Intranasal Delivery of Pure Nanodrug Loaded Liposomes for Alzheimer's Disease Treatment by Efficiently Regulating Microglial Polarization.

The activated M1-like microglia induced neuroinflammation is the critical pathogenic event in Alzheimer's disease (AD). Microglial polarization from pro-inflammatory M1 toward anti-inflammatory M2 phenotype is a promising strategy. To efficiently accomplish this, amyloid-ß (Aß) aggregates as the culprit of M1 microglia activation should be uprooted. Interestingly, this study finds out that the self-reassembly of curcumin molecules into carrier-free curcumin nanoparticles (CNPs) exhibits multivalent binding with Aß to achieve higher inhibitory effect on Aß aggregation, compared to free curcumin with monovalent effect. Based on this, the CNPs loaded cardiolipin liposomes are developed for efficient microglial polarization. After intranasal administration, the liposomes decompose to release CNPs and cardiolipin in response to AD oxidative microenvironment. The CNPs inhibit Aß aggregation and promote Aß phagocytosis/clearance in microglia, removing roadblock to microglial polarization. Subsequently, CNPs are endocytosed by microglia and inhibit TLR4/NF-κB pathway for microglia polarization (M1→M2). Meanwhile, cardiolipin is identified as signaling molecule to normalize microglial dysfunction to prevent pro-inflammatory factors release. In AD transgenic mice, neuroinflammation, Aß burden, and memory deficits are relieved after treatment. Through combined attack by extracellularly eradicating roadblock of Aß aggregation and intracellularly inhibiting inflammation-related pathways, this nanotechnology assisted delivery system polarizes microglia efficiently, providing a reliable strategy in AD treatment.

Combined targeting of Hedgehog/GLI1 and Wnt/ß-catenin pathways in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. Challenges in its treatment include relapse, drug resistance, and a short survival period. The Hedgehog/GLI1 (Hh/GLI1) and Wnt/ß-catenin pathways are crucial in cancer cell proliferation, survival, and drug resistance, making them significant targets for anticancer research. This study aimed to assess the effectiveness of combining inhibitors for both pathways against MCL and investigate the underlying molecular mechanisms. The co-expression of key proteins from the Hh/GLI1 and Wnt/ß-catenin pathways was observed in MCL. Targeting the Hh/GLI1 pathway with the GLI1 inhibitor GANT61 and the Wnt/ß-catenin pathway with the CBP/ß-catenin transcription inhibitor ICG-001, dual-target therapy was demonstrated to synergistically suppressed the activity of MCL cells. This approach promoted MCL cell apoptosis, induced G0/G1 phase blockade, decreased the percentage of S-phase cells, and enhanced the sensitivity of MCL cells to the drugs adriamycin and ibrutinib. Both GANT61 and ICG-001 downregulated GLI1 and ß-catenin while upregulating GSK-3ß expression. The interaction between Hh/GLI1 and Wnt/ß-catenin pathways was mediated by GANT61-dependent Hh/GLI1 inhibition. Moreover, GLI1 knockdown combined with ICG-001 synergistically induced apoptosis and increased drug sensitivity of MCL cells to doxorubicin and ibrutinib. GANT61 attenuated the overexpression of ß-catenin and decreased the inhibition of GSK-3ß in MCL cells. Overall, the combined targeting of both the Hh/GLI1 and Wnt/ß-catenin pathways was more effective in suppressing proliferation, inducing G0/G1 cycle retardation, promoting apoptosis, and increasing drug sensitivity of MCL cells than mono treatments. These findings emphasize the potential of combinatorial therapy for treating MCL patients.

A comparison of the Mini-Mental State Examination (MMSE) with the Montreal Cognitive Assessment (MoCA) for mild cognitive impairment screening in Chinese middle-aged and older population: a cross-sectional study.

BACKGROUND: The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are the most commonly used scales to detect mild cognitive impairment (MCI) in population-based epidemiologic studies. However, their comparison on which is best suited to assess cognition is scarce in samples from multiple regions of China. METHODS: We conducted a cross-sectional analysis of 4923 adults aged ≥55 years from the Community-based Cohort Study on Nervous System Diseases. Objective cognition was assessed by Chinese versions of MMSE and MoCA, and total score and subscores of cognitive domains were calculated for each. Education-specific cutoffs of total score were used to diagnose MCI. Demographic and health-related characteristics were collected by questionnaires. Correlation and agreement for MCI between MMSE and MoCA were analyzed; group differences in cognition were evaluated; and multiple logistic regression model was used to clarify risk factors for MCI. RESULTS: The overall MCI prevalence was 28.6% for MMSE and 36.2% for MoCA. MMSE had good correlation with MoCA (Spearman correlation coefficient = 0.8374, p < 0.0001) and moderate agreement for detecting MCI with Kappa value of 0.5973 (p < 0.0001). Ceiling effect for MCI was less frequent using MoCA versus MMSE according to the distribution of total score. Percentage of relative standard deviation, the measure of inter-individual variance, for MoCA (26.9%) was greater than for MMSE (19.0%) overall (p < 0.0001). Increasing age (MMSE: OR = 2.073 for ≥75 years; MoCA: OR = 1.869 for≥75 years), female (OR = 1.280 for MMSE; OR = 1.163 for MoCA), living in county town (OR = 1.386 and 1.862 for MMSE and MoCA, respectively) or village (OR = 2.579 and 2.721 for MMSE and MoCA, respectively), smoking (OR = 1.373 and 1.288 for MMSE and MoCA, respectively), hypertension (MMSE: OR = 1.278; MoCA: OR = 1.208) and depression (MMSE: OR = 1.465; MoCA: OR = 1.350) were independently associated with greater likelihood of MCI compared to corresponding reference group in both scales (all p < 0.05). CONCLUSIONS: MoCA is a better measure of cognitive function due to lack of ceiling effect and with good detection of cognitive heterogeneity. MCI prevalence is higher using MoCA compared to MMSE. Both tools identify concordantly modifiable factors for MCI, which provide important evidence for establishing intervention measures.

Detachable Nanoparticle-Enhanced Chemoimmunotherapy Based on Precise Killing of Tumor Seeds and Normalizing the Growing Soil Strategy.

Although immunogenic cell death (ICD)-based chemoimmunotherapy elicits an immune response, it always focuses on eliminating "seeds" (tumor cells) but neglects "soil" (tumor microenvironment, TME), leading to tumor growth and metastasis. Herein, a type of detachable core-shell nanoplatform (DOX@HA-MMP-2-DEAP/CXB) is developed, which could swell in the acidic TME because of the protonation of the 3-diethylaminopropyl isothiocyanate (DEAP) inner core for celecoxib (CXB) release, while hyaluronic acid@doxorubicine (HA@DOX) prodrug in the outer shell could release by the cleavage of matrix metalloproteinase-2 (MMP-2) peptide. HA@DOX targets tumor cells precisely for triggering ICD. And CXB acts on multiple immune cells to remodulate TME, such as increasing the infiltration of dendritic cells (DCs) and T cells, decreasing the infiltration of the immunosuppressive cells, and eliminating the physical barriers between T cells and tumor cells. For comparison, HA-DOCA/DOX/CXB traditional nanoparticles are constructed. And DOX@HA-MMP-2-DEAP/CXB performs an impressive antitumor effect, which shows potential in enhancing the effect of chemoimmunotherapy.

The dual PI3K/mTOR inhibitor NVP-BEZ235 inhibits proliferation and induces apoptosis of burkitt lymphoma cells.

BACKGROUND: Phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway is a therapy target of cancer. We aimed to confirm the effect of dual PI3K/mTOR inhibitor NVP-BEZ235 on cell proliferation and apoptosis in Burkitt lymphoma (BL) cells. METHODS: Two human BL cell lines, CA46 and RAJI were used in this study. The proliferation of BL cells was detected by manganese tricarbonyl transfer (MTT) assay. Cell cycle and apoptosis assay were examined by flow cytometric analysis. The phosphorylation levels of AKT (Thr308), AKT (Ser473), and RPS6 were evaluated by western blot analysis. RESULTS: NVP-BEZ235 significantly inhibited the proliferation of BL cells (CA46 and RAJI) and the inhibition effect was time and dose-dependent. Cell cycle analysis indicated that the cells (CA46 and RAJI) were mostly arrested in G1/G0 phase. Cell apoptosis assay showed that the late apoptotic cells were significantly increased after 72 h treatment by 100 nmol/L of NVP-BEZ235. In addition, results also found that NVP-BEZ235 reduced the phosphorylation levels of AKT (Thr308), AKT (Ser473), and PRS6 in BL cells (CA46 and RAJI). Moreover, this inhibition effect on phosphorylation was dose-dependent. CONCLUSIONS: NVP-BEZ235 effectively inhibited cell proliferation by G0/G1 cell-cycle arrest and induced apoptosis through deregulating PI3K/Akt/mTOR pathway in BL cells.

Investigating long-term changes in surface water temperature of Dongting Lake using Landsat imagery, China.

Lake surface water temperature (LSWT) plays a crucial role in assessing the health of aquatic ecosystems. Variations in LSWT can significantly impact the physical, chemical, and biological processes within lakes. This study investigates the long-term changes in surface water temperature of the Dongting Lake, China. The LSWT is retrieved using Landsat thermal infrared imageries from 1988 to 2022 and validated with in situ observations, and the change characteristics of LSWT and near-surface air temperature (NSAT) as well as the spatial distribution characteristics of LSWT are analyzed. Additionally, the contribution rates of different meteorological factors to LSWT are quantified. The results show that the accuracy assessment of satellite-derived temperatures indicates a Nash-Sutcliffe efficiency coefficient (NSE) of 0.961, suggesting an accurate retrieval of water temperature. From 1988 to 2022, both the annual average LSWT and NSAT of Dongting Lake exhibit an increasing trend, with similar rates of warming. They both undergo a mutation in 1997 and have the main periods on the 11-year and 4-year time scales. The changes in NSAT emerge as one of the important factors contributing to variations in LSWT. Among the multiple meteorological factors, NSAT exhibits a significant correlation with LSWT (R = 0.822, α < 0.01). Furthermore, NSAT accounts for the highest contribution rate to LSWT, amounting to 67.5%. The distribution of LSWT within Dongting Lake exhibits spatial variations, with higher LSWT observed on the west part compared to the east part during summer, while lower LSWT occurs on the west part during winter. The findings of this study can provide a scientific understanding for the long-term thermal regimes of lakes and help advance sustainable lake management.

In-situ fabrication of manganese ferrite grafted polyaniline nanocomposite: A magnetically reusable visible light photocatalyst and a robust electrode material for supercapacitor.

Herein, we reported the in-situ preparation of manganese ferrite (MnFe2O4) grafted polyaniline (Pani), a magnetic nanocomposite for the potential visible light photocatalytic material as well as electrode material for supercapacitor. The physical characterization of the prepared nanoparticle and nanocomposite was examined with various spectroscopic and microscopic analyses. The peaks observed in the X-ray diffraction study confirm the face-centered cubic phase of MnFe2O4 nanoparticles with a grain size of ∼17.6 nm. The surface morphology analysis revealed the uniform distribution of spherical-like MnFe2O4 nanoparticles on the surface of Pani. The degradation of malachite green (MG) dye under exposure to visible light was investigated using MnFe2O4/Pani nanocomposite as a photocatalyst. The results exposed the faster degradation of MG dye was accomplished by MnFe2O4/Pani nanocomposite than MnFe2O4 nanoparticles. The energy storage performance of the MnFe2O4/Pani nanocomposite was analyzed through cyclic voltammetry, galvanostatic charge/discharge, and electrochemical impedance spectroscopy analyses. The results exposed that the MnFe2O4/Pani electrode achieved a capacitance of 287.1 F/g than the MnFe2O4 electrode (94.55 F/g). Further, the respectable capacitance of 96.92% was achieved even after 3000 repetitive cycles stability . Based on the outcomes, the MnFe2O4/Pani nanocomposite can be suggested as a promising material for both photocatalytic and supercapacitor applications.

Multifunctional Oxygen-Generating Nanoflowers for Enhanced Tumor Therapy.

Sonodynamic therapy (SDT) and chemotherapy have received great attention as effective methods for tumor treatment. However, the inherent hypoxia of the tumor greatly hinders its therapeutic efficacy. In this work, a tumor microenvironment-responsive biodegradable nanoplatform SiO2-MnO2-PEG-Ce6&DOX (designated as SMPC&D) is fabricated by encapsulating manganese oxide (MnO2) into silica nanoparticles and anchoring poly(ethylene glycol) (PEG) onto the surface for tumor hypoxia relief and delivery, then loaded with sonosensitizer Chlorin e6 (Ce6) and chemotherapeutic drug doxorubicin (DOX) for hypoxic tumor treatment. We evaluated the physicochemical properties of SMPC&D nanoparticles and the tumor therapeutic effects of chemotherapy and SDT under ultrasound stimulation in vitro and in vivo. After endocytosis by tumor cells, highly expressed glutathione (GSH) triggers biodegradation of the nanoplatform and MnO2 catalyzes hydrogen peroxide (H2O2) to generate oxygen (O2), thereby alleviating tumor hypoxia. Depleting GSH and self-supplying O2 effectively improve the SDT efficiency both in vitro and in vivo. Ultrasonic stimulation promoted the release and cellular uptake of chemotherapy drugs. In addition, the relieved hypoxia reduced the efflux of chemotherapy drugs by downregulating the expression of the P-gp protein, which jointly improved the effect of chemotherapy. This study demonstrates that the degradable SMPC&D as a therapeutic agent can achieve efficient chemotherapy and SDT synergistic therapy for hypoxic tumors.

Implication of proteins containing tetratricopeptide repeats in conditional virulence phenotypes of Legionella pneumophila.

Legionella pneumophila, the causative agent of Legionnaires' disease, is a ubiquitous freshwater bacterium whose virulence phenotypes require a type IV secretion system (T4SS). L. pneumophila strain JR32 contains two virulence-associated T4SSs, the Dot/Icm and Lvh T4SSs. Defective entry and phagosome acidification phenotypes of dot/icm mutants are conditional and reversed by incubating broth-grown stationary-phase cultures in water (WS treatment) prior to infection, as a mimic of the aquatic environment of Legionella. Reversal of dot/icm virulence defects requires the Lvh T4SS and is associated with a >10-fold induction of LpnE, a tetratricopeptide repeat (TPR)-containing protein. In the current study, we demonstrated that defective entry and phagosome acidification phenotypes of mutants with changes in LpnE and EnhC, another TPR-containing protein, were similarly reversed by WS treatment. In contrast to dot/icm mutants for which the Lvh T4SS was required, reversal for the ΔlpnE or the ΔenhC mutant required that the other TPR-containing protein be present. The single and double ΔlpnE and ΔenhC mutants showed a hypersensitivity to sodium ion, a phenotype associated with dysfunction of the Dot/Icm T4SS. The ΔlpnE single and the ΔlpnE ΔenhC double mutant showed 3- to 9-fold increases in translocation of Dot/Icm T4SS substrates, LegS2/SplY and LepB. Taken together, these data identify TPR-containing proteins in a second mechanism by which the WS mimic of a Legionella environmental niche can reverse virulence defects of broth-grown cultures and implicate LpnE and EnhC directly or indirectly in translocation of Dot/Icm T4SS protein substrates.

Mitochondria-Targeted Degradable Nanocomposite Combined with Laser and Ultrasound for Synergistic Tumor Therapies.

Although the development of safe and efficient cancer therapeutic agents is essential, this process remains challenging. In this study, a mitochondria-targeted degradable nanoplatform (PDA-MnO2-IR780) for synergistic photothermal, photodynamic, and sonodynamic tumor treatment was investigated. PDA-MnO2-IR780 exhibits superior photothermal properties owing to the integration of polydopamine, MnO2, and IR780. IR780, a photosensitizer and sonosensitizer, was used for photodynamic therapy and sonodynamic therapy. When PDA-MnO2-IR780 was delivered to the tumor site, MnO2 was decomposed by hydrogen peroxide, producing Mn2+ and oxygen. Meanwhile, alleviating tumor hypoxia promoted the production of reactive oxygen species during photodynamic therapy and sonodynamic therapy. Moreover, large amounts of reactive oxygen species could reduce the expression of heat shock proteins and increase the heat sensitivity of tumor cells, thereby improving the photothermal treatment effect. In turn, hyperthermia caused by photothermal therapy accelerated the production of reactive oxygen species in photodynamic therapy. IR780 selectively accumulation in mitochondria also promoted tumor apoptosis. In this system, the mutual promotion of photothermal therapy and photodynamic therapy/sonodynamic therapy had an enhanced therapeutic effect. Moreover, the responsive degradable characteristic of PDA-MnO2-IR780 in the tumor microenvironment ensured excellent biological safety. These results reveal a great potential of PDA-MnO2-IR780 for safe and highly-efficiency synergistic therapy for cancer.

Dual-Targeted Fe3O4@MnO2 Nanoflowers for Magnetic Resonance Imaging-Guided Photothermal-Enhanced Chemodynamic/Chemotherapy for Tumor.

The construction of high-efficiency tumor theranostic platform will be of great interest in the treatment of cancer patients; however, significant challenges are associated with developing such a platform. In this study, we developed high-efficiency nanotheranostic agent based on ferroferric oxide, manganese dioxide, hyaluronic acid and doxorubicin (FMDH-D NPs) for dual targeting and imaging guided synergetic photothermal-enhanced chemodynamic/chemotherapy for cancer, which improved the specific uptake of drugs at tumor site by the dual action of CD44 ligand hyaluronic acid and magnetic nanoparticles guided by magnetic force. Under the acidic microenvironment of cancer cells, FMDH-D could be decomposed into Mn2+ and Fe2+ to generate •OH radicals by triggering a Fenton-like reaction and responsively releasing doxorubicin to kill cancer cells. Meanwhile, alleviating tumor hypoxia improved the efficacy of chemotherapy in tumors. The photothermal properties of FMDH generated high temperatures, which further accelerated the generation of reactive oxygen species, and enhanced effects of chemodynamic therapy. Furthermore, FMDH-D NPs proved to be excellent T1/T2-weighted magnetic resonance imaging contrast agents for monitoring the tumor location. These results confirmed the considerable potential of FMDH-D NPs in a highly efficient synergistic therapy platform for cancer treatment.

Self-Cleaning Nanofiltration Membranes by Coordinated Regulation of Carbon Quantum Dots and Polydopamine.

Performance declination of nanofiltration (NF) membranes caused by concentration polarization (CP) and membrane fouling has severely restricted their practical application in many fields. This work reports the construction of a novel interlayer between the substrate and the selective layer of conventional composite membranes by coordinating regulation of carbon quantum dots (CQDs) and polydopamine (PDA). Unlike traditional methods that treat CP and fouling separately, the new strategy grants the membrane with dual functions at one time. First, the insertion of the PDA-CQDs layer reformulates the interfacial polymerization process that reduces the solute transport resistance and mitigates the CP issue. Second, the sandwiched photoactive CQDs can degrade organic molecules adsorbed on the membrane surface under visible light, which is promising for low-cost fouling remediation. This study may offer valuable insights into the preparation of durable self-cleaning NF membranes for the effective treatment of complex wastewater in various industries.

Biomimetic Decoy Inhibits Tumor Growth and Lung Metastasis by Reversing the Drawbacks of Sonodynamic Therapy.

Sonodynamic therapy (SDT) shows tremendous potential to induce immunogenic cell death (ICD) and activate antitumor immunity. However, it can aggravate hypoxia and release platelet (PLT)-associated danger-associated molecular patterns (DAMPs), which impede therapeutic efficacy and promote tumor metastasis. In order to solve these problems, a biomimetic decoy (designated as Lipo-Ce6/TPZ@MH ) is constructed to reverse the drawbacks of SDT by loading sonosensitizer chlorin e6 (Ce6) and hypoxia-activated tirapazamine (TPZ) in the red blood cells-PLTs hybrid membrane (MH )-camouflaged pH-sensitive liposome. After administration, the decoy exhibits enhanced cancer accumulation and retention abilities due to the immune escape and specific targeting behaviors by biomimetic surface coating. Upon local ultrasound, Ce6 produces toxic reactive oxygen species for SDT, and the resulting hypoxia microenvironment activates TPZ, which can realize a high-effective synergistic therapy. Meanwhile, DAMPs-mediated tumor metastasis is significantly inhibited, because the decoy retains platelet binding functions but is incapable of platelet-mediated metastasis. In addition, ICD-mediated strong antitumor immunities further prevent the growth and metastasis of the residual tumors left behind after synergistic treatment. Taken together, this study highlights the potential of using this cascade therapeutic therapy plus biomemitic decoy in one nanosystem to both eliminate melanoma in situ and suppress lung metastasis.

A two-step precise targeting nanoplatform for tumor therapy via the alkyl radicals activated by the microenvironment of organelles.

With the in-depth research of organelles, the microenvironment characteristics of their own, such as the acid environment of lysosomes and the high temperature environment of mitochondria, could be used as a natural and powerful condition for tumor therapy. Based on this, we constructed a two-step precise targeting nanoplatform which can realize the drug release and drug action triggered by the microenvironment of lysosomes (endosomes) and mitochondria, respectively. To begin with, the mesoporous silica nanoparticles (MSNs) were modified with triphenylphosphonium (TPP) and loaded with 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH). Then, folic acid (FA) targeted pH-sensitive liposomes containing docetaxel (Lipo/DTX-FA) were prepared by thin-film dispersion method, and the core-shell AIPH/MSN-TPP@Lipo/DTX-FA nanoparticles were constructed by self-assembly during the hydration of the liposomes. When this nanoplatform entered into the tumor cells through FA receptor-mediated endocytosis, the pH-sensitive liposomes were destabilized in the lysosomes, resulting in the release of DTX and AIPH/MSN-TPP nanoparticles. After that, AIPH was delivered to mitochondria by AIPH/MSN-TPP, and the alkyl radicals produced by AIPH under the high temperature environment can cause oxidative damage to mitochondria. Not only that, the DTX could enhance the anti-tumor effect of AIPH by downregulating the expression of anti-apoptotic Bcl-2 protein. The in vitro and in vivo results demonstrate that this delivery system could induce apoptosis based on organelles' s own microenvironment, which provides a new approach for tumor therapy.

An improved Richardson-Lucy iterative algorithm for C-scan image restoration and inclusion size measurement.

The accuracy of measuring inclusion size in direct C-scan image of immersion ultrasonic testing is restricted by the lateral resolution of the focused transducer, even if a high frequency is used, and the blurred edge due to scattering of sound waves at inclusions. In this work, an improved image restoration method that is based on the Richardson-Lucy (RL) iterative algorithm is proposed, which is used to restore the C-scan image and improve the accuracy of inclusion size measurement in immersion ultrasonic testing. For the improved RL iterative algorithm, the point spread function (PSF) is derived based on the multi-Gaussian beam model and Kirchhoff approximation, which considers the propagation properties of sound waves at water-steel interface and the spectral characteristics of the transducer with high frequency. In order to determine the final iteration number, the relationship between final iteration number and size of the inclusion in the image is established by restoring the simulated C-scan image and further calibrated with size correction factor. The size correction factor considers the effect of sound attenuation and electro-mechanical transformation encountered in practical testing equipment. Experimental results show that the inclusion sizes measured in restored C-scan images agree well with the optical micrograph results, which prove the effectiveness of the proposed method.

[Evaluation and Comparison of Thromboelastography and Conventional Coagulation Tests for Blood Coagulation Function in Children with Henoch-Schönlein Purpura].

OBJECTIVE: To investigate the efficacy of disease control, survival time and safely in treatment of newly diagnosed multiple mycloma patients with different dose of tenalidomide regimens. METHODS: The clinical data of 116 patients with multiple myeloma from June 2011 to June 2015 were collected and analyzed retrospectively. According to doses of used lenalidomide based on dexamethasone plus lenalidomide regimen 116 patients were divided into 2 groups: conventional dose group (58 cases) and low dose group (58 cases). The ORR, PFS rate and OS rate during followed-up for 3 years, KPS score, RNS score and immunophenotypic index before and after treatment and drug toxicity incidence were compared between 2 groups. RESULTS: The ORR for 2 treatment courses of low dose group was significantly lower than that in conventienal dose group (P＜0.05). The ORR for 4 and 6 treatment courses was not significantly different between 2 groups (P＞0.05). The PFS rate and OS rate during followed-up for 3 years was no significantly different between 2 groups (P＞0.05). The KPS score and RNS score after treatment of low dose group were significantly better than those in conventional dose group and before treatment (P＜0.05). The levels of immunophenotypic index after treatment of both groups were significantly better than those before treatment (P＜0.05). The incidence of III-IV grade hematological toxicity, pulmonary infection and herpes were not significantly different between 2 groups (P＞0.05). The incidence of peripheral neuropathy and gastrointestinal reactions in the low dose group were significantly lower than that in conventional dose group (P＜0.05). CONCLUSION: Conventional and low doses of lenalidomide possess the same control effects and survival time for treatment of newly dingnosed patients with multiple myeloma; Despite, the initiation of effects from the low dose lenalidomide is relatively slower, it contributes to raise the overall quality of life and reduce the risk of drug toxicity.

Amplified Cancer Immunotherapy of a Surface-Engineered Antigenic Microparticle Vaccine by Synergistically Modulating Tumor Microenvironment.

Efficient cancer vaccines not only require the co-delivery of potent antigens and highly immunostimulatory adjuvants to initiate robust tumor-specific host immune response but also solve the spatiotemporal consistency of host immunity and tumor microenvironment (TME) immunomodulation. Here, we designed a biomaterials-based strategy for converting tumor-derived antigenic microparticles (T-MPs) into a cancer vaccine to meet this conundrum and demonstrated its therapeutic potential in multiple murine tumor models. The internal cavity of T-MPs was employed to store nano-Fe3O4 (Fe3O4/T-MPs), and then dense adjuvant CpG-loaded liposome arrays (CpG/Lipo) were tethered on the surface of Fe3O4/T-MP through mild surface engineering to get a vaccine (Fe3O4/T-MPs-CpG/Lipo), demonstrating that co-delivery of Fe3O4/T-MPs and CpG/Lipo to antigen presenting cells (APCs) could elicit strong tumor antigen-specific host immune response. Meanwhile, vaccines distributed in the TME could reverse infiltrated tumor-associated macrophages into a tumor-suppressive M1 phenotype by nano-Fe3O4, amazingly induce abundant infiltration of cytotoxic T lymphocytes, and transform a "cold" tumor into a "hot" tumor. Furthermore, amplified antitumor immunity was realized by the combination of an Fe3O4/T-MPs-CpG/Lipo vaccine and immune checkpoint PD-L1 blockade, specifically inhibiting ∼83% of the progression of B16F10-bearing mice and extending the median survival time to 3 months. Overall, this study synergistically modulates the tumor immunosuppressive network and host antitumor immunity in a spatiotemporal manner, which suggests a general cell-engineering strategy tailored to a personalized vaccine from autologous cancer cell materials of each individual patient.

C-C Chemokine Ligand 2 (CCL2) Recruits Macrophage-Membrane-Camouflaged Hollow Bismuth Selenide Nanoparticles To Facilitate Photothermal Sensitivity and Inhibit Lung Metastasis of Breast Cancer.

Poor tumor accumulation, rapid clearance from blood circulation, and high risk of invasive and metastasis are the major barriers that encumber the conventional nanodrug-based tumor therapy. In this work, macrophage membrane (M)-camouflaged quercetin (QE)-loaded hollow bismuth selenide nanoparticles (abbreviated as M@BS-QE NPs) are fabricated for combination therapy of breast cancer. The resulting M@BS-QE NPs are comprehensively characterized, possessing prolonged circulation life, as well as accelerated and enhanced tumoritropic accumulation, compared with those of bare BS NPs because of the immune evading capacity, C-C chemokine ligand 2 (CCL2)-mediated recruitment properties, and active targeting ability. The subsequent QE release under near-infrared (NIR) laser irradiation can selectively sensitize cancer cells to photothermal therapy (PTT) by depleting heat shock protein 70 (HSP70, one malignancy-specific-overexpressed thermoresistance-related chaperone) to realize such a cascaded synergistic effect. At the same time, M@BS-QE NPs down-regulated p-Akt and matrix metalloproteinase-9 (MMP-9, which degrades the extracellular matrix to promote invasion and metastasis of tumors) signal axis to suppress breast cancer lung metastasis. Thus, our results provide a biomimetic strategy, using the characteristics of breast cancer and biological properties of macrophages, that hold great promise to enhance the therapeutic efficacy and improve the accuracy of treatment with minimal side effects on both primary and lung metastasis of breast cancer.

[Levels and Significance of Serum Interleukin-35 and the New Regulatory T Cells -iTR35 Cells in Myelodysplastic Syndrome Patients].

OBJECTIVE: To investigate the significance of serum interleukin-35 level and the new regulatory T cells -iTR35 cells in patients with myelodysplastic syndrome (MDS). METHODS: Twenty three cases of newly diagnosed MDS were enrolled in this study from January 2014 to January 2016 in Department of Hematology of The First Hospital of Quanzhou in Fujian Province. According to MDS International Prognostic Scoring System (IPSS), the 23 patients were divided into 4 groups: high-risk (n=4), intermediate risk-2 (n=10), intermediate risk-1 (n=5) and low-risk group(n=4). Twenty healthy people of routine physical examination were used as control during the same period. Enzyme Linked Immunosorbent assay(ELISA) and flow cytometry(FCM) were used to detect the expression level of serum IL-35, the proportion of iTR35 cells, and the expression levels of associated molecules such as IL-12p35,IL-27EBl3 respectively. RESULTS: The proportion of CD4+ CD25+ Foxp3+ Treg cells in peripheral blood of MDS patients was significantly higher than that in controls (P<0.01). The proportion of iTR35 cells was also higher than that in controls(P<0.01). However, the proportion of CD4+ CD25- Foxp3+ T cells was not significantly different between 2 groups (P>0.05). The level of serum IL-35 in MDS patients was significantly higher than that in control group (P<0.05). The expression levels of IL-12p35 and IL-27EBl3 in the Treg cells were also significantly upregulated than those in control group(P<0.05), the expression levels of IL-35, IL-12p35 and IL-27EBl3 in MDS group positively correlated with the proportion of iTR35 cells(r=0.92, 0.99 and 0.52, P<0.05, respectively). IL-35 level and the proportion of iTR35 cells in 4 groups of MDS showed significantly difference in general term, no significant difference was found in IL-35 level between the high-risk group and intermediate risk-2 group (P>0.05), but the IL-35 levels in both groups were significantly higher than those in intermediate risk-1 group and the low-risk group (P<0.05), and the level in the intermediate risk-2 group was significantly higher than that in the intermediate risk-1 group and the low-risk group (P<0.05), while there was not different between the intermediate risk-1group and the low risk group (P>0.05). The proportion of iTR35 cells was not significantly different between the high-risk group and the intermediate risk-2 group. The proportions of iTR35 cells in the high-risk group and the intermediate risk-2 group were higher than those in the intermediate risk-1 group and the low-risk group respectively (P<0.05), but there was no differentce in population of iTR35 between the intermediate risk-1 group and the low-risk group (P>0.05). CONCLUSION: The imbalance between IL-35 level and iTR35 cells propertion may play an important role in the development of MDS, which possibly to provides a new theoretical basis for the study of MDS immune targeting therapy.

Efficacy of the dual PI3K and mTOR inhibitor NVP-BEZ235 in combination with imatinib mesylate against chronic myelogenous leukemia cell lines.

BACKGROUND: Phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway is a therapy target of cancer. We aimed to confirm the effect of dual PI3K/mTOR inhibitor NVP-BEZ235 on proliferation, apoptosis, and autophagy of chronic myelogenous leukemia (CML) cells and sensitivity of tyrosine kinase inhibitor in vitro. METHODS: Two human CML cell lines, K562 and KBM7R (T315I mutant strain), were used. The proliferation of CML cells was detected by MTS (Owen's reagent) assay. Cell cycle and apoptosis assay were examined by flow cytometric analysis. The phosphorylation levels and the expression levels were both evaluated by Western blot analysis. NVP-BEZ235 in combination with imatinib was also used to reveal the effect on proliferation and apoptosis. RESULTS: NVP-BEZ235 significantly inhibited the proliferation in a time- and dose-dependent manner, and the half-maximal inhibitory concentration values of NVP-BEZ235 inhibiting the proliferation of K562 and KBM7R were 0.37±0.21 and 0.43±0.27 µmol/L, respectively, after 48 h. Cell apoptosis assay showed that NVP-BEZ235 significantly increased the late apoptotic cells. Cell cycle analysis indicated that the cells were mostly arrested in G1/G0 phase after treatment by NVP-BEZ235. In addition, results also found that, after treatment by NVP-BEZ235, phosphorylation levels of Akt kinase and S6K kinase significantly reduced, and the expression levels of cleaved caspase-3 significantly increased; meanwhile, the expression levels of caspase-3, B-cell lymphoma-2, cyclin D1, and cyclin D2 significantly decreased, and the ratio of LC3II/LC3I was significantly increased with increased LC3II expression level. Moreover, imatinib in combination with NVP-BEZ235 induced a more pronounced colony growth inhibition than imatinib alone. CONCLUSION: NVP-BEZ235 effectively inhibited cell proliferation by G0/G1 cell cycle arrest and induced apoptosis through deregulating PI3K/Akt/mTOR pathway in CML cells; in addition, NVP-BEZ235 can enhance cell autophagy, and is conducive to raising CML cell sensitivity to imatinib to inhibit the growth of imatinib-resistant cells.