z13 showed significant in vivo antitumor efficacy (TGI = 52.6 % at 40 mg/kg) without obvious toxicity in the B16-F10 melanoma model. Furthermore, flow cytometry analysis demonstrated that Z13 inhibited tumor growth in vivo by activating the tumor immune microenvironment. These findings indicate that Z13 is a promising PD-1/PD-L1 inhibitor deserving further investigation.

[Establishment and verification of a prognostic nomogram for survival of tongue squamous cell carcinoma patients who underwent cervical dissection].

OBJECTIVE: To evaluate the prognostic significance of inflammatory biomarkers, prognostic nutritional index and clinicopathological characteristics in tongue squamous cell carcinoma (TSCC) patients who underwent cervical dissection. METHODS: The retrospective cohort study consisted of 297 patients undergoing tumor resection for TSCC between January 2017 and July 2018. The study population was divided into the training set and validation set by 7 :3 randomly. The peripheral blood indices of interest were preoperative neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), systemic inflammation score (SIS) and prognostic nutritional index (PNI). Kaplan-Meier survival analysis and multivariable Cox regression analysis were used to evaluate independent prognostic factors for overall survival (OS) and disease-specific survival (DSS). The nomogram's accuracy was internally validated using concordance index, receiver operating characteristic (ROC) curve, area under the curve (AUC), calibration plot and decision curve analysis. RESULTS: According to the univariate Cox regression analysis, clinical TNM stage, clinical T category, clinical N category, differentiation grade, depth of invasion (DOI), tumor size and pre-treatment PNI were the prognostic factors of TSCC. Multivariate Cox regression analysis revealed that pre-treatment PNI, clinical N category, DOI and tumor size were independent prognostic factors for OS or DSS (P < 0.05). Positive neck nodal status (N≥1), PNI≤50.65 and DOI > 2.4 cm were associated with the poorer 5-year OS, while a positive neck nodal status (N≥1), PNI≤50.65 and tumor size > 3.4 cm were associated with poorer 5-year DSS. The concordance index of the nomograms based on independent prognostic factors was 0.708 (95%CI, 0.625-0.791) for OS and 0.717 (95%CI, 0.600-0.834) for DSS. The C-indexes for external validation of OS and DSS were 0.659 (95%CI, 0.550-0.767) and 0.780 (95%CI, 0.669-0.890), respectively. The 1-, 3- and 5-year time-dependent ROC analyses (AUC = 0.66, 0.71 and 0.72, and AUC = 0.68, 0.77 and 0.79, respectively) of the nomogram for the OS and DSS pronounced robust discriminative ability of the model. The calibration curves showed good agreement between the predicted and actual observations of OS and DSS, while the decision curve confirmed its pronounced application value. CONCLUSION: Pre-treatment PNI, clinical N category, DOI and tumor size can potentially be used to predict OS and DSS of patients with TSCC. The prognostic nomogram based on these variables exhibited good accurary in predicting OS and DSS in patients with TSCC who underwent cervical dissection. They are effective tools for predicting survival and helps to choose appropriate treatment strategies to improve the prognosis.

Genetic characteristics predict response to venetoclax plus hypomethylating agents in relapsed or refractory acute myeloid leukemia.

BACKGROUND: The heterogeneity of relapsed or refractory (R/R) acute myeloid leukemia (AML) leads to no response to venetoclax (VEN)-based therapy in more than half of the patients. Genetic characteristics are considered important predictors for response to treatment in adults with AML. However, the association of genetic characteristics with outcomes receiving VEN-based therapy is incompletely understood in R/R AML. OBJECTIVE: To evaluate the efficacy of VEN combined with hypomethylating agents (HMA) and identify the potential genetic predictors of response in R/R AML. METHODS: A total of 150 R/R AML patients treated with VEN combined with HMA were enrolled in this retrospective study. Outcomes of the response and overall survival (OS) were analyzed. The predictors of response and OS were analyzed by logistic regression or Cox proportional hazards model. RESULTS: With a median of two (range, 1-4) cycles of therapy, the overall response rate was 56.2%, including 22.0% complete remission (CR), 21.3% CR with incomplete hematologic recovery, 2.0% morphologic leukemia-free state, and 10.7% partial remission, in which 25 patients achieved measurable residual disease (MRD)-negative response. With a median follow-up of 11.2 [95% confidence interval (CI), 7.2-14.8] months, 1- and 2-year OS were 46.9% (95% CI, 37.8%-58.1%) and 38.9% (95% CI, 28.7%-52.9%), respectively. Adverse cytogenetics and European Leukemia Net (ELN) risk predicted inferior response to VEN-based therapy. Mutations in IDH1/2, NPM1, ASXL1, and chromatin-cohesin genes predicted superior response to VEN-based therapy, whereas mutations in active signaling genes such as FLT3-ITD and K/NRAS predicted inferior response. CONCLUSION: VEN combined with HMA was effective with R/R AML patients, and the response to treatment was associated with genetic characteristics.

Dirac semimetal-assisted near-field radiative thermal rectifier and thermostat based on phase transition of vanadium dioxide.

The near-field thermal radiation has broad application prospects in micro-nano-scale thermal management technology. In this paper, we report the Dirac semimetal-assisted (AlCuFe quasicrystal) near-field radiative thermal rectifier (DSTR) and thermostat (DST), respectively. The DSTR is made of a Dirac semimetal-covered vanadium dioxide (VO2) plate and silicon dioxide (SiO2) plate separated by a vacuum gap. The left and right sides of DST are consisted of the SiO2 covered with Dirac semimetal, and the intermediate plate is the VO2. The strong coupling of the surface electromagnetic modes between the Dirac semimetal, SiO2, and insulating VO2 leads to enhance near-field radiative transfer. In the DSTR, the net radiative heat flux of VO2 in the insulating state is much larger than that in metallic state. When the vacuum gap distance d=100 nm, Fermi level EF=0.20 eV, and film thickness t=12 nm, the global rectification factor of DSTR is 3.5, which is 50% higher than that of structure without Dirac semimetal. In the DST, the equilibrium temperature of the VO2 can be controlled accurately to achieve the switching between the metallic and insulating state of VO2. When the vacuum gap distance d=60 nm, intermediate plate thickness δ=30 nm, and film thickness t=2 nm, with the modulation of Fermi level between 0.05-0.15 eV, the equilibrium temperature of VO2 can be controlled between 325-371 K. In brief, when the crystalline state of VO2 changes between the insulating and metallic state with temperature, the active regulation of near-field thermal radiation can be realized in both two-body and three-body parallel plate structure. This work will pave a way to further improve performance of near-field radiative thermal management and modulation.

Hypomethylating agents plus modified priming regimens compared with venetoclax-based regimens based on molecular characteristics for newly diagnosed patients with acute myeloid leukemia: a multi-center cohort study.

Venetoclax (VEN)-based regimens are the standard of care for elderly or unfit patients with newly diagnosed (ND) acute myeloid leukemia (AML). Some single-arm studies have implied that hypomethylating agents (HMAs) plus priming regimens may potentially provide an alternative therapeutic approach, owing to encouraging efficacy seen. However, no comparative data exists yet regarding these two treatment approaches. In this retrospective multi-center cohort study, we enrolled 294 ND AML patients, allocating 167 to the HMA + priming group and 127 to the VEN-based group. Treatment response and overall survival (OS) were compared between groups. Molecular subgroup analyses were also conducted. With a median of two cycles for HMA + priming group, the overall response (ORR) was 65.3%, including 55.1% complete remission (CR), 9.6% CR with incomplete hematologic recovery (CRi) and 0.6% morphologic leukemia-free state (MLFS). With a median of two cycles for VEN-based group, the ORR was 70.9%, including 46.5% CR, 18.9% CRi, and 5.5% MLFS. Response differences (ORR or CR/CRi) between groups were not significant (p > 0.05). With a median follow-up of 10.1 months, median OSs were similar between groups (20.9 vs 16.3 months, p = 0.41). However, VEN regimens demonstrated superior CR/CRi for patients with mutations in FLT3, IDH1/2, and NPM1 compared to HMA + priming (80.0% vs 35.0%, p = 0.01; 90.9% vs 65.5%, p = 0.02; 90.9% and 65.5%, p = 0.02, respectively). In conclusion, HMAs plus modified priming regimens might be a potential alternative therapeutic approach for patients with ND AML, but VEN-based regimens presented predominance in specific molecular subgroups. Molecular characteristics contribute to guiding choice of treatment.

Idarubicin plus BuCy versus BuCy conditioning regimens for intermediate-risk acute myeloid leukemia in first complete remission undergoing auto-HSCT: An open-label, multicenter, randomized phase 3 trial.

We report a randomized prospective phase 3 study, designed to evaluate the efficacy and tolerability of idarubicin plus busulfan and cyclophosphamide (IDA-BuCy) versus BuCy in autologous hematopoietic stem-cell transplantation (auto-HSCT) for intermediate-risk acute myeloid leukemia (IR-AML) patients in first complete remission (CR1). One hundred and fifty-four patients were enrolled and randomized to receive IDA-BuCy (IDA 15 mg/m2/day on days -12 to -10, Bu 3.2 mg/kg/day on days -7 to -4, and Cy 60 mg/kg/day on days -3 to -2) or BuCy. The 2-year incidence of relapse was 15.6% and 19.5% in IDA-BuCy and BuCy groups (p = 0.482), respectively. There was no significant overall survival (OS) and disease-free survival (DFS) benefit for IR-AML patients receiving IDA-BuCy (2-year OS 81.8% in IDA-BuCy vs. 83.1% in BuCy, p = 0.798; 2-year DFS 76.6% in IDA-BuCy vs. 79.2% in BuCy, p = 0.693). Grade 3 or worse regimen-related toxicity (RRT) was reported for 22 (28.9%) of 76 and 9 (12.0%) of 75 patients in two groups (p = 0.015), respectively. AEs within 100 days with an outcome of death were reported for 4 (5.3%) and 0 patients in two groups. In conclusion, IDA-BuCy has higher RRT and similar anti-leukemic activity compared with BuCy in IR-AML patients in CR1 undergoing auto-HSCT. Thus, caution should be taken when choosing IDA-BuCy for IR-AML patients in CR1 with auto-HSCT. This trial is registered with ClinicalTrials.gov, NCT02671708, and is complete.

Development and validation of a new risk assessment model for immunomodulatory drug-associated venous thrombosis among Chinese patients with multiple myeloma.

BACKGROUND: Individuals with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs) are at risk of developing venous thromboembolism (VTE), a serious complication. There is no established clinical model for predicting VTE in the Chinese population. We develop a new risk assessment model (RAM) for IMiD-associated VTE in Chinese MM patients. METHODS: We retrospectively selected 1334 consecutive MM patients receiving IMiDs from 16 medical centers in China and classified them randomly into the derivation and validation cohorts. A multivariate Cox regression model was used for analysis. RESULTS: The overall incidence of IMiD-related VTE in Chinese MM patients was 6.1%. Independent predictive factors of VTE (diabetes, ECOG performance status, erythropoietin-stimulating agent use, dexamethasone use, and VTE history or family history of thrombosis) were identified and merged to develop the RAM. The model identified approximately 30% of the patients in each cohort at high risk for VTE. The hazard ratios (HRs) were 6.08 (P < 0.001) and 6.23 (P < 0.001) for the high-risk subcohort and the low-risk subcohort, respectively, within both the derivation and validation cohorts. The RAM achieved satisfactory discrimination with a C statistic of 0.64. The stratification approach of the IMWG guidelines yielded respective HRs of 1.77 (P = 0.053) and 1.81 (P = 0.063). The stratification approach of the SAVED score resulted in HRs of 3.23 (P = 0.248) and 1.65 (P = 0.622), respectively. The IMWG guideline and the SAVED score-based method yielded C statistics of 0.58 and 0.51, respectively. CONCLUSIONS: The new RAM outperformed the IMWG guidelines and the SAVED score and could potentially guide the VTE prophylaxis strategy for Chinese MM patients.

Discovery of novel benzohydroxamate-based histone deacetylase 6 (HDAC6) inhibitors with the ability to potentiate anti-PD-L1 immunotherapy in melanoma.

In this study, a novel series of histone deacetylases 6 (HDAC6) inhibitors containing polycyclic aromatic rings were discovered and evaluated for their pharmacological activities. The most potent compound 10c exhibited high HDAC6 inhibitory activity (IC50 = 261 nM) and excellent HDAC6 selectivity (SI = 109 for HDAC6 over HDAC3). 10c also showed decent antiproliferative activity in vitro with IC50 of 7.37-21.84 µM against four cancer cell lines, comparable to that of tubastatin A (average IC50 = 6.10 µM). Further mechanism studies revealed that 10c efficiently induced apoptosis and S-phase arrest in B16-F10 cells. In addition, 10c markedly increased the expression of acetylated-α-tubulin both in vitro and in vivo, without affecting the levels of acetylated-H3 (marker of HDAC1 inhibition). Furthermore, 10c (80 mg/kg) exhibited moderate antitumor efficacy in a melanoma tumour model with a tumour growth inhibition (TGI) of 32.9%, comparable to that (TGI = 31.3%) of tubastatin A. Importantly, the combination of 10c with NP19 (a small molecule PD-L1 inhibitor discovered by us before) decreased tumour burden substantially (TGI% = 60.1%) as compared to monotherapy groups. Moreover, the combination of 10c with NP19 enhanced the anti-tumour immune response, mediated by a decrease of PD-L1 expression levels and increased infiltration of anti-tumour CD8+ T cells in tumour tissues. Collectively, 10c represents a novel HDAC6 inhibitor deserving further investigation as a potential anti-cancer agent.

No-Touch Versus Conventional Vein Harvesting Techniques at 12 Months After Coronary Artery Bypass Grafting Surgery: Multicenter Randomized, Controlled Trial.

BACKGROUND: Vein graft occlusion is deemed a major challenge in coronary artery bypass grafting. Previous studies implied that the no-touch technique for vein graft harvesting could reduce occlusion rate compared with the conventional approach; however, evidence on the clinical benefit and generalizability of the no-touch technique is scare. METHODS: From April 2017 to June 2019, we randomly assigned 2655 patients undergoing coronary artery bypass grafting at 7 hospitals in a 1:1 ratio to receive no-touch technique or conventional approach for vein harvesting. The primary outcome was vein graft occlusion on computed tomography angiography at 3 months and the secondary outcomes included 12-month vein graft occlusion, recurrence of angina, and major adverse cardiac and cerebrovascular events. The generalized estimate equation model was used to account for the cluster effect of grafts from the same patient. RESULTS: During the follow-up, 2533 (96.0%) participants received computed tomography angiography at 3 months after coronary artery bypass grafting and 2434 (92.2%) received it at 12 months. The no-touch group had significantly lower rates of vein graft occlusion than the conventional group both at 3 months (2.8% versus 4.8%; odds ratio, 0.57 [95% CI, 0.41-0.80]; P<0.001) and 12 months (3.7% versus 6.5%; odds ratio, 0.56 [95% CI, 0.41-0.76]; P<0.001). Recurrence of angina was also less common in the no-touch group at 12 months (2.3% versus 4.1%; odds ratio, 0.55 [95% CI, 0.35-0.85]; P<0.01). Rates of major adverse cardiac and cerebrovascular events were of no significant difference between the 2 groups. The no-touch technique was associated with higher rates of leg wound surgical interventions at 3-month follow-up (10.3% versus 4.3%; odds ratio, 2.55 [95% CI, 1.85-3.52]; P<0.001). CONCLUSIONS: Compared with the conventional vein harvesting approach in coronary artery bypass grafting, the no-touch technique significantly reduced the risk of vein graft occlusion and improved patient prognosis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03126409.

All-sapphire fiber-optic pressure sensors for extreme harsh environments.

In this paper, an all-sapphire fiber-optic Fabry-Perot (F-P) pressure sensor is proposed. The sapphire pressure-sensitive diaphragm with low surface roughness is fabricated by MEMS wet etching. The direct bonding process is adopted to bond the sapphire-sensitive diaphragm and substrate together. And the sapphire fiber is adopted to be the lead-in fiber to ensure the sensor's resistance to high temperature. The performance of the sensor is tested within a pressure range of 0.1∼5 MPa and within the temperature range from room temperature to 1200°C. Experimental results show that the sensor could work stably at the temperature of 1200°C. The pressure sensitivity reaches up to 15nm/MPa. The nonlinearity of the sensor is 0.96% FS (full scale), and the relative resolution reaches 0.12%FS. The all-sapphire F-P sensor could be used for high-pressure testing in a high-temperature environment.

B4GALT5 high expression associated with poor prognosis of hepatocellular carcinoma.

BACKGROUND: B4GALT5 is postulated to be an important protein in sugar metabolism that catalyzes the synthesis of lactosylceramide (LacCer). However, its role in hepatocellular carcinoma (HCC) remains unknown. METHOD: We characterized the expression of B4GALT5 in HCC tissue compared to normal tissue, and explored its function of B4GALT5 in HCC by enrichment analysis based on its co-expressed gene set. Next, we checked whether B4GALT5 expression is correlated to immune infiltration level and clinical prognosis in hepatocellular carcinoma. Finally, we verified the expression of B4GALT5 using clinical samples evaluated by RT-PCR, and conducted in vitro experiments with B4GALT5-knockdown HCC cells to investigate the function of B4GALT5 in the HCC cell proliferation, migration and invasion. RESULTS: We found B4GALT5 mRNA and protein expression levels were significantly high in HCC tissue compared to normal tissue. The enrichment analysis of the gene sets that co-expressed with B4GALT5 showed specificity in HCC-related pathways and functions. Also, the expression pattern of B4GALT5 was significantly related to the immune infiltration level, especially CD4+ T cell and macrophage cells. B4GALT5 higher mRNA expression was associated with poor overall survival (OS) in HCC patients. Furthermore, In vitro experiments showed that depletion of B4GALT5 significantly inhibited HCC cell proliferation, migration and invasion. This study revealed the function and its mediated pathways of B4GALT5 in HCC, indicating that B4GALT5 may serve as a prognostic biomarker of HCC.

Pre- and postharvest measures used to control decay and mycotoxigenic fungi in potato (Solanum tuberosum L.) during storage.

Potato (Solanum tuberosum L.), a worldwide, staple food crop, is susceptible to postharvest rots caused by a variety of fungal pathogens, including Fusarium spp., Alternaria spp., Phytophthora infestans, Helminthosporium solani, Rhizoctonia solani, and Colletotrichum coccodes. Rots resulting from infections by these pathogens cause a significant reduction in potato quality and marketable yield. Importantly, some of these decay fungi also produce mycotoxins that represent a potential risk to human health. In the present review, an overview and discussion are provided on the epidemiology and pathogenesis of decay fungi, especially Fusarium spp., that include recent data derived from genomic and phylogenetic analyses. The biosynthesis and functional role of fungitoxic metabolites such as trichothecene mycotoxins and fusaric acid, produced in rotted potatoes are also reviewed. Advances in pre- and postharvest measures for rot management, especially eco-friendly methods including physical control, biological control, the use of natural compounds, and other agricultural management practices are also reviewed. Lastly, novel approaches to control potato dry rot such as the use of mycoviruses and CRISPR technology are highlighted.

Field-Tuning Mechanisms of Spin Switching and Spin Reorientation Transition in Praseodymium-Erbium Orthoferrite Single Crystals.

Field-tuning mechanisms of spin switching and spin reorientation (SR) transition were investigated in a series of high-quality single crystal samples of PrxEr1-xFeO3 (x = 0, 0.1, 0.3, 0.5) prepared using the optical floating zone method. The single crystal quality, structure, and axis orientation were determined by room-temperature powder X-ray diffraction, back-reflection Laue X-ray diffraction, and Raman scattering at room temperature. Magnetic measurements indicate that the type and temperature region of SR transition are tuned by introducing different ratios of Pr3+ doping (x = 0, 0.1, 0.3, 0.5). The trigger temperatures of spin switching and magnetization compensation temperature of PrxEr1-xFeO3 crystals can be adjusted by doping with different proportions of Pr3+. Furthermore, the trigger temperature of the two types of spin switching in Pr0.3Er0.7FeO3 along the a-axis can be regulated by an external field. Meanwhile, the isothermal magnetic field-triggered spin switching effect is also observed along the a and c-axes of Pr0.3Er0.7FeO3. An in-depth understanding of the magnetic coupling and competition between the R3+ and Fe3+ magnetic sublattices, within the RFeO3 system, has important implications for advancing the practical applications of the relevant spin switching materials.

Preparation of multifunctional mesoporous SiO2nanoparticles and anti-tumor action.

A targeted drug delivery system was developed to accumulate specific drugs around tumor cells based on the redox, temperature, and enzyme synergistic responses of mesoporous silica nanoparticles. Mesoporous silica nanoparticles (MSN-NH2) and Doxorubicin (DOX) for tumor therapy were prepared and loaded into the pores of MSN- NH2 to obtain DOX@MSN(DM NPs). Hyaluronic acid (HA) was used as the backbone and disulfide bond was used as the linker arm to graft carboxylated poly (N-isopropylacrylamide)(PNIPAAm-COOH) to synthesize the macromolecular copolymer (HA-SS-PNIPAAm), which was modified to DM NPs with capped ends to obtain the nano-delivery system DOX@MSN@HA-SS-PNIPAAm(DMHSP NPs), and a control formulation was prepared in a similar way. DMHSP NPs specifically entered tumor cells via CD44 receptor-mediated endocytosis; the high GSH concentration (10 mM) of cells severed the disulfide bonds, the hyaluronidase sheared the capped HA to open the pores, and increased tumor microenvironment temperature due to immune response can trigger the release of encapsulated drugs in thermosensitive materials.In vitroandin vivoantitumor and hemolysis assays showed that DMHSP NPs can accurately target hepatocellular carcinoma cells with a good safety profile and have synergistic effects, which meant DMHSP NPs had great potential for tumor therapy.

Design, synthesis, and bioevaluation of imidazo [1,2-a] pyrazine derivatives as tubulin polymerization inhibitors with potent anticancer activities.

Through structural optimization and ring fusion strategy, we designed a series of novel imidazo[1,2-a]pyrazine derivatives as potential tubulin inhibitors. These compounds displayed potent anti-proliferative activities (micromolar to nanomolar) against a panel of cancer cell lines (including HepG-2, HCT-116, A549 and MDA-MB-231 cells). Among them, compound TB-25 exhibited the strongest inhibitory effects against HCT-116 cells with an IC50 of 23 nM. Mechanism studies revealed that TB-25 could effectively inhibit tubulin polymerization in vitro, and destroy the dynamic equilibrium of microtubules in HCT-116 cells. In addition, TB-25 dose-dependently induced G2/M phase cell cycle arrest and apoptosis in HCT-116 cells. Furthermore, TB-25 suppressed HCT-116 cell migration in a concentration-dependent manner. Finally, molecular docking showed that TB-25 fitted well in the colchicine binding site of tubulin and overlapped nicely with CA-4. Collectively, these results suggest that TB-25 represents a promising tubulin inhibitor deserving further investigation.

Three-Way DNA Junction as an End Label for DNA in Atomic Force Microscopy Studies.

Atomic Force Microscopy (AFM) is widely used for topographic imaging of DNA and protein-DNA complexes in ambient conditions with nanometer resolution. In AFM studies of protein-DNA complexes, identifying the protein's location on the DNA substrate is one of the major goals. Such studies require distinguishing between the DNA ends, which can be accomplished by end-specific labeling of the DNA substrate. We selected as labels three-way DNA junctions (3WJ) assembled from synthetic DNA oligonucleotides with two arms of 39-40 bp each. The third arm has a three-nucleotide overhang, GCT, which is paired with the sticky end of the DNA substrate generated by the SapI enzyme. Ligation of the 3WJ results in the formation of a Y-type structure at the end of the linear DNA mole cule, which is routinely identified in the AFM images. The yield of labeling is 69%. The relative orientation of arms in the Y-end varies, such dynamics were directly visualized with time-lapse AFM studies using high-speed AFM (HS-AFM). This labeling approach was applied to the characterization of the nucleosome arrays assembled on different DNA templates. HS-AFM experiments revealed a high dynamic of nucleosomes resulting in a spontaneous unraveling followed by disassembly of nucleosomes.

Biochar-Stimulated Pumpkin Performance Under Cadmium Stress Is Strongly Linked to Metabolite Pattern.

In this study, pumpkin seedlings were subjected to cadmium stress (100 mg/L cadmium ion solution, 10 days) without or with wheat straw biochar at different concentrations (0%, 0.5%, 1%, and 2% w/v). As the biochar concentration increased, the amount of cadmium accumulated in the root and stem of pumpkin seedlings decreased and the fresh weight of root, stem and leaf increased. The highest cadmium concentration was in the root, followed by the stem and then the leaf. 1% and 2% biochar treatments reduced the oxidative stress of cadmium to seedlings, and added the contents of fatty acid, carbohydrate, amino acid and indoleacetic acid in the root. With the increase of biochar concentration, the metabolites promoting root growth increased. These results provide new information about how biochar alleviates cadmium stress by affecting the metabolic response.

[UHPLC-Q-Exactive Orbitrap MS/MS-based rapid identification of chemical components in substance benchmark of Kaixin San].

Ultra-performance liquid chromatography-quadrupole-electrostatic field Orbitrap mass spectrometry(UHPLC-Q-Exactive Orbitrap MS/MS) was used for rapid identification of the chemical components in Kaixin San substance benchmark. The gradient elution was performed through a Waters ACQUITY~(TM) BEH C_(18) column(2.1 mm×150 mm, 1.7 µm) with water-acetonitrile as mobile phase, a column temperature of 30 ℃, a flow rate of 0.3 mL·min~(-1), and a sample size of 1 µL. The scanning was performed in the negative ion mode. The complex component groups in Kaixin San substance benchmark were quickly and accurately identified and clearly assigned based on the comparison of the retention time and MS data with those of the reference substance as well as the relative molecular weight of the same or similar components in the mass spectrum database and literature. A total of 77 compounds were identified, including 26 saponins, 13 triterpenoid acids, 20 oligosaccharide esters, 5 xanthones, and 13 other compounds. The qualitative method established in this study can systematically, accurately, and quickly identify the chemical components in Kaixin San substance benchmark, which can provide a basis for the further analysis of its active components in vivo and the establishment of its quality control system.