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@#By regulating gene expression, nucleic acid drugs functioning in the cytoplasm or nucleus are of great significance in the treatment of acquired or inherited diseases and vaccine development.A variety of nucleic acid delivery vectors currently developed are suffering from low transfection efficiency due to endosome/lysosome entrapment.This paper introduces and summarizes the nucleic acid delivery strategies that bypass the endosomal/lysosomal pathway, including membrane translocation, membrane fusion, receptor/transporter-mediated non-endocytic uptake and caveolae-mediated endocytosis, and discusses the problems and challenges facing such strategies, aiming to facilitate the development of intracellular delivery of nucleic acid drugs bypassing lysosomal pathway.
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Most drugs need to interact with cell membrane to reach the biological target, so that membrane affinity assay is an important early screening step in drug discovery. However, at present, the traditional oil-water distribution method is still used, a new, simple and accurate method for membrane affinity assay is urgently needed. In this study, according to the colorimetric principle, a new assay model based on polydiacetylene vesicles was optimized through a series of experiments including different concentrations of vesicle solution, temperature, or pH reaction environment. On this basis, tetracaine hydrochloride, 2-methylimidazole and histamine were used as model drugs to measure the membrane affinity constants and verify the between-batch precision of the optimized assay model (relative standard deviation less than 5%). In addition, polydiacetylene vesicles were stable for up to 180 days, demonstrating the potential application of the assay model. This strategy is simple, stable, reliable, with high reproducibility, low cost and easy to promote, which provided a new tool and a new direction for the high-throughput assay of membrane affinity.
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As a new technology with unique drug delivery advantages， nanoemulsion has been widely used in the field of traditional Chinese medicine （TCM） preparations. By searching， classifying and sorting out the literature reports at home and abroad in recent years， this paper systematically expounded the application advantages and production mechanism of nanoemulsion in delivering effective components of TCM from three aspects of improving oral bioavailability， enhancing targeting effect and delaying drug release. The current formulation optimization strategies， preparation processes and quality evaluation indicators commonly used in TCM nanoemulsion were summarized. Based on the research status of TCM nanoemulsion with different active components， the common problems and possible solutions in the development of TCM nanoemulsion were discussed， and the future research hotspots and directions of TCM nanoemulsion were prospected. This article clarifies the feasibility of nanoemulsion for enriching the selection of TCM dosage forms， which can provide reference for the subsequent rational design and improvement of TCM preparations. At the same time， it is revealed that the research focus of TCM nanoemulsion in the future lies in the integrated research of TCM compounds， and shows a trend of multi-disciplinary joint and targeted research.
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Drug target discovery is the basis of drug screening.It elucidates the cause of disease and the mechanism of drug action,which is the essential of drug innovation.Target discovery performed in biological sys-tems is complicated as proteins are in low abundance and endogenous compounds may interfere with drug binding.Therefore,methods to track drug-target interactions in biological matrices are urgently required.In this work,a Fe3O4 nanoparticle-based approach was developed for drug-target screening in biofluids.A known ligand-protein complex was selected as a principle-to-proof example to validate the feasibility.After incubation in cell lysates,ligand-modified Fe3O4 nanoparticles bound to the target protein and formed complexes that were separated from the lysates by a magnet for further analysis.The large surface-to-volume ratio of the nanoparticles provides more active sites for the modification of chemical drugs.It enhances the opportunity for ligand-protein interactions,which is beneficial for capturing target proteins,especially for those with low abundance.Additionally,a one-step magnetic separation simplifies the pre-processing of ligand-protein complexes,so it effectively reduces the endogenous interference.Therefore,the present nanoparticle-based approach has the potential to be used for drug target screening in biological systems.
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Metal-organic frameworks (MOFs) are porous crystalline polymers constructed from the coordination reaction between organic ligands and metal ions. Due to their advantages: adjustable periodic pore structure, large specific surface area and easy functional modification, etc., MOFs have been widely used in the fields of gas storage/separation, catalysis, sensing, biological imaging and drug delivery. In recent years, MOFs have shown great potential in disease diagnosis and treatment. This review summarizes the application of MOFs in the fields of bio-sensing, cell imaging, in vivo imaging, drug delivery, etc., discusses the problems and corresponding solutions in the application of MOFs for biomedicine. We hope this review can provide reference for the designing new methods for disease diagnosis and treatment.
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Metabolic reprogramming is an important feature of tumor cell metabolism. Glutamine, as a conditionally essential amino acid, provides material and energy for cell growth and maintains the redox homeostasis of tumor cells. This article reviews the role of glutamine in tumorigenesis, development and metastasis, discusses the relationship between glutamine and key biomacromolecules, and provides ideas for finding new targets in cancer therapy.
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Objective@#To understand demand for emergency education among college students and to analyze the influencing factors, to provide the evidence for college to make prevention and controlling measures.@*Methods@#A survey was conducted among college students who were selected by stratified random sampling from 4 colleges in Liaoning Province, and data were analyzed using general descriptive analysis, chi-square test and multivariate Logistic regression analysis.@*Results@#There were 90.7% of college students who had urgent needs for emergency education. Students who were female(93.9%), seniors(94.4%), learning in medical colleges(97.6%), having mothers with higher education levels(92.6%), and living in urban areas(94.4%) had higher educational needs. Multivariate analysis showed that gender (OR=5.00), school category (OR=3.87), emergency attitude (OR=8.02), active learning behavior (OR=3.91), emergency knowledge self-assessment (OR=6.64) were influencing factors(P<0.05).@*Conclusion@#The emergency knowledge and preparation of college students were insufficient and emergency education was needed. The government and schools should strengthen their attention and input, develop more effective ways to disseminate emergency knowledge among students so as to improve their response ability.
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Gold nanoclusters (AuNCs) are gold atom aggregates less than 2 nm (excluding the ligand shell) or 150 atoms. It has been widely studied due to its small size effect, fluorescence property, and catalytic activity. In this review, research progress in the preparation of gold nanoclusters containing accurate atom numbers using biomolecules and chemically synthesized molecules as ligands have been summarized. The factors that affect the preparation of gold nanoclusters have been discussed. The applications of AuNCs having accurate atomic numbers in the fields of analyte assay, catalysis, bioimaging, and drug delivery have been introduced. This review provides references to the further researches on the preparation technology and biomedical applications of AuNCs.
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Mitochondrion is an important organelle in cells and plays a crucial role in tumor development. Therefore, improvement of the targeting ability of anticancer drugs to mitochondria will increase the treatment efficacy for tumor and reduce the side effect on normal tissues. Here, research progresses in mitochondrial targeting have been reviewed in three aspects for tumors treatment: the potential, permeability and translocase of mitochondrial membrane. The review provides a reference for the development of mitochondria targeted therapeutic systems.
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Purpose To study the clinicopathologic characteristics,immunophenotype and Epstein-Barr virus (EBV) infection in infectious mononucleosis (IM),and to enhance the knowledge and diagnosis of the disease.Methods The clinical data,laboratory examination,and lymph nodes biopsy of 9 cases of IM were collected.Immunohistochemistry of EliVision twostep,flow cytometry and EBER in situ hybridization double labeling were studied in 9 cases.Relevant literatures were also reviewed.Results The average age of 9 cases of IM was 22 years old.Patients presented with acute onset,short disease duration,fever,and liver,spleen and lymph node enlargement,and increased abnormal lymphocyte.Also,it was positive in the antiEBV VCA-IgM detection.EBV-DNA copy numbers were all increased.Most WBC counts were increased.Liver function index was abnormal.The ratio of peripheral blood lymphoeytes obviously increased and the ratio of atypical lymphocyte was greater than 10％.Immunophenotype of peripheral blood flow cytometry was characterized by high expression of T cells markers and CD8.CD4 expression was significantly reduced or even not expressed.CD4+/CD8 + ratio was reversed.Lymph nodes were destroyed in different extent and presented mottling without the thickening of the capsule and interstitial fibrous hyperplasia.B cells differentiation spectrum was visible.The lesion cells were mostly CD3-positive cells.CD20,CD30-positive activated cells and immunoblast cells diffused distribution and showed different degrees of strength.The site of EBER in situ hybridization was mainly in T region.Conclusion IM is an EBV-related acute self-limiting lymphoproliferative disease.Taking clinical characteristics,morphology,EBV infection and immunophenotype into considerations will help to correct diagnoses.
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[Objective]To analyze the prognostic factors of resectable acral melanoma patients ,then develop a novel prognostic model and examined its prognostic value.[Methods]The study retrospectively analyzed clinicopathological characteristics and inflam?matory markers of 232 acral melanoma patients who underwent radical surgical resection between 2000 and 2011 at the Sun Yat-sen University Cancer Center. Kaplan-Meier curves were plotted to estimate overall survival. Significantly predictive factors were identified by multivariate Cox regression analyses and a prognostic model based on these variables was constructed to predict survival.[Results]Cox regression analysis revealed that age,lactic dehydrogenase(LDH),stage,globulin(GLB)and C-reactive protein (CRP)were independently related to survival. After computing these scores ,patients were classified into three risk groups. The new prognostic model identified three categories of patients with different prognoses(P<0.001)and significantly stratify patient prognosis in different tumor stages. The 5-year survival rate was 42.9%,25.7%,and 3.7%in groups 1,2,and 3,respectively. The AUC of new prognostic model is 0.664(95%CI:0.599-0.724).[Conclusion]Age,LDH,stage,GLB and CRP were independently related to survival in our study population,and the prognostic model is useful to stratify patients into different risk groups and it is a useful complement to AJCC staging for Asian patients with acral melanoma.
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More than 80% of patients with MM is present as intact monoclonal immunoglobulin (Ig). Usually, the patients with intact immunoglobulin MM (IIMM) show parallel fluctuations of their intact Ig and FLCs or BJP. In the era of novel agents, including thalidomide, lenalidomide and bortezomib, the natural disease development and classic relapse patterns have been changed, the relapse was characterized by an increase in sFLC or BJP without a corresponding increase in paraprotein level, a phenomenon termed "light chain escape", indicates a worse outcome in patients with MM. This review focuses on the mechanism, clinical significance and early diagnosis of light chain escape.
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Polymer-modified gold nanoparticles, which are more stable, less toxic to human body and have improved biocompatibility, have received intensive attention in biomedical applications, which can be used as or construct various therapy agents or carriers in cancer treatment. This review summarizes the current investigation of polymer-modified gold nanoparticles on their cancer treatment applications.
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Objective:To examine the oncogenic mutations involved in melanoma in Southern China and to provide a theoretical basis for the development of melanoma molecular targeted therapy strategy. Methods:The Sequenom platform (OncoCarta Panel v1.0 and MassARRAY System) was used to determine the prevalence of oncogene mutations in 28 acral melanoma samples, 28 mucosal mel-anoma samples, and 30 non-chronic sun-induced-damage (no-CSD) melanoma samples from Southern China. Results:At least one mu-tation was detected in 33 of the 86 melanomas (38.4%) with mutations observed in BRAF (16.3%), NRAS (10.5%), KIT (5.8%), EGFR (4.7%), HRAS (2.3%), KRAS (2.3%), MET (2.3%), and PIK3CA (1.2%). In BRAF, the age of patients with mutations was significantly lower than those without BRAF mutation (45.7±15.3 vs. 55.9±12.7, P=0.01). Patients with mutations in NRAS were more likely to have ulceration compared with patients without NRAS mutations (88.9%vs. 48.1%, P=0.049). Conclusions:This study represents a compre-hensive and concurrent analysis of the major recurrent oncogenic mutations involved in melanoma cases from Southern China areas. The data have implications for both clinical trial designs and therapeutic strategies.
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Inosiplex is a compound formulation composed of inosine and p-acetaminobenzoic acid (PABA) salt of N,N-dimethylamino-2-propanol (DIP). This study was to investigate the clinical plasma pharmacokinetic properties of DIP and PABA after single and multiple oral doses of inosiplex tablets in healthy Chinese volunteers. The established LC/MS/MS method for plasma DIP determination had a linear range of 0.02-10 mg/mL, and the HPLC method for plasma PABA determination had a linear range of 0.05-40 mg/mL. Linear pharmacokinetic characteristics were found with single oral doses of 0.5, 1.0 and 2.0 g. No obvious accumulation effects were observed for DIP and PABA.
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V-erb-a erythroblastic leukemia viral oncogene homolog 4 (ERBB4) has been reported to be somatically mutated in 19% of melanoma cases. To investigate the prevalence of ERBB4 mutations in melanoma patients from southern China, we analyzed 117 formalin-fixed, paraffin-embedded melanoma samples archived in the Sun Yat-sen University Cancer Center. A matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) platform was used to screen for mutations. No ERBB4 hotspot mutations were detected. Our results indicate that ERBB4 mutations may play a limited role in melanomas in China; therefore, targeting the ERBB4 mutation in melanoma patients from southern China may not be a promising strategy.
Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Asian People , Genetics , DNA, Neoplasm , Genetics , Extremities , Melanoma , Genetics , Metabolism , Mucous Membrane , Mutation , Paraffin Embedding , ErbB Receptors , Genetics , Metabolism , Receptor, ErbB-4 , Skin Neoplasms , Genetics , Metabolism , Spectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationABSTRACT
To evaluate the accuracy of detection for screening group A streptococci [GAS] in pediatric clinics using fluorescent in situ hybridization [FISH] and immunochromatographic assay [ICA]. A group of 630 children who attended an outpatient clinic with signs and symptoms of acute upper respiratory tract infection were enrolled in this study. Specimens were collected using a double-swab collection device. Culturing methods were employed as the gold standard for comparison. Discordant results [i.e., positive results for FISH or ICA along with negative culture results] were further evaluated by using Todd-Hewitt broth [THB] with subsequent subculture for group A selective streptococcus agar. True-positive or false-positive of GAS was determined by the presence or absence of THB subculture. The diagnostic characteristics of FISH and ICA were assessed. After discrepant analysis, the sensitivity, specificity and positive and negative predictive values were as follows: 89.2, 100, 100 and 95.4%, respectively, for FISH; corresponding values for ICA were 76.8, 98.6, 96.1 and 90.5%. The results demonstrated that the FISH assay had a higher detection sensitivity than ICA and is suitable for rapid and accurate GAS screening in pediatric clinics
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Although the anti-malaria drug chloroquine (CQ) has been shown to enhance chemotherapy and radiation sensitivity in clinical trials, the potential mechanisms underlying this enhancement are still unclear. Here, we examined the relevant mechanisms by which the multipotent CQ enhanced the cytotoxicity of topotecan (TPT). The lung cancer cell line A549 was treated with TPT alone or TPT combined with CQ at non-cytotoxic concentrations. Cell viability was assessed using the MTT assay. The percentage of apoptotic cells and the presence of a side population of cells were both determined by flow cytometry. Autophagy and the expression of Bcl-2 family proteins were examined by Western blotting. The accumulation of YFP-LC3 dots and the formation of acidic vesicular organelles were examined by confocal microscopy. CQ sensitized A549 cells to TPT and enhanced TPT-induced apoptosis in a Bcl-2 family protein-independent fashion. CQ inhibited TPT-induced autophagy, which modified the cytotoxicity of TPT. However, CQ failed to modify the transfer of TPT across the cytoplasmic membrane and did not increase lysosomal permeability. This study showed that CQ at non-cytotoxic concentrations potentiated the cytotoxicity of TPT by interfering with autophagy, implying that CQ has significant potential as a chemotherapeutic enhancer.
Subject(s)
Humans , Apoptosis , Apoptosis Regulatory Proteins , Metabolism , Autophagy , Bcl-2-Like Protein 11 , Cell Line, Tumor , Cell Proliferation , Chloroquine , Pharmacology , Drug Synergism , Lung Neoplasms , Metabolism , Pathology , Membrane Proteins , Metabolism , Proto-Oncogene Proteins , Metabolism , Proto-Oncogene Proteins c-bcl-2 , Metabolism , Topoisomerase I Inhibitors , Pharmacology , Topotecan , Pharmacology , bcl-2-Associated X Protein , MetabolismABSTRACT
Objective: To observe the tolerability of Chinese melanoma patients to four-week high-dose interferon alfa-2b(INTRON A(R)，Schering-Plough)therapy. Methods:A total of 29 patients with high risk melanoma[American Joint Committee on Cancer Staging(AJCC)ⅡB-ⅢC]who received adjuvant interferon therapy in our hospital between September 2007 and May 2009 were retrospectively reviewed.Patients received 4 hours of intravenous infusion of interferon alfa-2b fdose range，22.00 million international unit(MIU)to 33.75 MIU]Ⅳ 5 days/week for 4 weeks.The adverse events were evaluated with National Cancer Institute Common Toxicity Criteria(NCI 2.0 version). Results: The average daily dose was 17.63 MIU/(m~2·d).The therapy was ended in two patients because of poor wound healing or intolerability to severe fatigue.The most common adverse events were myelosuppression.Grade 3/4 neutropenia was observed in 69% (20/29)patients and was rapidly reversed after conventional support interventions.Grade 1/2 abnormal hepatic function occurred in 18 cases(62%).Twenty-six patients were followed up for 3 to 22 months.Five patients developed early progression:one with local recurrence，two with regional lymph node metastasis one with in-transit metastasis in the affected limb,and one with distant metastasis. Conclusion: High-dose interferon alfa-2b regimen can be well tolerated by Chinese patients but cannot effectively inhibit subclinical lesions.
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AIM: Recombinant human adenovirus-p53 injection (rAd-p53) is the first marketed gene therapeutic drug worldwide. This study aimed to evaluate the safety and primary efficacy of rAd-p53 administrated on advanced solid tumors. METHODS: 24 patients with advanced solid tumor treated with rAd-p53 were reviewed, including 5 cases of renal carcinoma, 4 of nasopharyngeal carcinoma, 4 of colorectal carcinoma, 2 of melanoma, 1 of non-small-celllung cancer, 1 of esophageal carcinoma, 1 of gastric cardia carcinoma, 1 of thymic carcinoma, 1 of duodenal carcinoma, 1 of thyroid carcinoma, 1 of pancreatic carcinoma, 1 of endometrial carcinoma and 1 of rhabdomyosarcoma. RAd-p53 was weekly administrated at the dose of 1?10~ 12 VP, and 4 times of administration was defined as one cycle. Administration approach included intratumoral injection,intrabronchial drop in, intraperitoneal injection, intra-arterial infusion and intravenous drip. Combined therapy was given with chemotherapy in 18 cases, radiotherapy in 2, concomitant chemotherapy and radiotherapy in 1, abdominal thermotherapy and orally gefitinib in 1, cytokine immunotherapy in 1 and without combination therapy in 1. RESULTS: 23 cases underwent 35 cycles of therapy except for 1 case discontinued because of early progression. Among the 21 evaluable cases 5 PR, 5 SD and 11 PD were observed. Overall response rate was 23.8%(5/21) and disease control rate was 47.6%(10/21). Grade I-II injection site pain, chill, fever and myalgia were the most frequent side effects. Grade III fever developed in 2 cases and grade III-IV myelosuppression in 4 cases combined with chemotherapy. Furthermore, severe ostealgia occurred in 2 cases and transient hypotension in 1. CONCLUSION: RAd-p53 is tolerable in patients with advanced solid tumor. A further randomized clinical trial is necessary to confirm the antitumor activity of rAd-p53 combined with conventional strategies.