[Risk Assessment of Antibiotics in Agricultural Environment].

Antibiotics are widely used in animal husbandry, planting, and aquaculture in agricultural industries. A large amount of the parent antibiotics used are released into the environment through discharge via feces and urine, posing potential risks to human health and ecosystems. It is thus very important to understand how antibiotics in the agricultural environment threaten the ecological environment and human health. Accordingly, risk assessment of antibiotics in the environment has become the research focus in recent years. The aim of this study was to review the risk assessment methods of antibiotics. The results showed that the ecological environment risk has mainly been assessed by the risk quotient (RQ). Predicted no-impact concentrations (PNECs) are an important indicator for ecological environment risk assessment, but a definite value is still controversial. The hazard quotient (HQ) is generally used to assess health risks. At present, it is necessary to clarify the selection of antibiotic exposure pathways and toxicological thresholds. However, neither of these two methods have currently considered either mixed pollution or the risk of antibiotic metabolites. Further analysis indicated that the ecological risks of antibiotics in the water environment and feces/manure/soil environment were widespread, which had an impact on both the soil and water environment. The types of antibiotics with high risk were different for various cultivated types. The factors including test species, testing conditions, calculation methods, and soil types all affected the detection of PNECs. Human health risk caused by dietary intake of antibiotics was minimal, but it cannot be ignored given the seafood consumption in coastal areas. Moreover, quinolones have both high ecological and human health risks in the agricultural environment. Based on the amount of antibiotics in agriculture and the residual concentration or toxicity of antibiotics in the related environment, this study proposed a priority-control list of antibiotics in the agricultural environment and summarized the main problems in the current antibiotic risk assessment. It will provide helpful support for the scientific optimization of antibiotic risk assessment and the effective control of antibiotics in agricultural environments.

A comparative study on the application of different endoscopic diagnostic methods in the differential diagnosis of benign and malignant bile duct strictures.

Objective: To compare the diagnostic value of cytobrush, ERCP-guided biopsy, SpyGlass direct visual impression and SpyGlass-guided biospy (SpyBite) in the differential diagnosis of benign and malignant bile duct strictures. Methods: The data of 1,008 patients who were clinically diagnosed with indeterminate biliary strictures and underwent ERCP-guided biopsy, cytobrush, SpyGlass direct visual impression or SpyBite at the First Affiliated Hospital of Nanchang University between January 2010 and December 2019 were collected and analyzed retrospectively. The final diagnose was determined by surgical pathological specimen or follow-up (Malignant stricture can be identified if the stricture showed malignant progression during one year of follow-up). The differential diagnostic value of the above endoscopic diagnostic methods was evaluated by means of sensitivity, specificity, accuracy, positive predictive value, negative predictive value, etc. and safety was evaluated by the incidence rate of adverse events. Results: In terms of sensitivity, standard biopsy group (48.6%) and SpyBite group (61.5%) were significantly higher than cytobrush group (32.0%), and visual impression group (100%) was significantly higher than any other group. As far as specificity was concerned, cytobrush group (99.0%), standard biopsy group (99.3%) and the SpyBite group (100%) were significantly higher than visual impression (55.6%), but there was no statistical difference among the three groups above. As far as accuracy was concerned, standard biopsy group (65.3%), and SpyBite group (80.0%) were significantly higher than cytobrush group (44.4%), and SpyBite group (80.0%) was significantly higher than visual impression group (54.8%). In terms of safety, visual impression group and SpyBite group were significantly higher than cytobrush group and standard biopsy group in post-ERCP cholangitis. Conclusion: SpyBite combined with SpyGlass-guided visual impression was better for differential diagnosis of benign and malignant bile duct strictures in terms of sensitivity and accuracy compared with conventional endoscopic diagnostic methods such as cytobrush and standard biopsy. Furthmore, the incidence rates of adverse events after SpyGlass examination was similar to those after conventional endoscopic diagnostic methods except for higher cholangitis, which could be controlled by antibiotics and might be avoided by adequate biliary drainage.

Comparison of two stitches versus one stitch for emergency cervical cerclage to prevent preterm birth in singleton pregnancies.

OBJECTIVE: To compare the efficacy of two stitches versus one stitch in women with emergency cervical cerclage. METHODS: A retrospective case-control study of 26 women with singleton pregnancies who underwent emergency cervical cerclage before 26 weeks. A comparison was made between patients with two stitches versus one stitch at the time of cervical cerclage placement. The primary outcome was gestational age (GA) at delivery and preterm birth (PTB) before 37, 34, 32, 28, and 24 weeks. RESULTS: Average GA at delivery in the two-stitches group was significantly greater than in the one-stitch group (32.71 ± 5.54 weeks vs 27.99 ± 4.70 weeks, P = 0.028). There were significant decreases in the incidence of spontaneous PTB at <34 weeks and less than 32 weeks in the two-stitches group (P = 0.034; P = 0.013, respectively). The neonatal intensive care unit (NICU) admissions rate and length of stay in the NICU in the two-stitches group were significantly reduced (P = 0.035 and P = 0.018, respectively). However, there was no significant difference in neonatal mortality between the two groups. CONCLUSION: Compared with emergency cervical cerclage placement with one stitch, the procedure with two stitches can prolong the pregnancy and improve the neonatal prognosis more effectively.

Case report: Amisulpride therapy induced reversible elevation of creatine kinase-MB and bradycardia in schizophrenia.

Introduction: Schizophrenia is regarded as one of the most severe, disabling, and costly mental illnesses. Hence, early effective prevention and treatment are critical to the prognosis of patients. Amisulpride, a first-line atypical antipsychotic medication that acts as a blocker of the D2 and D3 dopamine receptors, is used in varying doses for the treatment of both positive and negative symptoms of schizophrenia. Reversible amisulpride-induced elevation of the myocardial enzyme spectrum with bradycardia is a rare condition. Case presentation: We report a 26-year-old patient diagnosed with first-episode schizophrenia. This patient was treated with amisulpride (400 mg/d), but no clinical benefits were obtained. Meanwhile, amisulpride caused elevation of the myocardial enzyme spectrum with asymptomatic bradycardia. After stopping the medication, these parameters normalized. Conclusion: We described a rare side reaction of amisulpride. Psychiatrists should take this side effect seriously in the clinical setting. The mechanism of this adverse reaction warrants further investigation and debate. When this side effect occurs during treatment, reducing the dosage of amisulpride and subsequently discontinuing medication, along with monitoring the electrocardiogram and serum myocardial enzymes, may be the most appropriate treatment protocol.

PIWIL1 promotes gastric cancer via a piRNA-independent mechanism.

Targeted cancer therapy aims to achieve specific elimination of cancerous but not normal cells. Recently, PIWI proteins, a subfamily of the PAZ-PIWI domain (PPD) protein family, have emerged as promising candidates for targeted cancer therapy. PPD proteins are essential for small noncoding RNA pathways. The Argonaute subfamily partners with microRNA and small interfering RNA, whereas the PIWI subfamily partners with PIWI-interacting RNA (piRNA). Both PIWI proteins and piRNA are mostly expressed in the germline and best known for their function in transposon silencing, with no detectable function in mammalian somatic tissues. However, PIWI proteins become aberrantly expressed in multiple types of somatic cancers, thus gaining interest in targeted therapy. Despite this, little is known about the regulatory mechanism of PIWI proteins in cancer. Here we report that one of the four PIWI proteins in humans, PIWIL1, is highly expressed in gastric cancer tissues and cell lines. Knocking out the PIWIL1 gene (PIWIL1-KO) drastically reduces gastric cancer cell proliferation, migration, metastasis, and tumorigenesis. RNA deep sequencing of gastric cancer cell line SNU-1 reveals that KO significantly changes the transcriptome, causing the up-regulation of most of its associated transcripts. Surprisingly, few bona fide piRNAs exist in gastric cancer cells. Furthermore, abolishing the piRNA-binding activity of PIWIL1 does not affect its oncogenic function. Thus, PIWIL1 function in gastric cancer cells is independent of piRNA. This piRNA-independent regulation involves interaction with the UPF1-mediated nonsense-mediated mRNA decay (NMD) mechanism. Altogether, our findings reveal a piRNA-independent function of PIWIL1 in promoting gastric cancer.

Circular RNA circRNA_000203 aggravates cardiac hypertrophy via suppressing miR-26b-5p and miR-140-3p binding to Gata4.

AIMS: Circular RNAs (circRNAs) are involved in gene regulation in a variety of physiological and pathological processes. The present study aimed to investigate the effect of circRNA_000203 on cardiac hypertrophy and the potential mechanisms involved. METHODS AND RESULTS: CircRNA_000203 was found to be up-regulated in the myocardium of Ang-II-infused mice and in the cytoplasma of Ang-II-treated neonatal mouse ventricular cardiomyocytes (NMVCs). Enforced expression of circRNA_000203 enhances cell size and expression of atrial natriuretic peptide and ß-myosin heavy chain in NMVCs. In vivo, heart function was impaired and cardiac hypertrophy was aggravated in Ang-II-infused myocardium-specific circRNA_000203 transgenic mice (Tg-circ203). Mechanistically, we found that circRNA_000203 could specifically sponge miR-26b-5p, -140-3p in NMVCs. Further, dual-luciferase reporter assay showed that miR-26b-5p, -140-3p could interact with 3'-UTRs of Gata4 gene, and circRNA_000203 could block the above interactions. In addition, Gata4 expression is transcriptionally inhibited by miR-26b-5p, -140-3p mimic in NMVCs but enhanced by over-expression of circRNA_000203 in vitro and in vivo. Functionally, miR-26b-5p, -140-3p, and Gata4 siRNA, could reverse the hypertrophic growth in Ang-II-induced NMVCs, as well as eliminate the pro-hypertrophic effect of circRNA_000203 in NMVCs. Furthermore, we demonstrated that NF-κB signalling mediates the up-regulation of circRNA_000203 in NMVCs exposed to Ang-II treatment. CONCLUSIONS: Our data demonstrated that circRNA_000203 exacerbates cardiac hypertrophy via suppressing miR-26b-5p and miR-140-3p leading to enhanced Gata4 levels.

Corticotropin-releasing hormone 1 receptor antagonism attenuates chronic unpredictable mild stress-induced depressive-like behaviors in rats.

Hyperactivity of the hypothalamic-pituitary-adrenal axis and impairment of the central corticotropin-releasing factor system are factors in the pathogenesis of depression. Though several antagonists of the corticotropin-releasing factor 1 receptor were effective in the recognized behavioral tests for antidepressant activity, there is still little information on the potential interactions between corticotropin-releasing factor 1 receptor inhibitors and conventional antidepressant therapy. The aim of our study was to assess the influence of CP154526, a corticotropin-releasing factor 1 receptor blocker, which presented some signs of depression. Our results revealed that CP154526 (5 and 10 mg/kg) or fluoxetine (10 mg/kg) treatment notably improved the sucrose consumption, produced anti-depressive-like behavior in open-field test, as well as immobility time in forced swimming test. The levels of interleukin-6, interleukin-1ß, tumor necrosis factor-α, and corticotropin-releasing hormone concentration in the serum were inhibited effectively by CP154526 or fluoxetine administration. Real-time quantitative PCR and western blot analysis showed the upregulated levels of brain-derived neurotrophic factor and growth associated protein 43 (GAP43) in the hypothalamus of the rats exposed to chronic unpredictable mild stress (CUMS), while different degrees of downregulation in their expression were detected after CP154526 (5 and 10 mg/kg) or fluoxetine (10 mg/kg) treatment, respectively. Thus, our data demonstrated that CP154526 exhibited antidepressant effect in CUMS rats, which might be mediated by decreasing the brain-derived neurotrophic factor and GAP43 expression in the hypothalamus.

Tuberous Sclerosis Complex in Chinese patients: Phenotypic analysis and mutational screening of TSC1/TSC2 genes.

PURPOSE: Tuberous sclerosis complex (TSC) is characterized by the development of hamartomas in multiple organ systems. This study attempted to screen mutations and to investigate the mutation distribution and related phenotypes including epilepsy of Chinese TSC patients. METHODS: We performed the genotypic analysis of TSC1 and TSC2 genes in 77 unrelated Chinese TSC patients using direct Sanger sequencing and Multiplex ligation-dependent probe amplification (MLPA). RESULTS: Mutations were identified in a total of 63 (81.8%) cases, including 18 TSC1 mutations (8 nonsense mutations, 6 frameshift, 1 in-frame shift, 1 missense and 2 splice-site) and 45 TSC2 mutations (13 missense, 3 nonsense, 6 splicing, 6 in-frame shift,12 frameshift mutations and 5 large deletions). Large deletions were presented exclusively in TSC2 gene, accounting for 7.9% of all mutations in this study. Fourteen novel mutations were identified in this study. CONCLUSIONS: Epilepsy occurs in approximately 75.3% (58/77) of patients. Hypomelanotic macules occurred significantly more often in patients with TSC2 mutations and cases with TSC1/TSC2 mutations had a significantly higher frequency of cortical nodule than patients with no mutations identified. Overall, our data expands the spectrum of mutations associated with the TSC loci and will be of value to the genetic counseling in patients with the disease.

Heat shock protein DNAJA1 stabilizes PIWI proteins to support regeneration and homeostasis of planarian Schmidtea mediterranea.

PIWI proteins are key regulators of germline and somatic stem cells throughout different evolutionary lineages. However, how PIWI proteins themselves are regulated remains largely unknown. To identify candidate proteins that interact with PIWI proteins and regulate their stability, here we established a yeast two-hybrid (Y2H) assay in the planarian species Schmidtea mediterranea We show that DNAJA1, a heat shock protein 40 family member, interacts with the PIWI protein SMEDWI-2, as validated by the Y2H screen and co-immunoprecipitation assays. We found that DNAJA1 is enriched in planarian adult stem cells, the nervous system, and intestinal tissues. DNAJA1-knockdown abolished planarian regeneration and homeostasis, compromised stem cell maintenance and PIWI-interacting RNA (piRNA) biogenesis, and deregulated SMEDWI-1/2 target genes. Mechanistically, we observed that DNAJA1 is required for the stability of SMEDWI-1 and SMEDWI-2 proteins. Furthermore, we noted that human DNAJA1 binds to Piwi-like RNA-mediated gene silencing 1 (PIWIL1) and is required for PIWIL1 stability in human gastric cancer cells. In summary, our results reveal not only an evolutionarily conserved functional link between PIWI and DNAJA1 that is essential for PIWI protein stability and piRNA biogenesis, but also an important role of DNAJA1 in the control of proteins involved in stem cell regulation.

Combination therapy with micellarized cyclopamine and temozolomide attenuate glioblastoma growth through Gli1 down-regulation.

Glioblastoma multiforme (GBM) is the most common and deadly brain cancer, characterized by its aggressive proliferation to adjacent tissue and high recurrence rate. We studied the efficacy and related mechanisms of the combination of cyclopamine (Cyp, a Sonic-hedgehog pathway (Shh) inhibitor) and temozolomide (TMZ, the clinically most used chemotherapeutic agent) in anti-GBM treatment. The micellarized Cyp (MCyp) showed better performance than Cyp solution in inhibiting GBM cells proliferation (3.77-fold against U87 MG cells and 3.28-fold against DBTRG-05MG cells) and clonogenity (1.35-fold against U87 MG cells and 2.17-fold against DBTRG-05MG cells), and preferred behavior of inhibiting cell invasion, colony formation through attenuated Gli1 expression. In addition, combination of MCyp and TMZ exhibited synergistic cytotoxicity, correlating with their ability in inducing apoptosis and eliminating neurospheres formation, and the combination of TMZ was accompanied with the enhanced blockage of Shh pathway. The optimal ratio of MCyp combined to TMZ was 1:20. So we proposed to use TMZ to kill tumor parenchyma and MCyp as the cancer stem cells inhibitor to resist tumor recurrence. These findings demonstrated that combination of TMZ with micellarized Cyp is a promising strategy for exerting different functions of drugs for tumor treatment.

Delivering siRNA and Chemotherapeutic Molecules Across BBB and BTB for Intracranial Glioblastoma Therapy.

For aggressive brain glioblastoma, the therapy is significantly impaired by blood-brain barrier (BBB) and blood-tumor barrier (BTB). Choosing more than one target from the pool of tumor-stroma interactions is profoundly beneficial to therapeutic approaches. Thus, a multifunctional liposomal system based on anchoring two receptor-specific and penetrable peptides was designed for the combination delivery of BBB-impermeable siRNA and chemotherapeutic docetaxel to brain glioblastoma. Both macroscopic and microscopic specific distributions and targeting effect of the liposomes in the intracranial glioblastoma were confirmed. Superiority in therapeutic efficacies of the siRNA and DTX combination delivery system was revealed from encouraged VEGF gene silencing, tumor cell apoptosis, prolonged survival time, subdued glioblastoma cells in intracranial glioblastoma, and negligible system toxicities after systemic application. Furthermore, the liposomes made better modulation of glioblastoma microenvironment such as the down-regulation of CD31-positive tumor vessels and HIF-1α expression. The transport mechanism of the liposomes delivering the cargos across BBB via receptor-mediated transcytosis without destroying the integrity of BBB has been evaluated from in vitro and in vivo. Therefore, the dual peptides-modified liposomal system provides a safe and noninvasive approach for the delivery of siRNA and chemotherapeutic molecules across the BBB and BTB to target therapy of brain glioblastoma.

Synthesis, antitumor evaluation and 3D-QSAR studies of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine derivatives.

A series of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine derivatives have been synthesized and their structures were confirmed by single-crystal X-ray diffraction. Compared to some reported structures of 1,6-dihydro-1,2,4,5-tetrazine, these compounds can't be considered as having homoaromaticity. Their antiproliferative activities were evaluated against MCF-7, Bewo and HL-60 cells in vitro. Two compounds were highly effective against MCF-7, Bewo and HL-60 cells with IC50 values in 0.63-13.12µM. Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were carried out on 51 [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine derivatives with antiproliferative activity against MCF-7 cell. Models with good predictive abilities were generated with the cross validated q(2) values for CoMFA and CoMSIA being 0.716 and 0.723, respectively. Conventional r(2) values were 0.985 and 0.976, respectively. The results provide the tool for guiding the design and synthesis of novel and more potent tetrazine derivatives.

Synthesis, antitumor evaluation and molecular docking studies of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine derivatives.

A series of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine derivatives have been synthesized and evaluated for their antitumor activities. These compounds exhibited potent antiproliferative activities against MCF-7, Bewo and HL-60 cells and c-Met kinase inhibitory activities. Three compounds were highly effective against MCF-7, Bewo and HL-60 cells with IC50 values in 1.09-2.24µM. Molecular docking was further performed to study the inhibitor-c-Met kinase interactions, and the results show that compound 4j was potently bound to the c-Met kinase with three hydrogen bonds. The further research on acute toxicity and in vivo antitumor activity of compound 4j to ICR (Institute of Cancer Research) mice were carried out, and found 4j with a certain toxicity but good efficacy in vivo. Based on the preliminary results, it is deduced that compound 4j with potent c-Met kinase inhibitory activity may be a potential anticancer agent.

Nitratireductor soli sp. nov., isolated from phenol-contaminated soil.

Strain ZZ-1(T), a Gram-negative, rod-shaped bacterium, motile by flagella, was isolated from phenol-contaminated soil. Strain ZZ-1(T) was found to grow at 15-37 °C (optimum 25-30 °C), at pH 6.0-10.0 (optimum pH 7.5) and with 0-8.0% (w/v) NaCl (optimum 0.5%). The isolate was found to be able to reduce nitrate to nitrite, but not to nitrogen. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain ZZ-1(T) is a member of the genus Nitratireductor, and shows high sequence similarities to Nitratireductor pacificus MCCC 1A01024(T) (98.5%) and lower (<97%) sequence similarities to all other Nitratireductor species. Chemotaxonomic analysis revealed that strain ZZ-1(T) possesses Q-10 as the predominant ubiquinone and Summed feature 8(C(18:1) ω6c and/or C(18:1) ω7c; 66.6%), C(19:0) ω8c cyclo (23.3%), C(18:0) (3.4%), iso-C(17:0) (2.3%) and C(17:0) (1.0%) as the major fatty acids. The polar lipids of strain ZZ-1(T) were determined to be diphosphatidylglycerol, phosphatidylcholine, phospholipids, aminolipids, a glycolipid and an aminophospholipid. The DNA G+C content was determined to be 64.1 mol%. Based on the draft genome sequence, the DNA-DNA hybridization estimate value between strain ZZ-1(T) and N. pacificus MCCC 1A01024(T) was 46.5 ± 3.0% and ANI was 75.9 %. The combination of phylogenetic analysis, phenotypic characteristics, chemotaxonomic data and DNA-DNA hybridization supports the conclusion that strain ZZ-1(T) represents a novel species of the genus Nitratireductor, for which the name Nitratireductor soli sp. nov. is proposed. The type strain is ZZ-1(T) (=JCM 30640(T) = MCCC 1K00508(T)).

Enhance Cancer Cell Recognition and Overcome Drug Resistance Using Hyaluronic Acid and α-Tocopheryl Succinate Based Multifunctional Nanoparticles.

Multidrug resistance (MDR) presents a clinical obstacle to cancer chemotherapy. The main purpose of this study was to evaluate the potential of a hyaluronic acid (HA) and α-tocopheryl succinate (α-TOS) based nanoparticle to enhance cancer cell recognition and overcome MDR, and to explore the underlying mechanisms. A multifunctional nanoparticle, HTTP-50 NP, consisted of HA-α-TOS (HT) conjugate and d-α-tocopheryl polyethylene glycol succinate (TPGS) with docetaxel loaded in its hydrophobic core. The promoted tumor cell recognition and accumulation, cytotoxicity, and mitochondria-specific apoptotic pathways for the HTTP-50 NP were confirmed in MCF-7/Adr cells (P-gp-overexpressing cancer model), indicating that the formulated DTX and the conjugated α-TOS in the HTTP-50 NP could synergistically circumvent the acquired and intrinsic MDR in MCF-7/Adr cells. In vivo investigation on the MCF-7/Adr xenografted nude mice models confirmed that HTTP-50 NP possessed much higher tumor tissue accumulation and exhibited pronouncedly enhanced antiresistance tumor efficacy with reduced systemic toxicity compared with HTTP-0 NP and Taxotere. The mechanisms of the multifunctional HTTP-50 NP to overcome MDR and enhance antiresistance efficacy may be contributed by CD44 receptor-targeted delivery and P-gp efflux inhibition, and meanwhile to maximize antitumor efficacy by synergism of DTX and mitocan of α-TOS killing tumor cells.

A Tröger's base-derived microporous organic polymer: design and applications in CO2/H2 capture and hydrogenation of CO2 to formic acid.

A Tröger's base-derived microporous organic polymer (TB-MOP) was designed, which could adsorb CO2 and coordinate with a Ru(III) complex. The resultant TB-MOP-Ru showed good CO2 and H2 adsorbing performances, and high efficiency for catalysing hydrogenation of CO2 to HCOOH with a turnover number up to 2254 at 40 °C.

Efficient CO2 capture by tertiary amine-functionalized ionic liquids through Li(+)-stabilized zwitterionic adduct formation.

Highly efficient CO2 absorption was realized through formation of zwitterionic adducts, combining synthetic strategies to ionic liquids (ILs) and coordination. The essence of our strategy is to make use of multidentate cation coordination between Li(+) and an organic base. Also PEG-functionalized organic bases were employed to enhance the CO2-philicity. The ILs were reacted with CO2 to form the zwitterionic adduct. Coordination effects between various lithium salts and neutral ligands, as well as the CO2 capacity of the chelated ILs obtained were investigated. For example, the CO2 capacity of PEG150MeBu2N increased steadily from 0.10 to 0.66 (mol CO2 absorbed per mol of base) through the formation of zwitterionic adducts being stabilized by Li(+).

Fluorinated microporous organic polymers: design and applications in CO2 adsorption and conversion.

Fluorinated microporous organic polymers (F-MOPs) were designed, showing twice higher CO2 adsorption capacity than corresponding non-fluorous MOPs. The incorporation of phenanthroline moieties into F-MOPs afforded them the ability to coordinate with Ag(I), and the resultant F-MOP-Ag(I) displayed high efficiency for the reaction of CO2 with propargyl alcohols to form α-alkylidene cyclic carbonates at 25 °C.

Tumor-targeting dual peptides-modified cationic liposomes for delivery of siRNA and docetaxel to gliomas.

Combinations of drugs promoting anti-angiogenesis and apoptosis effects are meaningful for cancer therapy. In the present study, dual peptides-modified liposomes were designed by attaching two receptor-specific peptides, specifically low-density lipoprotein receptor-related protein receptor (Angiopep-2) and neuropilin-1 receptor (tLyP-1) for brain tumor targeting and tumor penetration. Vascular endothelial growth factor (VEGF) siRNA and chemotherapeutic docetaxel (DTX) were chosen as the two payloads because VEGF is closely associated with angiogenesis, and DTX can kill tumor cells efficiently. Binding to glioma cells, co-delivery of siRNA and DTX in human glioblastoma cells (U87 MG) and murine brain microvascular endothelial cells (BMVEC), VEGF gene silencing, antiproliferation and anti-tumor effects of the dual peptides-modified liposomes were evaluated in vitro and in vivo. The dual peptides-modified liposomes persisted the binding ability to glioma cells, enhanced the internalization via specific receptor mediated endocytosis and tissue penetration, thus the dual peptides-modified liposomes loading VEGF siRNA and DTX possessed stimulative gene silencing and antiproliferation activity compared with non-modified and single peptide-modified liposomes. The co-delivery research revealed different intracellular behavior of hydrophilic large molecular and lipophilic small molecule, the former involves endocytosis and subsequent escape of endosome/lysosomes, while the latter experiences passive diffusion of lipophilic small drugs after its release. Furthermore, the dual peptides-modified liposomes showed superiority in anti-tumor efficacy, combination of anti-angiogenesis by VEGF siRNA and apoptosis effects by DTX, after both intratumor and system application against mice with U87 MG tumors, and the treatment did not activate system-associated toxicity or the innate immune response. Combination with the dual peptides-guided tumor homing and penetration, the dual peptides-modified liposomes provide a strategy for effective targeting delivery of siRNA and DTX into the glioma cell and inhibition of tumor growth in a synergistic manner.

Giant biliary cystadenoma complicated with polycystic liver: a case report.

Biliary cystadenoma (BCA) is a rare hepatic neoplasm. Although considered a benign cystic tumor of the liver, BCA has a high risk of recurrence with incomplete excision and a potential risk for malignant degeneration. Correct diagnosis and complete tumor excision with negative margins are the mainstay of treatment. Unfortunately, due to the lack of presenting symptoms, and normal laboratory results in most patients, BCA is hard to distinguish from other cystic lesions of the liver such as biliary cystadenocarcinoma, hepatic cyst, hydatid cyst, Caroli disease, undifferentiated sarcoma, intraductal papillary mucinous tumor, and hepatocellular carcinoma. Ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI) may be necessary. They demonstrate intrahepatic cystic lesions with features such as mural nodules, varying wall thickness, papillary projections, and internal septations. Nevertheless, surgery is still the only means of accurate diagnosis. Definitive diagnosis requires histological examination following formal resection. We describe a 57-year-old woman initially diagnosed with polycystic liver who was subsequently diagnosed with giant intrahepatic BCA in the left hepatic lobe. This indicates that both US physicians and hepatobiliary specialists should attach importance to hepatic cysts, and CT or MRI should be performed for further examination when a diagnosis of BCA is suspected.