Genetic association between smoking and DLCO in idiopathic pulmonary fibrosis patients.

BACKGROUND: Observational studies have shown that smoking is related to the diffusing capacity of the lungs for carbon monoxide (DLCO) in individuals with idiopathic pulmonary fibrosis (IPF). Nevertheless, further investigation is needed to determine the causal effect between these two variables. Therefore, we conducted a study to investigate the causal relationship between smoking and DLCO in IPF patients using two-sample Mendelian randomization (MR) analysis. METHODS: Large-scale genome-wide association study (GWAS) datasets from individuals of European descent were analysed. These datasets included published lifetime smoking index (LSI) data for 462,690 participants and DLCO data for 975 IPF patients. The inverse-variance weighting (IVW) method was the main method used in our analysis. Sensitivity analyses were performed by MR‒Egger regression, Cochran's Q test, the leave-one-out test and the MR-PRESSO global test. RESULTS: A genetically predicted increase in LSI was associated with a decrease in DLCO in IPF patients [ORIVW = 0.54; 95% CI 0.32-0.93; P = 0.02]. CONCLUSIONS: Our study suggested that smoking is associated with a decrease in DLCO. Patients diagnosed with IPF should adopt an active and healthy lifestyle, especially by quitting smoking, which may be effective at slowing the progression of IPF.

TGF-ß1 mediates tumor immunosuppression aggravating at the late stage post-high-light-dose photodynamic therapy.

Photodynamic therapy (PDT) is an emerging clinical treatment that is expected to become an important adjuvant strategy for the immunotherapeutic cancer treatment. Recently, numerous works have reported combination strategies. However, clinical data showed that the anti-tumor immune response of PDT was not lasting though existing. The immune activation effect will eventually turn to immunosuppressive effect and get aggravated at the late stage post-PDT. So far, the mechanism is still unclear, which limits the design of specific correction strategies and further development of PDT. Several lines of evidence suggest a role for TGF-ß1 in the immunosuppression associated with PDT. Herein, this study systematically illustrated the dynamic changes of immune states post-PDT within the tumor microenvironment. The results clearly demonstrated that high-light-dose PDT, as a therapeutic dose, induced early immune activation followed by late immunosuppression, which was mediated by the activated TGF-ß1 upregulation. Then, the mechanism of PDT-induced TGF-ß1 accumulation and immunosuppression was elucidated, including the ROS/TGF-ß1/MMP-9 positive feedback loop and CD44-mediated local amplification, which was further confirmed by spatial transcriptomics, as well as by the extensive immune inhibitory effect of local high concentration of TGF-ß1. Finally, a TGF-ß blockade treatment strategy was presented as a promising combinational strategy to reverse high-light-dose PDT-associated immunosuppression. The results of this study provide new insights for the biology mechanism and smart improvement approaches to enhance tumor photodynamic immunotherapy.

Enhanced Anti-Rheumatoid Arthritis Activity of Total Alkaloids from Picrasma Quassioides in Collagen-Induced Arthritis Rats by a Targeted Drug Delivery System.

New drug delivery systems have rarely been used in the formulation of traditional Chinese medicine, especially those that are crude active Chinese medicinal ingredients. In the present study, hyaluronic acid decorated lipid-polymer hybrid nanoparticles were used to prepare a targeted drug delivery system (TDDS) for total alkaloid extract from Picrasma quassioides (TAPQ) to improve its targeting property and anti-inflammatory activity. Picrasma quassioides, a common-used traditional Chinese medicine (TCM), containing a series of hydrophobic total alkaloids including ß-carboline and canthin-6-one alkaloids show great anti-inflammatory activity. However, its high toxicity (IC50= 8.088±0.903 µg/ml), poor water solubility (need to dissolve with 0.8% Tween-80) and poor targeting property severely limits its clinical application. Herein, hyaluronic acid (HA) decorated lipid-polymer hybrid nanoparticles loaded with TAPQ (TAPQ-NPs) were designed to overcome above mentioned deficiencies. TAPQ-NPs have good water solubility, strong anti-inflammatory activity and great joint targeting property. The in vitro anti-inflammatory activity assay showed that the efficacy of TAPQ-NPs was significantly higher than TAPQ(P<0.001). Animal experiments showed that the nanoparticles had good joint targeting property and had strong inhibitory activity against collagen-induced arthritis (CIA). These results indicate that the application of this novel targeted drug delivery system in the formulation of traditional Chinese medicine is feasible.

Non-Invasive and Real-Time Monitoring of the Breast Cancer Metastasis Degree via Metabolomics.

Breast cancer (BC) is a serious threat to women's health and metastasis is the major cause of BC-associated mortality. Various techniques are currently used to preoperatively describe the metastatic status of tumors, based on which a comprehensive treatment protocol was determined. However, accurately staging a tumor before surgery remains a challenge, which may lead to the miss of optimal treatment options. More severely, the failure to detect and remove occult micrometastases often causes tumor recurrences. There is an urgent need to develop a more precise and non-invasive strategy for the detection of the tumor metastasis in lymph nodes and distant organs. Based on the facts that tumor metastasis is closely related to the primary tumor microenvironment (TME) evolutions and that metabolomics profiling of the circulatory system can precisely reflect subtle changes within TME, we suppose whether metabolomic technology can be used to achieve non-invasive and real-time monitoring of BC metastatic status. In this study, the metastasis status of BC mouse models with different tumor-bearing times was firstly depicted to mimic clinical anatomic TNM staging system. Metabolomic profiling together with metastasis-related changes in TME among tumor-bearing mice with different metastatic status was conducted. A range of differential metabolites reflecting tumor metastatic states were screened and in vivo experiments proved that two main metastasis-driving factors in TME, TGF-ß and hypoxia, were closely related to the regular changes of these metabolites. The differential metabolites level changes were also preliminarily confirmed in a limited number of clinical BC samples. Metabolite lysoPC (16:0) was found to be useful for clinical N stage diagnosis and the possible cause of its changes was analyzed by bioinformatics techniques.

Dual-responsive nanosystem based on TGF-ß blockade and immunogenic chemotherapy for effective chemoimmunotherapy.

The antitumor immune response induced by chemotherapy has attracted considerable attention. However, the immunosuppressive tumor microenvironment hinders the immune activation effect of cancer chemotherapy. TGF-ß plays a key role in driving tumor immunosuppression and can prevent effective antitumor immune response through multiple roles. In this study, a dual-responsive prodrug micelle (PAOL) is designed to co-deliver LY2109761 (a TGF-ß receptor I/II inhibitor) and oxaliplatin (OXA, a conventional chemotherapy) to remodel tumor microenvironment and trigger immunogenic cell death (ICD) to induce antitumor immunity response. Under hypoxia tumor environment, the polyethylene glycol shell of the micelle cleavages, along with the release of LY2109761 and OXA prodrug. Cytotoxic effect of OXA is then activated by glutathione-mediated reduction in tumor cells and the activated OXA significantly enhances tumor immunogenicity and promotes intratumoral accumulation of cytotoxic T lymphocytes. Meanwhile, TGF-ß blockade through LY2109761 reprograms tumor microenvironment by correcting the immunosuppressive state and regulating tumor extracellular matrix, which further maintaining OXA induced immune response. Therefore, due to the capability of boosting tumor-specific antitumor immunity, the bifunctional micelle presents markedly synergistic antitumor efficacies and provides a potent therapeutic strategy for chemoimmunotherapy of solid tumors.

Luteimonas deserti sp. nov., a novel strain isolated from desert soil.

A Gram-stain-negative, non-motile, rod-shaped bacterial strain, named SJ-16T, was isolated from desert soil collected in Inner Mongolia, northern PR China. Strain SJ-16T grew at pH 6.0-11.0 (optimum, pH 8.0-9.0), 4-40 °C (optimum, 30-35 °C) and in the presence of 0-8 % (w/v) NaCl (optimum, 0-2 %). The strain was negative for catalase and positive for oxidase. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain SJ-16T clustered with Luteimonas chenhongjianii 100111T and Luteimonas terrae THG-MD21T, and had 98.8, 98.6, 98.3 and <97.9 % of 16S rRNA gene sequence similarity to strains L. chenhongjianii 100111T, L. terrae THG-MD21T, L. aestuarii B9T and all other type strains of the genus Luteimonas, respectively. The major cellular fatty acids were iso-C15 : 0, iso-C16 : 0, summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c) and summed feature 9 (C16 : 0 10-methyl and/or iso-C17 : 1 ω9c). Diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine were the major polar lipids, and ubiquinone-8 was the only respiratory quinone. The genomic DNA G+C content was 69.3 mol%. The digital DNA-DNA hybridization and average nucleotide identity values of strain SJ-16T to L. chenhongjianii 100111T, L. terrae THG-MD21T, L. rhizosphaerae 4-12T and L. aestuarii B9T were 36.9, 37.5, 24.0 and 21.1 %, and 80.9, 80.6, 80.7 and 76.3 %, respectively. Based on phenotypic, physiological and phylogenetic results, strain SJ-16T represents a novel species of the genus Luteimonas, for which the name Luteimonas deserti is proposed. The type strain is SJ-16T (=CGMCC 1.17694T=KCTC 82207T).

An Activatable Theranostic Nanoprobe for Dual-Modal Imaging-Guided Photodynamic Therapy with Self-Reporting of Sensitizer Activation and Therapeutic Effect.

Intelligent systems that offer traceable cancer therapy are highly desirable for precision medicine. Although photodynamic therapy (PDT) has been approved in the clinic for decades, determining where the tumor is, when to irradiate, and how long to expose to light still confuse the clinicians. Patients are always suffering from the phototoxicity of the photosensitizer in nonmalignant tissues. Herein, an activatable theranostic agent, ZnPc@TPCB nanoparticles (NPs), is prepared by doping a photosensitizer, ZnPc, with an aggregation-induced emission probe, TPCB. The assembled or disassembled ZnPc@TPCB NPs in various phases have behaved differently in fluorescence intensity, photoacoustic (PA) signals, and PDT efficiency. The intact nanoparticles are non-emissive in aqueous media while showing strong PA signals and low PDT efficiency, which can eliminate the phototoxicity and self-monitor their distribution and image the tumors' location. Disassembling of the NPs leads to the release of ZnPc and its red fluorescence turn-on to self-report the photosensitizer's activation. Upon light irradiation, the reactive oxygen species (ROS) generated by ZnPc can induce cell apoptosis and activate the ROS sensor, TPCB, which will yield intense orange-red fluorescence and instantly predict the therapeutic effect. Moreover, enhanced PDT efficacy is achieved via the GSH-depleting adjuvant quinone methide produced by the activated TPCB. The well-designed ZnPc@TPCB NPs have shown promising potential for finely controlled PDT with good biosafety and broad application prospects in individual therapy, which may inspire the development of precision medicine.

A Simple Aggregation-Induced Emission Nanoprobe with Deep Tumor Penetration for Hypoxia Detection and Imaging-Guided Surgery in Vivo.

The pan-cancer detection and precise visualization of tiny tumors in surgery still face great challenges. As tumors grow aggressively, hypoxia is a common feature of solid tumors and has supplied a general way for detecting tumors. Herein, we report a simple aggregation-induced emission nanoprobe-TPE-4NE-O that can specifically switch on their fluorescence in the presence of cytochrome P450 reductase, a reductase which is overexpressed under hypoxia conditions. The probe can selectively light up the hypoxia cells and has shown enhanced deep tumor penetration via charge conversion both in vitro and in vivo. After being modified with FA-DSPE-PEG, higher tumor uptake can be seen and FA-DSPE/TPE-4NE-O showed specific visualization to the hypoxia cancer cells. Excitingly, much brighter fluorescence was accumulated at the tumors in the FA-DSPE/TPE-4NE-O group, even though the tumor was as small as 2.66 mm. The excellent performance of FA-DSPE/TPE-4NE-O in detecting tiny tumors has made it possible for imaging-guided tumor resection. More importantly, the probe exhibited good biocompatibility with negligible organ damage and eliminated a hemolysis risk. The simple but promising probe has supplied a new strategy for pan-cancer detection and tiny tumor visualization, which have shown great potential in clinical translation.

Specific-oxygen-supply functionalized core-shell nanoparticles for smart mutual-promotion between photodynamic therapy and gambogic acid-induced chemotherapy.

Photodynamic therapy (PDT) and chemotherapy of cancer both meet respective challenges. Tumor hypoxia, low penetration and high glutathione (GSH) level bear the brunt. Herein, a core-shell nanoparticle, with multi-function of hypoxia-responsiveness, specific oxygen supply and deep tumor penetration, was constructed for smart mutual-promotion between the both to overcome the respective restrictions. The nano platform (GC@MCS NPs) was composed of hypoxia-responsive hyaluronic acid-nitroimidazole (HA-NI) as shells, MnO2 NPs as oxygen modulators and reduction-responsive functionalized poly (l-glutamic acid) derivatives (γ-PFGA) as cores to deliver gambogic acid (GA) and Chlorine6 (Ce6). After endocytosis, the approximately 100 nm of GC@MCS NPs achieved hypoxia-responsive shell degradation and MnO2 release, followed by reduction-activated charge conversion to form positively charged cores. With the damage effect of superficial tumor cells by the partially released GA, GA&Ce6-loadedγ-PFGA penetrated deep inside through electronic interaction step by step. Upon irradiated with 638 nm of laser, widely permeated Ce6 was activated for enhanced PDT under the high oxygenation by MnO2 NPs. The generated reactive oxygen species (ROS) in return facilitated the GA-induced paraptosis by clearing high level of GSH. As a result, this mutual promotion strategy contributed to 92.41% of 4T1 tumor inhibition rate, exhibiting outstanding advantages. Our GC@MCS NPs provided a smart combination of chemo-photodynamic therapy and focused on addressing the tumor hypoxia and low penetration issues.

Self-Delivered and Self-Monitored Chemo-Photodynamic Nanoparticles with Light-Triggered Synergistic Antitumor Therapies by Downregulation of HIF-1α and Depletion of GSH.

Photodynamic therapy (PDT), a clinically approved cancer treatment, has faced many drawbacks that restricted its applications. For example, the hypoxia-induced elevated hypoxia-inducible factor-1α (HIF-1α) may desensitize tumors to PDT, and the high concentration of glutathione (GSH) in cancer cells can also neutralize the generated reactive oxygen species (ROS) during PDT, resulting in insufficient therapy. Moreover, extra probes for imaging-guided visualization therapy are always needed to track drug release or distribution, while it may decrease the drug loading of the drug delivery system (DDS). In the present study, we have designed and prepared a novel multifunctional combined therapy nanoparticle (ZnPc@Cur-S-OA NPs), in which curcumin (Cur) was not only used as a chemotherapy drug to achieve a combination therapy with PDT via downregulating HIF-1α and depleting GSH in B16F10 cells but also designed as a small-molecule ROS-triggered release prodrug to deliver the photosensitizer (PS). The red fluorescence of PS in the nanoparticles (NPs) can be used to track the NPs distribution, while the green fluorescence of Cur showed an "OFF-ON" activation, which enables additional imaging and real-time self-monitoring capabilities. These results proved that the prepared combined therapy NPs were more effective to inhibit the growth of B16F10 mouse melanoma tumor than was monotherapy without eliciting systemic toxicity either in vitro or in vivo, which indicated the combined therapy NPs as an effective way to improve the PDT efficacy via downregulation of HIF-1α and depletion of GSH. Thus, the strategy of using a multifunctional natural product as the stimuli-responsive carrier as well as the synergist with PDT for enhancing antitumor efficacy via multiple pathways may open an alternative avenue to fabricate new self-delivery combination therapy nanodrugs. Besides, the fluorescence emitted from the drug can be used for real-time self-monitoring of drug release and distribution, which has great potential in clinic to adjust the administration dose and irradiation time for different tumor types and stages for individual therapy.

Lysobacter alkalisoli sp. nov., a chitin-degrading strain isolated from saline-alkaline soil.

Strains of Lysobacter, thought to play vital roles in the environment for their high enzyme production capacity, are ubiquitous in various ecosystems. During an analysis of bacterial diversity in saline soil, a Gram-stain-negative, aerobic, chitin-degrading bacterial strain, designated SJ-36T, was isolated from saline-alkaline soil sampled at Tumd Right Banner, Inner Mongolia, PR China. Strain SJ-36T grew at 4-40 °C (optimum, 30 °C), pH 5.0-10.0 (optimum, pH 7.0-8.0) and 0-6 % NaCl (optimum, 1.0 %). Oxidase and catalase activities were positive. A phylogenetic tree based on 16S rRNA gene sequences and the phylogenomic tree both showed that strain SJ-36T formed a tight clade with Lysobacter maris KMU-14T (sharing 97.6 % 16S rRNA gene similarity) and Lysobacter aestuarii S2-CT (97.8 %). The major polar lipids of strain SJ-36T were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, two unidentified lipids and one unidentified phospholipid. The major fatty acids were iso-C15 : 0 (37.5 %), summed feature 9 (14.0 %; iso-C17 : 1ω9c and/or C16 : 0 10-methyl) and iso-C11 : 0 (10.6 %). Q-8 was the predominant ubiquinone. Its genomic DNA G+C content was 66.6 mol%. The average nucleotide identity values of strain SJ-36T to L. maris KMU-14T, L. aestuarii S2-CT and other type strains were 81.5, 79.1 and <79.0 %, respectively. The results of physiological, phenotypic and phylogenetic characterizations allowed the discrimination of strain SJ-36T from its phylogenetic relatives. Lysobacter alkalisoli sp. nov. is therefore proposed with strain SJ-36T (=CGMCC 1.16756T=KCTC 43039T) as the type strain.

Circular RNA cESRP1 sensitises small cell lung cancer cells to chemotherapy by sponging miR-93-5p to inhibit TGF-ß signalling.

Circular RNAs (circRNAs) are novel RNA molecules that play important roles in chemoresistance in different cancers, including breast and gastric cancers. However, whether circRNAs are involved in the response to chemotherapy in small cell lung cancer (SCLC) remains largely unknown. In this study, we observed that cESRP1 (circular RNA epithelial splicing regulatory protein-1) expression was significantly downregulated in the chemoresistant cells compared with the parental chemosensitive cells. cESRP1 enhanced drug sensitivity by repressing miR-93-5p in SCLC. Cytoplasmic cESRP1 could directly bind to miR-93-5p and inhibit the posttranscriptional repression mediated by miR-93-5p, thereby upregulating the expression of the miR-93-5p downstream targets Smad7/p21(CDKN1A) and forming a negative feedback loop to regulate transforming growth factor-ß (TGF-ß) mediated epithelial-mesenchymal transition. Furthermore, cESRP1 overexpression and TGF-ß pathway inhibition both altered tumour responsiveness to chemotherapy in an acquired chemoresistant patient-derived xenograft model. Importantly, cESRP1 expression was downregulated in SCLC patient tissues and was associated with survival. Our findings reveal, for the first time, that cESRP1 plays crucial a role in SCLC chemosensitivity by sponging miR-93-5p to inhibit the TGF-ß pathway, suggesting that cESRP1 may serve as a valuable prognostic biomarker and a potential therapeutic target in SCLC patients.

LncRNA MIR4435-2HG-mediated upregulation of TGF-ß1 promotes migration and proliferation of nonsmall cell lung cancer cells.

The roles of long noncoding RNAs (lncRNAs) have been shown to play critical roles in tumor progression. Here, it was identified that lncRNA MIR4435-2HG was highly expressed in lung cancer tissues, especially in nonsmall cell lung cancer (NSCLC). A consistent result was obtained in lung cancer cells. Functional experiments showed that knockdown of MIR4435-2HG reduced the proliferation and migration ability of NSCLC cells. Transcriptome-sequencing analysis indicated that TGF-ß signaling was mostly enriched in NSCLC cells with MIR4435-2HG knockdown. Furthermore, MIR4435-2HG was identified as an miRNA sponge for TGF-ß1 and thus activated TGF-ß signaling. Additionally, re-activation of TGF-ß1 rescued MIR4435-2HG knockdown-mediated inhibition on the progression of NSCLC cells. Therefore, this work indicates a novel MIR4435-2HG/TGF-ß1 axis responsible for NSCLC cell progression.

A stage-specific cancer chemotherapy strategy through flexible combination of reduction-activated charge-conversional core-shell nanoparticles.

Precision medicine has increased the demand for stage-specific cancer chemotherapy. Drugs with different properties are needed for different stages of tumor development, which is, inducing rapid destruction in the early stage and facilitating deep penetration in the advanced stage. Herein, we report a novel reduction-activated charge-conversional core-shell nanoparticle (CS NP) formula based on ring-closing metathesis of the thiamine disulfide system (TDS) to deliver the chemotherapeutic agent-gambogic acid (GA). Methods: The shell consisted of hyaluronic acid-all-trans retinoid acid with a disulfide bond as the linker (HA-SS-ATRA). The core was selected from poly (γ-glutamic acid) with different grafting rates of the functional group (Fx%) of TDS. GA/CF100%S NPs, with the strongest reduction-responsive drug release, and GA/CF60%S NPs with the strongest penetration have been finally screened. On this basis, a stage-specific administration strategy against a two-stage hepatocellular carcinoma was proposed. Results: The developed CS NPs have been confirmed as inducing reduction-activated charge conversion from about -25 to +30 mV with up to 95% drug release within 48 h. The administration strategy, GA/CF100%S NPs for the early-stage tumor, and sequential administration of GA/CF60%S NPs followed by GA/CF100%S NPs for the advanced-stage tumor, achieved excellent tumor inhibition rates of 93.86±2.94% and 90.76±6.43%, respectively. Conclusions: Our CS NPs provide a novel platform for charge conversion activated by reduction. The stage-specific administration strategy showed great promise for cancer therapy.

Improved druggability of gambogic acid using core-shell nanoparticles.

Gambogic acid (GA) is a natural antitumor drug candidate with advantages of broad-spectrum activity, low toxicity and multiple mechanisms. Its clinical application is hindered, however, by low aqueous solubility, instability and poor pharmacokinetic properties. In this research, core-shell hybrid nanoparticles have been developed to improve the druggability of GA. The nanoparticles are composed of a benzylamidated poly(γ-glutamic acid) (BzPGA) derivative as a core material and an amphiphilic hyaluronic acid derivative grafted with all-trans retinoic acid (HA-C6-ATRA) as a shell material. Through π-π stacking interactions, GA is encapsulated into BzPGA to form the "core" of the hybrid nanoparticle and the "shell" is formed by HA-C6-ATRA with a π-π stacking mediated "molecular fence". The nanovehicle, with sub 100 nm size, provides almost 100% encapsulation efficiency, a good protective effect and a sustained release profile for GA. A series of evaluations suggest that the core-shell nanoparticles provide a stable aqueous injection formulation (I), improved stability (II), prolonged circulation time and conferred tumor targeting properties (III) for GA. As a result, the anti-tumor activity of GA is significantly enhanced without causing higher toxicity, indicating that the designed nanoplatform dramatically improves the druggability of GA. This study may also provide inspiration for drug development research.

Long noncoding RNA PCAT6 inhibits colon cancer cell apoptosis by regulating anti-apoptotic protein ARC expression via EZH2.

Prostate cancer-associated ncRNA transcript 6 (PCAT6) is a long intergenic noncoding RNA that is involved in the progression of prostate and lung cancer, acting as a potential diagnostic and prognostic biomarker in nonsmall cell lung cancer. However, little is known about PCAT6 expression and its clinical significance in colon cancer. Here, we aimed to investigate the clinical significance of PCAT6 in colon cancer and its underlying mechanism. The expression of PCAT6 was analyzed in colon cancer tissues using public databases, and a series of in vitro and in vivo experiments was performed to investigate the biological functions of PCAT6 in colon cancer cells and the underlying mechanisms. Our results demonstrated that PCAT6 was upregulated in colon cancer tissues compared with that in noncancerous tissues, correlating with poorer clinical stages and a worse survival status. In vitro and in vivo experiments illustrated PCAT6 promoted cell growth and inhibited cell apoptosis in colon cancer. Mechanistically, PCAT6 enhanced the coenrichment of EZH2 and H3K4me3 at the apoptosis repressor with caspase recruitment domain (ARC) genomic region, promoting the transcriptional activity of ARC. Our data highlighted that PCAT6 acts as a key activator of ARC expression by forming a complex with EZH2, inhibiting cell apoptosis and contributing to colon cancer progression. These findings elucidated that PCAT6 may be a novel prognostic predictor and therapeutic target of colon cancer.

Redox-sensitive micelles for targeted intracellular delivery and combination chemotherapy of paclitaxel and all-trans-retinoid acid.

The application of paclitaxel (PTX) in clinic has been restricted due to its poor solubility. Several traditional nano-medicines have been developed to improve this defect, while they are still lack of tumor targeting ability and rapid drug release. In this work, an amphiphilic polymeric micelle of hyaluronic acid (HA) - all-trans-retinoid acid (ATRA) with a disulfide bond, was developed successfully for the co-delivery of PTX and ATRA. The combination chemotherapy of PTX and ATRA can strengthen the anti-tumor activity. Along with self-assembling to micelles in water, the delivery system displayed satisfying drug loading capacities for both PTX (32.62% ± 1.39%) and ATRA, due to directly using ATRA as the hydrophobic group. Rapid drug release properties of the PTX-loaded redox-sensitive micelles (HA-SS-ATRA) in vitro were confirmed under reducing condition containing GSH. Besides, HA-CD44 mediated endocytosis promoted the uptake of HA-SS-ATRA micelles by B16F10 cells. Due to these properties, cytotoxicity assay verified that PTX-loaded HA-SS-ATRA micelles showed concentration-dependent cytotoxicity and displayed obvious combination therapy of PTX and ATRA. Importantly, HA-SS-ATRA micelles could remarkably prolong plasma circulation time after intravenously administration. Therefore, redox-sensitive HA-SS-ATRA micelles could be utilized and explored as a promising drug delivery system for cancer combination chemotherapy.

Reticuloendothelial System Pre-Block Strategy to Improve Tumor Targeting Efficacy for Hyaluronic Acid Related Drug Delivery System.

Hyaluronic acid (HA) is widely used in many tumor targeting drug delivery systems (TDDS) due to its biocompatibility and modifiability. Moreover, HA receptors are over-expressed on many tumor cells. However, the clearance of the HA-related TDDS by the reticuloendothelial system (RES) need urgent consideration on account of the high affinity between HA and related receptors in RES. A pre-block strategy before TDDS administration had been designed to overcome RES clearance. In order to avoid the rapid RES clearance and further improve tumor targeting efficiency for HA-related TDDS, we designed a novel strategy of selectively pre-blocking HA receptors in RES by injecting HA-coated blank liposome (pre-block formulation) prior to dosing of HA-related TDDS. The molecule weight and surface density of HA in pre-block formulation as well as TDDS, the time interval between dosing, and the concentration of pre-block formulation, were optimized by a series of in vitro cellular uptake studies in macrophages and 4T1 tumor cell lines, which was further confirmed by in vivo studies. The result shows that that the optimized pre-block formulation can saturate the RES, by which the RES clearance is weakened and the tumor targeting efficiency for HA-related TDDS is finally improved.

Heterotopic ossification following anti-NMDA receptor encephalitis: a case report.

BACKGROUND: Heterotopic ossification (HO) is defined as the formation of true bone tissue in non-osseous tissues. HO may occur under several conditions such as soft tissue injury, central nervous system injury and many other diseases like arthopathies, and vasculopathies. The underlying mechanisms of HO are not well elucidated. Anti-NMDA receptor encephalitis is a newly recognized autoimmune mediated disease which is predominant in young female patients with ovarian teratomas. Encephalitis complicated with HO has rarely been reported. CASE PRESENTATION: Here we report a case of anti-NMDA receptor encephalitis with severe muscle ossifications. A 15 years old female patient presented with fever, changed mental status of confusion, rigidity of the arms and legs, and oral-facial dyskinesias. Diagnosis of anti-NMDA receptor encephalitis was confirmed by detection of anti-NMDA receptor antibodies both in serum and CSF. Due to the severity of the disease, 3-weeks' intensive care and mechanical ventilation were administrated for the patient. Image of pelvic CT and MRI of the patient showed dynamic changing process of HO. The muscles showed edema and scattered inflammation at the very beginning, and then gradually formed mature bone tissue. CONCLUSIONS: Anti-NMDA receptor encephalitis often presents with severe neurologic symptoms and requires long time intensive care and mechanical ventilation, which makes the patient easily complicate with HO. More studies are required to elucidate the mechanisms of HO and more attention should be paid to patients with encephalitis who might develop severe muscle ossifications requiring early interventions.

[Research on the ultraviolet reflectivity characteristic of simulative targets of oil spill on the ocean].

The authors set up an experiment instrument to measure the ultraviolet (UV) characteristic of oil spill simulation targets for the marine oil spill. After selecting appropriate conditions for experiments, the authors tested UV reflective spectrum of four simulation targets for oil spill (gasoline, kerosene, diesel fuel, lubricating oil). The authors calculated the UV absolute spectrum reflectivity of all testing targets from the standard white board as reference, whose UV reflectivity was given. With processing and analyzing the data from experiments, the authors got the reflective characteristics of them in contrast to the reflectivity of water, which was measured in the same conditions. All targets were tested from 320 to 400 nm, and UV reflectivity wave-band between 360 and 380 nm was representative. Testing data were shown as follows: (1) The reflectivity of water was from 5.3% to 5.5%. (2) When the thickness of oil film was 400 microm, the reflectivity of gasoline was from 8.5% to 8.8%, 5.4%-5.8% for kerosene, 8.3%-8.4% for diesel fuel, and 9.4%-9.7% for lubricating oil in the same wave-band between 360 and 380 nm. Correspondingly, the indeterminacy of reflectivity was 0.32%, 0.45%, 0.25%, and 0.33% respectively. (3) Hence the thickness of oil film changed, the rule of the UV reflectivity varied depending on the sort of oil spill. The results show that there were some obvious reflectivity differences among oil films and water, which were mainly determined by the sort and thickness of oil film. This experiment method is also fit for the actual oil spill target, and it will fulfill some theory and experimental foundation for inspecting the marine oil spill by UV remote sensing in the future.