Publications by authors named "Xiaohui Wei"

89 Publications

Peptidomes and Structures Illustrate Two Distinguishing Mechanisms of Alternating the Peptide Plasticity Caused by Swine MHC Class I Micropolymorphism.

Front Immunol 2021 26;12:592447. Epub 2021 Feb 26.

Department of Microbiology and Immunology, College of Veterinary Medicine, China Agricultural University, Beijing, China.

The micropolymorphism of major histocompatibility complex class I (MHC-I) can greatly alter the plasticity of peptide presentation, but elucidating the underlying mechanism remains a challenge. Here we investigated the impact of the micropolymorphism on peptide presentation of swine MHC-I (termed swine leukocyte antigen class I, SLA-I) molecules immunopeptidomes that were determined by our newly developed random peptide library combined with the mass spectrometry (MS) sequencing method (termed RPLD-MS) and the corresponding crystal structures. The immunopeptidomes of SLA-1*04:01, SLA-1*13:01, and their mutants showed that mutations of residues 156 and 99 could expand and narrow the ranges of peptides presented by SLA-I molecules, respectively. R156A mutation of SLA-1*04:01 altered the charge properties and enlarged the volume size of pocket D, which eliminated the harsh restriction to accommodate the third (P3) anchor residue of the peptide and expanded the peptide binding scope. Compared with 99 of SLA-1*0401, 99 of SLA-1*13:01 could not form a conservative hydrogen bond with the backbone of the P3 residues, leading to fewer changes in the pocket properties but a significant decrease in quantitative of immunopeptidomes. This absent force could be compensated by the salt bridge formed by P1-E and 170. These data illustrate two distinguishing manners that show how micropolymorphism alters the peptide-binding plasticity of SLA-I alleles, verifying the sensitivity and accuracy of the RPLD-MS method for determining the peptide binding characteristics of MHC-I and helping to more accurately predict and identify MHC-I restricted epitopes.
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http://dx.doi.org/10.3389/fimmu.2021.592447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952875PMC
February 2021

The Crystal Structure of the MHC Class I (MHC-I) Molecule in the Green Anole Lizard Demonstrates the Unique MHC-I System in Reptiles.

J Immunol 2021 Apr 26;206(7):1653-1667. Epub 2021 Feb 26.

Department of Microbiology and Immunology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China

The reptile MHC class I (MCH-I) and MHC class II proteins are the key molecules in the immune system; however, their structure has not been investigated. The crystal structure of green anole lizard peptide-MHC-I-β2m (pMHC-I or p-UA*0101) was determined in the current study. Subsequently, the features of p-UA*0101 were analyzed and compared with the characteristics of pMHC-I of four classes of vertebrates. The amino acid sequence identities between -UA*0101 and MHC-I from other species are <50%; however, the differences between the species were reflected in the topological structure. Significant characteristics of p-UA*0101 include a specific flip of ∼88° and an upward shift adjacent to the C terminus of the α1- and α2-helical regions, respectively. Additionally, the lizard MHC-I molecule has an insertion of 2 aa (VE) at positions 55 and 56. The pushing force from 55-56VE triggers the flip of the α1 helix. Mutagenesis experiments confirmed that the 55-56VE insertion in the α1 helix enhances the stability of p-UA*0101. The peptide presentation profile and motif of p-UA*0101 were confirmed. Based on these results, the proteins of three reptile lizard viruses were used for the screening and confirmation of the candidate epitopes. These data enhance our understanding of the systematic differences between five classes of vertebrates at the gene and protein levels, the formation of the pMHC-I complex, and the evolution of the MHC-I system.
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http://dx.doi.org/10.4049/jimmunol.2000992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980529PMC
April 2021

Effect of the ammonium salt anion on the structure of doxorubicin complex and PEGylated liposomal doxorubicin nanodrugs.

Biochim Biophys Acta Gen Subj 2021 May 15;1865(5):129849. Epub 2021 Jan 15.

Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; The Center for Nanoscience and Nanotechnology of the Hebrew University of Jerusalem, Jerusalem, Israel. Electronic address:

Background: In Doxil®, PEGylated nanoliposomes are created by hydration of the lipids in ammonium sulfate, and are remotely loaded with doxorubicin by a transmembrane ammonium gradient. The ammonium sulfate is then removed from the external aqueous phase, surrounding the liposomes, and replaced by an isoosmotic sucrose solution in 10 mM histidine buffer at pH 6.5.

Methods: We prepared PEGylated liposomal doxorubicin (PLD) with a series of ammonium monovalent salts that after remote loading became the intraliposome doxorubicin counteranions. We analyzed the liposomes by solution X-ray scattering, differential scanning calorimetry, and electron micropscopy.

Results: PLDs prepared with sulfonic acid derivatives as counteranion exhibited chemical and physical stabilities. We determined the effect of these ammonium salt counteranions on the structure, morphology, and thermotropic behavior of the PEGylated nanoliposomes, formed before and after doxorubicin loading, and the bulk properties of the doxorubicin-counteranion complexes. By comparing the structure of the doxorubicin complexes in the bulk and inside the nanoliposomes, we revealed the effect of confinement on the structure and doxorubicin release rate for each of the derivatives of the ammonium sulfonic acid counteranions.

Conclusions: We found that the extent and direction of the doxorubicin confinement effect and its release rate were strongly dependent on the type of counteranion. The counteranions, however, neither affected the structure and thermotropic behavior of the liposome membrane, nor the thickness and density of the liposome PEG layers. In an additional study, it was demonstrated that PLD made with ammonium-methane sulfonate exhibit a much lower Hand and Foot syndrome.

General Significance: The structure, physical state, and pharmacokinetics of doxorubicin in PEGylated nanoliposomes, prepared by transmembrane remote loading using gradients of ammonium salts, strongly depend on the counteranions.
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http://dx.doi.org/10.1016/j.bbagen.2021.129849DOI Listing
May 2021

Long Non-Coding RNA LINC02747 Promotes the Proliferation of Clear Cell Renal Cell Carcinoma by Inhibiting miR-608 and Activating TFE3.

Front Oncol 2020 23;10:573789. Epub 2020 Dec 23.

Department of Urinary Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China.

With the rapid development of biotechnology, long noncoding RNAs (lncRNAs) have exhibited good application prospects in the treatment of cancer, and they may become new treatment targets for cancer. This study aimed to explore lncRNAs in clear cell renal cell carcinoma (ccRCC). Differentially expressed lncRNAs in 54 pairs of ccRCC tissues and para-carcinoma tissues were analyzed in The Cancer Genome Atlas (TCGA), and the most significant lncRNAs were selected and verified in ccRCC tissues. We found that lncRNA LINC02747 was highly expressed in ccRCC ( < 0.001) and was closely related to high TNM stage ( = 0.006) and histological grade ( = 0.004) and poor prognosis of patients ( < 0.001). In vivo and experiments confirmed that LINC02747 could promote the proliferation of ccRCC cells. We also found that LINC02747 regulated the proliferation of RCC cells by adsorbing miR-608. Subsequent mechanistic research showed that miR-608 is downregulated in ccRCC ( < 0.001), and overexpression of miR-608 inbibited the proliferation of RCC cells. Moreover, we found that TFE3 is a direct target gene of miR-608. MiR-608 regulated the proliferation of RCC cells by inhibiting TFE3. In conclusion, LINC02747 upregulates the expression of TFE3 by adsorbing miR-608, ultimately promoting the proliferation of ccRCC cells. The above findings indicate that LINC02747 acts as an oncogene in ccRCC and may be developed as a molecular marker for the diagnosis and prognosis of ccRCC. The LINC02747/miR-608/TFE3 pathway may become a new therapeutic target for ccRCC.
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http://dx.doi.org/10.3389/fonc.2020.573789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786277PMC
December 2020

US Food and Drug Administration (FDA): Benefit-Risk Considerations for Cefiderocol (Fetroja®).

Clin Infect Dis 2020 Dec 2. Epub 2020 Dec 2.

Division of Anti-Infectives, Office of Infectious Diseases, Center for Drug Evaluation and Research, US Food and Drug Administration (FDA), Silver Spring, Maryland, USA.

In November 2019, the Food and Drug Administration (FDA) approved cefiderocol for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by susceptible gram-negative bacteria in adults with limited to no alternative treatment options based on a randomized, double-blind, noninferiority cUTI trial (APEKS-cUTI). In a randomized, open-label trial (CREDIBLE-CR) in patients with cUTI, nosocomial pneumonia, bloodstream infections, or sepsis due to carbapenem-resistant gram-negative bacteria, an increase in all-cause mortality was observed in patients treated with cefiderocol as compared to best available therapy. The cause of the increased mortality was not established, but some deaths were attributed to treatment failure. Preliminary data from a randomized, double-blind trial (APEKS-NP) in patients with nosocomial pneumonia due to carbapenem-susceptible gram-negative bacteria showed a similar rate of mortality as compared to meropenem. We describe the uncertainties and challenges in the interpretation of the CREDIBLE-CR trial and some benefit-risk considerations for the use of cefiderocol in clinical practice.

Clinical Trials Registration: NCT02714595.
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http://dx.doi.org/10.1093/cid/ciaa1799DOI Listing
December 2020

A Co-Design-Based Reliable Low-Latency and Energy-Efficient Transmission Protocol for UWSNs.

Sensors (Basel) 2020 Nov 8;20(21). Epub 2020 Nov 8.

Department of Computer and Information Sciences, Temple University, Philadelphia, PA 19122, USA.

Recently, underwater wireless sensor networks (UWSNs) have been considered as a powerful technique for many applications. However, acoustic communications in UWSNs bring in huge QoS issues for time-critical applications. Additionally, excessive control packets and multiple copies during the data transmission process exacerbate this challenge. Faced with these problems, we propose a reliable low-latency and energy-efficient transmission protocol for dense 3D underwater wireless sensor networks to improve the QoS of UWSNs. The proposed protocol exploits fewer control packets and reduces data-packet copies effectively through the co-design of routing and media access control (MAC) protocols. The co-design method is divided into two steps. First, the number of handshakes in the MAC process will be greatly reduced via our forwarding-set routing strategy under the guarantee of reliability. Second, with the help of information from the MAC process, network-update messages can be used to replace control packages through mobility prediction when choosing a route. Simulation results show that the proposed protocol has a considerably higher reliability, and lower latency and energy consumption in comparison with existing transmission protocols for a dense underwater wireless sensor network.
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http://dx.doi.org/10.3390/s20216370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664662PMC
November 2020

Controlled release of monodisperse silver nanoparticles via in situ cross-linked polyvinyl alcohol as benign and antibacterial electrospun nanofibers.

Colloids Surf B Biointerfaces 2021 Jan 28;197:111370. Epub 2020 Sep 28.

Institute of Medical Support, Academy of Military Sciences, Tianjin, 300161, China. Electronic address:

A facile methodology was explored by using glutaraldehyde as a cross-linking reagent for in situ modification of polyvinyl alcohol (PVA) electrospun nanofibers doped with monodisperse silver nanoparticles (AgNPs) via the one-pot reactions. The hydroxyl groups along the PVA molecule chains can serve as both the reactive sites and stabilizers for AgNPs. Meanwhile, the cross-linking degree can be easily tuned by controlling the charged amounts of glutaraldehyde to obtain either partial or cured cross-linked PVA nanofibrous mats doped with AgNPs. It was revealed that such different cross-linking degrees could effectively control the release contents and rates of the embedded Ag to the surrounding aqueous solution. Furthermore, such release behavior was also found to be pH-responsive and acid-labile due to the formation of acetal groups during the cross-linking reactions. Besides both the partial and cured cross-linked PVA doped with Ag nanoparticles can still bear good antibacterial efficacy against S. aureus while have low cytotoxicity against mouse embryo fibroblasts (NIH3T3), human embryonic kidney cells (293T) and human histiocytic lymphoma cells (U937).
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http://dx.doi.org/10.1016/j.colsurfb.2020.111370DOI Listing
January 2021

Clinical Characteristics of Six Cases of Tracheobronchopathia Osteochondroplastica.

Can Respir J 2020 16;2020:8685126. Epub 2020 Jun 16.

People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China.

Objective: To investigate the clinical characteristics of tracheobronchopathia osteochondroplastica (TO).

Methods: The clinical data of six patients with TO from November 2016 to November 2018 were retrospectively analyzed. The etiology, clinical manifestations, diagnosis, and treatment of TO were summarized.

Result: All six patients with TO were middle-aged males, confirmed by histopathological examination. The main clinical symptoms were cough, sputum, hemoptysis, chest pain, and repeated pulmonary infection. Some patients could make a preliminary diagnosis by chest CT, and bronchoscopy showed that TO mainly occurred in the trachea and the main bronchus and was more likely to invade the right bronchus. The treatment mainly includes anti-infection, phlegm-resolving, and other symptomatic treatment.

Conclusion: TO is a benign disease predisposing to adults, and males are more likely to be affected. Its clinical manifestations are lack of specificity, and the cause may be related to chronic infection. Bronchoscopy combined with histopathological examination is the primary approach for the diagnosis of TO. There is no well-recognized treatment standard for TO, and the judgment of therapeutic effect is inconsistent. It is necessary to improve the understanding of this disease from a clinical perspective.
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http://dx.doi.org/10.1155/2020/8685126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315312PMC
June 2020

Semimechanistic Modeling of Eravacycline Pharmacodynamics Using Time-Kill Data with MIC Incorporated in an Adaptive Resistance Function.

Antimicrob Agents Chemother 2020 08 20;64(9). Epub 2020 Aug 20.

Division of Infectious Disease Pharmacology, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, USA

Effective bacterial infection eradication requires not only potent antibacterial agents but also proper dosing strategies. Current practices generally utilize point estimates of the effects of therapeutic agents, even though the actual kinetics of exposure are much more complex and relevant. Here, we use a full time course of the observed effects to develop a semimechanistic pharmacokinetic-pharmacodynamic model for eravacycline against multiple Gram-negative bacterial pathogens. This model incorporates components such as pharmacokinetics, bacterial life cycle, and drug effects to quantitatively describe the time course of antibacterial killing and the emergence of resistance. Model discrimination was performed by comparing goodness of fit, convergence diagnostics, and objective function values. Models were validated by assessing their abilities to describe bacterial count time courses in visual predictive checks. The final model describes 576 bacterial counts (expressed in log CFU per milliliter) from 144 time-kill experiments with low residual error and high precision. We characterize antibacterial susceptibility as a function of the MIC and adaptive resistance. In doing so, we show that the MIC is proportional to initial susceptibility at 0 h and the development of resistance over the course of 16 h. Altogether, this model may be useful in supporting dose selection, since it incorporates pharmacodynamics and clinically observed individual drug susceptibilities.
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http://dx.doi.org/10.1128/AAC.01308-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449204PMC
August 2020

N -Methyladenosine Reader Protein YT521-B Homology Domain-Containing 2 Suppresses Liver Steatosis by Regulation of mRNA Stability of Lipogenic Genes.

Hepatology 2021 Jan 25;73(1):91-103. Epub 2020 Oct 25.

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China.

Background And Aims: Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of excessive triglycerides (TGs) in hepatocytes. Obesity is a major risk factor for developing fatty liver, although the intracellular molecular basis remains largely unclear. N -methyladenosine (m A) RNA methylation is the most common internal modification in eukaryotic mRNA.

Approach And Results: In the present study, by m A sequencing and RNA sequencing, we found that both m A enrichment and mRNA expression of lipogenic genes were significantly increased in leptin-receptor-deficient db/db mice. Importantly, our results showed that YT521-B homology domain-containing 2 (Ythdc2), an m A reader, was markedly down-regulated in livers of obese mice and NAFLD patients. Suppression of Ythdc2 in livers of lean mice led to TG accumulation, whereas ectopic overexpression of Ythdc2 in livers of obese mice improved liver steatosis and insulin resistance. Mechanistically, we found that Ythdc2 could bind to mRNA of lipogenic genes, including sterol regulatory element-binding protein 1c, fatty acid synthase, stearoyl-CoA desaturase 1, and acetyl-CoA carboxylase 1, to decrease their mRNA stability and inhibit gene expression.

Conclusions: Our findings describe an important role of the m A reader, Ythdc2, for regulation of hepatic lipogenesis and TG homeostasis, which might provide a potential target for treating obesity-related NAFLD.
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http://dx.doi.org/10.1002/hep.31220DOI Listing
January 2021

Evaluation of Hemodialysis Effect on Pharmacokinetics of Meropenem/Vaborbactam in End-Stage Renal Disease Patients Using Modeling and Simulation.

J Clin Pharmacol 2020 08 9;60(8):1011-1021. Epub 2020 Mar 9.

Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Springs, Maryland, USA.

The objectives of this study were to evaluate the effect of hemodialysis (HD) on the pharmacokinetics (PK) of meropenem/vaborbactam, an approved beta-lactam/beta-lactamase inhibitor combination, and provide the rationale for the recommended timing of meropenem/vaborbactam administration relative to HD in end-stage renal disease (ESRD) patients. Population PK models were developed separately for meropenem and vaborbactam in subjects with normal renal function and different degrees of renal impairment, including those receiving HD. Simulations were performed to evaluate the exposure of meropenem and vaborbactam in ESRD patients who received a fixed dose of 0.5 g/0.5 g meropenem/vaborbactam every 12 hours as a 3-hour intravenous infusion under various drug administration schedules relative to HD. The probability of target attainment (PTA) analyses were conducted with pharmacokinetic/pharmacodynamic (PK/PD) targets of meropenem and vaborbactam. Simulations showed that HD reduces the accumulation of vaborbactam, but the exposure of vaborbactam is still above the PK/PD target regardless of whether meropenem/vaborbactam is administered predialysis or postdialysis. For meropenem, drug infusion completed right prior to initiation of HD may substantially reduce exposure leading to poor PTA results. In contrast, drug infusion completed at least 2 hours prior to initiation of HD is not predicted to result in efficacy loss based on PTA analysis. The results of simulation indicate that meropenem/vaborbactam infusion completed at least 2 hours prior to initiation of HD or administered immediately after the end of HD can avoid potential efficacy loss in ESRD patients.
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http://dx.doi.org/10.1002/jcph.1595DOI Listing
August 2020

Illumination of PRRSV Cytotoxic T Lymphocyte Epitopes by the Three-Dimensional Structure and Peptidome of Swine Lymphocyte Antigen Class I (SLA-I).

Front Immunol 2019 8;10:2995. Epub 2020 Jan 8.

Department of Microbiology and Immunology, College of Veterinary Medicine, China Agricultural University, Beijing, China.

To investigate CTL epitope applications in swine, SLA-11502-restricted peptide epitopes matching porcine reproductive and respiratory syndrome virus (PRRSV) strains were explored by crystallography, biochemistry, and the specific pathogen-free (SPF) swine experiments. First, nine predicted PRRSV peptides were tested by assembly of the peptide-SLA-11502 (pSLA-11502) complexes, and the crystal structure of the SLA-11502 complex with one peptide (NSP9-TMP9) was determined. The NSP9-TMP9 peptide conformation presented by pSLA-11502 is different from that of the peptides presented by the known pSLA-10401 and pSLA-3hs0202 complexes. Two consecutive Pro residues make the turn between P3 and P4 of NSP9-TMP9 much sharper. The D pocket of pSLA-11502 is unique and is important for peptide binding. Next, the potential SLA-11502-restricted peptide epitopes matching four typical genetic PRRSV strains were identified based on the peptide-binding motif of SLA-11502 determined by structural analysis and alanine scanning of the NSP9-TMP9 peptide. The tetrameric complex of SLA-11502 and NSP9-TMP9 was constructed and examined. Finally, taking NSP9-TMP9 as an example, the CTL immunogenicity of the identified PRRSV peptide epitope was evaluated. The SPF swine expressing the SLA-11502 alleles were divided into three groups: modified live vaccine (MLV), MLV+NSP9-TMP9, and the blank control group. NSP9-TMP9 was determined as a PRRSV CTL epitope with strong immunogenicity by flow cytometry and IFN-γ expression. Our study developed an integrated approach to identify SLA-I-restricted CTL epitopes from various important viruses and is helpful in designing and applying effective peptide-based vaccines for swine.
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http://dx.doi.org/10.3389/fimmu.2019.02995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960135PMC
November 2020

Solubilization and delivery of Ursolic-acid for modulating tumor microenvironment and regulatory T cell activities in cancer immunotherapy.

J Control Release 2020 04 8;320:168-178. Epub 2020 Jan 8.

School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China; School of Pharmacy and Chemistry, Dali University, China. Electronic address:

Ursolic acid (UA) is a potent triterpenoid compound found in plants and fruits with activities modulating key cell signaling pathways involving STATs, NF-κB, and TRAIL. But it's highly hydrophobic and very poorly soluble in nature. It had been prepared as nanocrystals, solid dispersion and loaded in nanoparticles but the achieved systemic exposure and circulation half-life were not ideal. We reported the development of UA-liposomes made by HPβCD assisted active loading. Compared to lipid suspensions of UA (Lipid-UA) with similar lipid composition, the novel process enabled the formation of UA-Ca crystalline structures inside the liposomes and therefore sustained release of UA in vivo. While the UA-liposomes were not generally toxic towards 4T1 triple negative breast cancer cells, they could effectively modulate CD4CD25Foxp3 T cells from 4T1 tumor bearing mouse by inhibiting STAT5 phosphorylation and IL-10 secretion. In vivo administration of UA-liposomes at 10 mg/kg dose led to reduced numbers of myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs) residing in tumor tissues. These changes signified the correction of the tumor mediated immune-suppressive microenvironment. The UA-liposomes treatment alone was already effective in deterring tumor growth. Such a formulation may be highly promising as an immunotherapy agent and be combined with chemotherapeutics or targeted drugs.
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http://dx.doi.org/10.1016/j.jconrel.2020.01.015DOI Listing
April 2020

Self-Illuminating Photodynamic Therapy with Enhanced Therapeutic Effect by Optimization of the Chemiluminescence Resonance Energy Transfer Step to the Photosensitizer.

Bioconjug Chem 2020 03 8;31(3):595-604. Epub 2020 Jan 8.

Institute of Medical Support Technology, Academy of Military Sciences, Tianjin 300161, China.

The major obstacles to the wider application of photodynamic therapy (PDT) are drawbacks of the current photosensitizers and the tissue penetration limit of the common outer light source. In the present study, the chemiluminescence (CL) from the luminol-HO-horseradish peroxidase reaction was explored as a potential inner light source for the intracellular activation of carbon dots (CDs)-based PDT system. To fully use the light and enhance the overall PDT yield, the nanocarrier of CDs, the light of CL, and the PDT agent chlorin e6 (Ce6) were carefully selected and designed to form an efficient and united system. Bright-yellow-emissive CDs (y-CDs) were synthesized through purposeful regulation of the absorption and emission spectra to enhance the overlapping areas in the chemiluminescence resonance energy transfer (CRET) and fluorescence resonance energy transfer (FRET) processes. Our results reflected CL-induced y-CDs-Ce6 system (10 μM) successfully generated reactive oxygen species (ROS, 35.93%), killed ∼90% SMMC-7721 cells in vitro, and significantly delayed tumor growth in vivo. On the basis of immunohistochemical observations of proliferating cell nuclear antigen (PCNA) and platelet/endothelial cell adhesion molecule-1 (PECAM-1 or CD31) results, we concluded that the CL-induced y-CDs-Ce6 system had excellent performance in cancer therapy. The enhanced therapeutic effect was ascribed to two pathways: a direct CRET process and another process of CRET with subsequent y-CD-mediated FRET (CRET-to-FRET).
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00740DOI Listing
March 2020

Upregulated expression of eIF3C is associated with malignant behavior in renal cell carcinoma.

Int J Oncol 2019 Dec 21;55(6):1385-1395. Epub 2019 Oct 21.

Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, P.R. China.

Eukaryotic initiation factor 3c (eIF3C) is involved in the initiation of protein translation. Aberrant eIF3C expression has been reported in different types of human cancer. The present study aimed to assess the role of eIF3C in the malignant behavior of renal cell carcinoma in vitro and in vivo. eIF3C expression was assessed in 16 pairs of renal cell carcinoma (RCC) and matched distant normal tissues, and in RCC cell lines using immunohistochemistry. Subsequently, eIF3C was depleted using lentiviral short hairpin RNA and cell proliferation, cell cycle distribution and apoptosis of these eIF3C‑depleted cells were examined. Additionally, tumor cell xenograft assays in nude mice, Affymetrix microarrays and ingenuity pathway analyses were performed. eIF3C expression was upregulated in RCC tissues and cell lines. Depletion of eIF3C reduced tumor cell proliferation and arrested them at the G1 stage, thus promoting their apoptosis in vitro. Depletion of eIF3C also inhibited the formation and growth of tumor cell xenografts in nude mice. In addition, depletion of eIF3C altered the expression levels of 994 differentially expressed genes in RCC cells (516 genes were upregulated and 478 genes were downregulated). The expression levels of phosphorylated‑AKT, c‑JUN and NFKB inhibitor α were lower in the shorth hairpin RNA eIF3C‑transfected RCC cells compared with in the control group. In conclusion, the present study demonstrated that upregulated eIF3C expression contributed to the development and progression of RCC. Future studies should further evaluate whether eIF3C could be used as a potential strategy for RCC targeting therapy.
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http://dx.doi.org/10.3892/ijo.2019.4903DOI Listing
December 2019

Untargeted metabolomic analysis of the carotenoid-based orange coloration in Haliotis gigantea using GC-TOF-MS.

Sci Rep 2019 10 10;9(1):14545. Epub 2019 Oct 10.

State Key Laboratory of Marine Environmental Science, Xiamen, 361002, China.

Seafood coloration is typically considered an indicator of quality and nutritional value by consumers. One such seafood is the Xishi abalone (Haliotis gigantea), which displays muscle color polymorphism wherein a small subset of individuals display orange coloration of muscles due to carotenoid enrichment. However, the metabolic basis for carotenoid accumulation has not been thoroughly investigated in marine mollusks. Here, GC-TOF-MS-based untargeted metabolite profiling was used to identify key pathways and metabolites involved in differential carotenoid accumulation in abalones with variable carotenoid contents. Cholesterol was the most statistically significant metabolite that differentiated abalones with orange muscles against those with common white muscles. This observation is likely due to the competitive interactions between cholesterol and carotenoids during cellular absorption. In addition, the accumulation of carotenoids was also related to fatty acid contents. Overall, this study indicates that metabolomics can reflect physiological changes in organisms and provides a useful framework for exploring the mechanisms underlying carotenoid accumulation in abalone types.
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http://dx.doi.org/10.1038/s41598-019-51117-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787195PMC
October 2019

The Delivery of a Wnt Pathway Inhibitor Toward CSCs Requires Stable Liposome Encapsulation and Delayed Drug Release in Tumor Tissues.

Mol Ther 2019 09 5;27(9):1558-1567. Epub 2019 Jul 5.

Pharmacy School, Shanghai Jiaotong University, Shanghai 200240, China. Electronic address:

The Wnt signaling pathway is involved in tumorigenesis and various stages of tumor progression, including the epithelial-mesenchymal transition, metastasis, and drug resistance. Many efforts have been made to develop drugs targeting this pathway. CGX1321 is a porcupine inhibitor that can effectively block Wnt ligand synthesis and is currently undergoing clinical trials. However, drugs targeting the Wnt pathway may frequently cause adverse events in normal tissues, such as the intestine and skin. Formulation of the drug inside liposomes could enable preferential drug delivery to solid tumor tissues and limit drug exposure in normal organs. We developed a strategy to stably encapsulate CGX1321 inside liposomes with minimal drug releases in circulation. The liposomal drugs were shown to interfere with the aberrant Wnt signaling specifically in tumor tissues, resulting in focused effects on LGR5 CSCs (cancer stem cells), while sparing other cells from significant cytotoxicity. We showed it is feasible to use such a CSC elimination approach to treat malignant cancers prone to rapid progression using a LoVo tumor model as well as a GA007 patient derived xenograft (PDX) model. Nano drug delivery systems may be required for precision medicine in cancer therapy.
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http://dx.doi.org/10.1016/j.ymthe.2019.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732336PMC
September 2019

Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling.

Cell Commun Signal 2019 06 6;17(1):58. Epub 2019 Jun 6.

Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, No.24, Tongjiaxiang, Nanjing, China.

Background: Breast cancer cells recruit surrounding stromal cells, such as cancer-associated fibroblasts (CAFs), to remodel collagen and promote tumor metastasis. Adipocytes are the most abundant stromal partners in breast tissue, local invasion of breast cancer leads to the proximity of cancer cells and adipocytes, which respond to generate cancer-associated adipocytes (CAAs). These cells exhibit enhanced secretion of extracellular matrix related proteins, including collagens. However, the role of adipocyte-derived collagen on breast cancer progression still remains unclear.

Methods: Adipocytes were cocultured with breast cancer cells for 3D collagen invasion and collagen organization exploration. Breast cancer cells and adipose tissue co- implanted mouse model, clinical breast cancer samples analysis were used to study the crosstalk between adipose and breast cancer cells in vivo. A combination of proteomics, enzyme-linked immunosorbent assay, loss of function assay, qPCR, western blot, database analysis and chromatin immunoprecipitation assays were performed to study the mechanism mediated the activation of PLOD2 in adipocytes.

Results: It was found that CAAs remodeled collagen alignment during crosstalk with breast cancer cells in vitro and in vivo, which further promoted breast cancer metastasis. Tumor-derived PAI-1 was required to activate the expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in CAAs. Pharmacologic blockade of PAI-1 or PLOD2 disrupted the collagen reorganization in CAAs. Mechanistically, it was observed that PI3K/AKT pathway was activated in adipocytes upon co-culturing with breast cancer cells or treatment with recombinant PAI-1, which could promote the translocation of transcription factor FOXP1 into the nucleus and further enhanced the promoter activity of PLOD2 in CAAs. In addition, collagen reorganization at the tumor-adipose periphery, as well as the positive relevance between PAI-1 and PLOD2 in invasive breast carcinoma were confirmed in clinical specimens of breast cancer.

Conclusion: In summary, our findings revealed a new stromal collagen network that favors tumor invasion and metastasis establish between breast cancer cells and surrounding adipocytes at the tumor invasive front, and identified PLOD2 as a therapeutic target for metastatic breast cancer treatment.
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http://dx.doi.org/10.1186/s12964-019-0373-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554964PMC
June 2019

Structure and Peptidome of the Bat MHC Class I Molecule Reveal a Novel Mechanism Leading to High-Affinity Peptide Binding.

J Immunol 2019 06 10;202(12):3493-3506. Epub 2019 May 10.

Department of Microbiology and Immunology, College of Veterinary Medicine, China Agricultural University, Haidian District, Beijing 100094, China;

Bats are natural reservoir hosts, harboring more than 100 viruses, some of which are lethal to humans. The asymptomatic coexistence with viruses is thought to be connected to the unique immune system of bats. MHC class I (MHC I) presentation is closely related to cytotoxic lymphocyte immunity, which plays an important role in viral resistance. To investigate the characteristics of MHC I presentation in bats, the crystal structures of peptide-MHC I complexes of , Ptal-N*01:01/HEV-1 (DFANTFLP) and Ptal-N*01:01/HEV-2 (DYINTNLVP), and two related mutants, Ptal-N*01:01/HEV-1 (DFANTFLL) and Ptal-N*01:01/HEV-1, were determined. Through structural analysis, we found that Ptal-N*01:01 had a multi-Ala-assembled pocket B and a flexible hydrophobic pocket F, which could accommodate variable anchor residues and allow Ptal-N*01:01 to bind numerous peptides. Three sequential amino acids, Met, Asp, and Leu, absent from the α1 domain of the H chain in other mammals, were present in this domain in the bat. Upon deleting these amino acids and determining the structure in p/Ptal-N*01:01/HEV-1, we found they helped form an extra salt-bridge chain between the H chain and the N-terminal aspartic acid of the peptide. By introducing an MHC I random peptide library for de novo liquid chromatography-tandem mass spectrometry analysis, we found that this insertion module, present in all types of bats, can promote MHC I presentation of peptides with high affinity during the peptide exchange process. This study will help us better understand how bat MHC I presents high-affinity peptides from an extensive binding peptidome and provides a foundation to understand the cellular immunity of bats.
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http://dx.doi.org/10.4049/jimmunol.1900001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545463PMC
June 2019

DT-13 suppresses breast cancer metastasis by modulating PLOD2 in the adipocytes microenvironment.

Phytomedicine 2019 Jun 2;59:152778. Epub 2018 Dec 2.

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China. Electronic address:

Background: Metastasis is the main cause of death in breast cancer and previous researches have indicated the pivotal role of adipocytes in breast cancer metastasis. DT-13, the saponin monomer 13 of the Dwarf lilyturf tuber, has been proved to exert potential anti-metastatic effect, the detailed mechanisms have not been well elucidated and the role of DT-13 in modulating adipocyte-breast cancer microenvironment has been given little attention.

Purpose: This study aims to explore the mechanisms of DT-13 in inhibiting breast cancer metastasis and whether DT-13 inhibit breast cancer metastasis via modulating the interactions between adipocytes and breast cancer cells.

Methods: The cytotoxic effect of DT-13 on breast cancer cell viability was detected by MTT assay. Migration assays was used to conduct the effect of DT-13 on breast cancer cells migration. Orthotopic xenograft tumor model was used to test the effect of DT-13 on breast cancer metastasis. qRT-PCR and Western blot were used to investigate the mechanisms of DT-13 inhibiting breast cancer metastasis.

Results: DT-13 inhibited breast cancer cells migration at the concentration without cytotoxicity. Furthermore, DT-13 decreased PLOD2 expression through modulating JAK/STAT3 and PI3K/AKT signaling pathways directly or indirectly in the adipocyte-breast cancer microenvironment. Orthotopic implantation mouse model of breast cancer further confirmed that DT-13 inhibited breast cancer metastasis via downregulating PLOD2 in vivo.

Conclusion: DT-13 suppressed breast cancer metastasis via reducing the expression of PLOD2.
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http://dx.doi.org/10.1016/j.phymed.2018.12.001DOI Listing
June 2019

Distribution of ancient α1 and α2 domain lineages between two classical MHC class I genes and their alleles in grass carp.

Immunogenetics 2019 05 2;71(5-6):395-405. Epub 2019 Apr 2.

Department of Microbiology and Immunology, College of Veterinary Medicine, China Agricultural University, Beijing, China.

Major histocompatibility complex (MHC) class I molecules play a crucial role in the immune response by binding and presenting pathogen-derived peptides to specific CD8 T cells. From cDNA of 20 individuals of wild grass carp (Ctenopharyngodon idellus), we could amplify one or two alleles each of classical MHC class I genes Ctid-UAA and Ctid-UBA. In total, 27 and 22 unique alleles of Ctid-UAA and Ctid-UBA were found. The leader, α1, transmembrane and cytoplasmic regions distinguish between Ctid-UAA and Ctid-UBA, and their encoded α1 domain sequences belong to the ancient lineages α1-V and α1-II, respectively, which separated several hundred million years ago. However, Ctid-UAA and Ctid-UBA share allelic lineage variation in their α2 and α3 sequences, in a pattern suggestive of past interlocus recombination events that transferred α2+α3 fragments. The allelic Ctid-UAA and Ctid-UBA variation involves ancient variation between domain lineages α2-I and α2-II, which in the present study was dated back to before the ancestral separation of teleost fish and spotted gar (> 300 million years ago). This is the first report with compelling evidence that recombination events combining different ancient α1 and α2 domain lineages had a major impact on the allelic variation of two different classical MHC class I genes within the same species.
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http://dx.doi.org/10.1007/s00251-019-01111-2DOI Listing
May 2019

DT-13 inhibited the proliferation of colorectal cancer via glycolytic metabolism and AMPK/mTOR signaling pathway.

Phytomedicine 2019 Feb 14;54:120-131. Epub 2018 Sep 14.

Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu, China. Electronic address:

Background: Emerging hallmark of cancer is reprogrammed cellular metabolism, increased glycolytic metabolism is physiological characteristic of human malignant neoplasms. Saponin monomer 13 of the dwarf lilyturf tuber (DT-13) is the main steroidal saponin from Liriopes Radix, which has been reported to exert anti-inflammation and anti-tumor activities but low toxicity to normal tissue. However, the effect of DT-13 on metabolism process is still unclear.

Purpose: This study aims to characterize the role of DT-13 in glucose metabolism in colorectal cancer cells, and investigate whether the metabolism process is involved in the anti-cancer response of DT-13.

Methods: Colony formation assay was employed to determine anti-proliferative effect induced by DT-13 at 2.5, 5, 10 μM. Apoptosis and cell cycle arrest were detected by Annexin V/PI staining and PI staining, respectively. Genetic inhibition of glycolytic metabolism was carried out by knockdown of GLUT1. Orthotopic implantation mouse model of colorectal cancer was used to assess in vivo antitumor effect of DT-13 (0.625, 1.25, 2.5 mg/kg). The chemoprevention effect of DT-13 (10mg/kg) was evaluated by using C57BL/6J APC mice model. Glycolytic-related key enzymes and AMPK pathway were detected by using quantitative real-time PCR, western blotting, and immunohistochemical staining.

Results: Our results showed that cell proliferation was significantly inhibited by DT-13 in a dose-dependent manner. DT-13 inhibited glucose uptake, ATP generation, and reduced lactate production. Furthermore, DT-13 remarkably inhibited GLUT1 expression in both mRNA and protein levels. Knocking down of GLUT1 led to reduced inhibition of glucose uptake after DT-13 treatment. Moreover, deletion of GLUT1 decreased inhibitory ratio of DT-13 on cancer growth. Orthotopic implantation mouse model of colorectal cancer further confirmed that DT-13 inhibited colorectal cancer growth via blocking GLUT1 in vivo. In addition, C57BL/6J APC mice model revealed that DT-13 dramatically reduced the total number of spontaneous adenomas in intestinal, which further confirmed the anti-tumor activity of DT-13 in colorectal cancer. Furthermore, the mechanistically investigation showed DT-13 activated AMPK and inhibited m-TOR to block cancer growth in vitro.

Conclusion: DT-13 is a potent anticancer agent for colorectal cancer.
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http://dx.doi.org/10.1016/j.phymed.2018.09.003DOI Listing
February 2019

A Fast Calibration and Compensation Method for Magnetometers in Strap-Down Spinning Projectiles.

Sensors (Basel) 2018 Nov 27;18(12). Epub 2018 Nov 27.

School of Electronic Information and Electrical Engineering, Huizhou University, Huizhou 516007, China.

Attitude measurement is an essential technology in projectile trajectory correction. Magnetometers have been used for projectile attitude measurement systems as they are small in size, lightweight, and low cost. However, magnetometers are seriously disturbed by the artillery magnetic field during launch. Moreover, the error parameters of the magnetometers, which are calibrated in advance, usually change after extended storage. The changed parameters have negative effects on attitude estimation of the projectile. To improve the accuracy of attitude estimation, the magnetometers should be calibrated again before launch or during flight. This paper presents a fast calibration method specific for a spinning projectile. At the launch site, the tri-axial magnetometer is calibrated, the parameters of magnetometer are quickly obtained by optimal ellipsoid fitting based on a least squares criterion. Then, the calibration parameters are used to compensate for magnetometer outputs during flight. The numerical simulation results show that the proposed calibration method can effectively determine zero bias, scale factors, and alignment angle errors. Finally, a semi-physical experimental system was designed to further verify the performance of the calibration method. The results show that pitch angle error reduces from 3.52° to 0.58° after calibration. The roll angle error is reduced from 2.59° to 0.65°. Simulations and experimental results indicate that the accuracy of magnetometer in strap-down spinning projectile has been greatly enhanced, and the attitude estimation errors are reduced after calibration.
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http://dx.doi.org/10.3390/s18124157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308640PMC
November 2018

RECRP: An Underwater Reliable Energy-Efficient Cross-Layer Routing Protocol.

Sensors (Basel) 2018 Nov 26;18(12). Epub 2018 Nov 26.

College of Computer Science and Technology, Jilin University, Changchun 130012, China.

A reliable energy-efficient routing protocol plays a key role in underwater data transmission. In the face of acoustic communication challenges in underwater wireless sensor networks (UWSNs), including long propagation delay, topology change, limited energy, and communication voids, we propose RECRP, a Reliable Energy-efficient Cross-layer Routing Protocol to achieve high data delivery rate. RECRP is a location-free single-copy protocol. The information of the physical layer such as Doppler scale shift measurement, Received Signal Strength Indication (RSSI), etc. are adopted to estimate the distance, thus no extra hardware is needed for localization. Moreover, the overhead introduced by redundant packets is avoided with the single-copy mechanism. To improve the two-hop packet delivery rate and balance energy consumption among adjacent nodes, an optimal max⁻min method is proposed that dynamically controls transmission power and channel frequency. Furthermore, a surface to bottom routing establishment method is also adopted to handle communication voids. Compared with depth-based routing (DBR) and hop-by-hop vector-based forwarding (HH-VBF) , RECRP is more energy-efficient with a higher delivery rate.
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http://dx.doi.org/10.3390/s18124148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308694PMC
November 2018

HAS⁴: A Heuristic Adaptive Sink Sensor Set Selection for Underwater AUV-Aid Data Gathering Algorithm.

Sensors (Basel) 2018 Nov 23;18(12). Epub 2018 Nov 23.

Department of Electrical & Computer Engineering, University of Houston, Houston, TX 77204, USA.

In this paper, we target solving the data gathering problem in underwater wireless sensor networks. In many underwater applications, it is not quick to retrieve sensed data, which gives us the opportunity to leverage mobile autonomous underwater vehicles (AUV) as data mules to periodically collect it. For each round of data gathering, the AUV visits part of the sensors, and the communication between AUV and sensor nodes is a novel high-speed magnetic-induction communication system. The rest of the sensors acoustically transmit their sensed data to the AUV-visit sensors. This paper deploys the HAS 4 (Heuristic Adaptive Sink Sensor Set Selection) algorithm to select the AUV-visited sensors for the purpose of energy saving, AUV cost reduction and network lifetime prolonging. By comparing HAS 4 with two benchmark selection methods, experiment results demonstrate that our algorithm can achieve a better performance.
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http://dx.doi.org/10.3390/s18124110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308401PMC
November 2018

Postpartum assessment of the beta cell function and insulin resistance for Chinese women with previous gestational diabetes mellitus.

Gynecol Endocrinol 2019 Feb 5;35(2):174-178. Epub 2018 Sep 5.

a Department of Endocrinology and Metabolism , Shanghai General Hospital Shanghai Jiao Tong University , Shanghai , China.

Gestational diabetes mellitus (GDM) imparts a high risk of developing postpartum diabetes and is considered to be an early stage of type 2 diabetes mellitus (T2DM). In this study, a 75-g oral glucose tolerance test was performed on 472 women with GDM at 6-8 weeks after delivery. The clinical and metabolic characteristics were compared between the patients with normal glucose tolerance (NGT) and abnormal glucose metabolism (AGM). These data were then compared between pre-diabetic and diabetic patients. A total of 37.7% of the women with GDM continued to have abnormal glucose levels after delivery. Compared with the women who reverted to normal, HOMA-IR was significantly higher in AGM. A multiple stepwise regression analysis revealed that age, the postpartum body mass index (BMI), low density lipoprotein-cholesterol (LDL-C), 2 h glucose load plasma glucose (2 h PG), triglycerides (TG), hemoglobin A1c (HbA1c), 1 h glucose load plasma insulin (INS) level, and 2 h INS level were independent risk factors for the development of insulin resistance after delivery. This study has identified a high prevalence of AGM after GDM. Insulin resistance appears to be the major contributor. Any treatment to reduce the postpartum BMI and lipids level may be beneficial to decrease insulin resistance.
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http://dx.doi.org/10.1080/09513590.2018.1512094DOI Listing
February 2019

Non-small cell lung cancer leptomeningeal metastases treated with intrathecal therapy plus osimertinib and temozolomide and whole-brain radiation therapy: a case report.

Onco Targets Ther 2018 10;11:4733-4738. Epub 2018 Aug 10.

Department of Medical Oncology, Shaanxi Provincial Cancer Hospital Affiliated to Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China,

Rationale: Leptomeningeal metastasis (LM) is an important cause of mortality in patients with non-small cell lung cancer (NSCLC). As the symptoms of LM and its early clinical manifestations are nonspecific, early diagnosis of LM is difficult. However, there are few treatment options for LM, which leads to a poor prognosis; thus, increased clinical attention is necessary. The effects of most systemic chemotherapies on metastatic brain tumors (brain metastases and LMs) are limited as they cannot pass the blood-brain barrier; therefore, whole-brain radiation therapy is a therapeutic option. Osimertinib is a potent and irreversible third-generation oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). It binds to EGFR with high affinity when the EGFR T790M mutation is present together with sensitizing mutations. The clinical efficacy of osimertinib in NSCLC patients carrying the T790M mutation has been demonstrated in clinical trial NCT02468661. Intrathecal injection of chemotherapeutic drugs can be directed to a specific lesion. Temozolomide is one such drug, and its effect has been confirmed.

Patient And Interventions: We treated a 38-year-old patient with NSCLC who carried the EGFR L858R mutation. We administered a combination of oral osimertinib and oral temozolomide plus an intrathecal injection of cytarabine and whole-brain radiation therapy for symptomatic multiple brain metastases.

Outcomes: The patient showed a marked response to this combination therapy. To date (after ~18 months), no recurrence or new lesions have been observed and he is asymptomatic. His disease-free survival surpasses that achieved with any monotherapy for LM.

Lessons: This is the first report to demonstrate the response to combination therapy in an NSCLC patient with LM. These findings indicate the potential utility of chemotherapy combined with radiotherapy combined with targeted therapy combined with local treatment, as each treatment acts via a different mechanism, enhancing their therapeutic effects.
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http://dx.doi.org/10.2147/OTT.S164968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091472PMC
August 2018

Two novel camptothecin derivatives inhibit colorectal cancer proliferation via induction of cell cycle arrest and apoptosis in vitro and in vivo.

Eur J Pharm Sci 2018 Oct 14;123:546-559. Epub 2018 Aug 14.

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China. Electronic address:

At present, chemotherapy is still to be the preferred and most significant therapeutic strategy for cancer patients in clinical practice. Although Camptothecin (CPT) has been discovered for over half century, a series of CPT derivatives such as Topotecan (TPT) and irinotecan (CPT-11) have been approved and are still to be the first-line medicines for clinical application. Up to now, the topoisomerase 1 inhibitor continues to be a significant drug development research field. Based on previous study of the structure-activity relationship, we consider that the introduction of lipophilic group at C7 position can prolong the retention time and the hydroxyl esterification at C20 can eliminate the hydrogen bond interaction, stabilize the E-lactone form and promote the anti-cancer effect. In this study, we carried out an optimization at C7 and C20 positions to afford two CPT derivatives 3g and 3j. Firstly, we predicted the possibly binding sites of two compounds with topoisomerase 1 by molecular docking. Then we evaluated the anti-proliferation effect of the two novel derivatives and compared the IC50 with CPT-11. Furthermore, the induction of cell cycle arrest and apoptosis was explored through karyomorphology, flow cytometry (FCM) and Western blot analysis. At last, we evaluated the anti-cancer effect and detected the mechanism in colorectal cancer xenograft model. In brief, all the data showed that the novel CPT derivatives (3g and 3j) could inhibit colorectal cancer proliferation via induction of cell cycle arrest and apoptosis in vitro and in vivo. It suggested that the two agents may be a new potential therapeutic strategy in the future.
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http://dx.doi.org/10.1016/j.ejps.2018.08.018DOI Listing
October 2018

Cardinal Role of Intraliposome Doxorubicin-Sulfate Nanorod Crystal in Doxil Properties and Performance.

ACS Omega 2018 Mar 2;3(3):2508-2517. Epub 2018 Mar 2.

Laboratory of Membrane and Liposome Research, The Hebrew University-Hadassah Medical School, IMRIC, Jerusalem 91120, Israel.

The uniqueness of Doxil can be attributed, to a large extent, to its intraliposomal doxorubicin-sulfate nanorod crystal. We re-examine these nanocrystal features and their mechanism of the formation by studying pegylated liposomal doxorubicins (PLDs) of the same lipid composition, size distribution, and extraliposome medium that were prepared at different ammonium sulfate (AS) concentrations. This study includes a comparison of the thermotropic behavior, morphology, and in vitro ammonia-induced doxorubicin release (relevant to Doxil's in vivo performance) of these PLDs. In this study, we confirm that a transmembrane ammonium gradient is critical for doxorubicin remote loading, and we demonstrate that the intraliposomal concentration of sulfate counteranions and ammonium ions determine to a large extent the physical state and stability of the PLDs' remote loaded doxorubicin. "Fully-developed" intraliposome doxorubicin-sulfate nanorod crystals (as defined by cryogenic transmission electron microscopy imaging) develop only when the ammonium sulfate (AS) concentration used for PLD preparation is ≥150 mM. Less than 10% of PLDs prepared with 100 mM AS show fully developed nanorod crystals. Intraliposomal AS concentration ≥200 mM is required to support the stable nanocrystallization in PLDs. The presence of nanocrystals and their melting enthalpy and phase transition co-operativity strongly affect the ammonia-induced doxorubicin release of PLDs. A quick, biphasic release occurs for PLDs that lack the nanorod crystals or have crystals of poor crystallinity, whereas PLDs prepared with ≥200 mM AS show a monophasic, zero-order slow release. This study also demonstrates that after remote loading, residual intraliposomal ammonium concentration and the transmembrane pH gradient related to it also play an important role in doxorubicin-sulfate intraliposomal crystallization and ammonia-induced doxorubicin release.
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http://dx.doi.org/10.1021/acsomega.7b01235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044617PMC
March 2018

Comparison of serum concentrations of humanin in women with and without gestational diabetes mellitus.

Gynecol Endocrinol 2018 Dec 17;34(12):1064-1067. Epub 2018 Jun 17.

a Department of Endocrinology and Metabolism , Shanghai General Hospital, Shanghai Jiao Tong University , Shanghai , China.

Humanin (MT-RNR2) is an endogenous polypeptide that is involved in many diseases, including T2DM. Gestational diabetes mellitus (GDM) is defined as hyperglycemia during pregnancy. The aim of this study was to evaluate serum humanin levels in women with or without GDM and to elucidate possible correlations with anthropometric parameters, metabolic parameters and the incidence of GDM. Eighty-four women with GDM and 73 control women were enrolled in this study. The clinical and biochemical parameters of all subjects were determined. Serum humanin levels were measured by an ELISA. Serum humanin levels were significantly lower in women with GDM than in control women. Moreover, humanin levels were significantly negatively correlated with the presence of GDM, body weight, BMI at 24 weeks of gestation, TG, FPG, 1 hPG, 2 hPG, FINS, and HOMA-IR. In contrast, humanin levels were significantly positively correlated with FT3 and FT4. A binary logistic analysis showed that humanin levels were associated with the incidence of GDM. Additional follow-up studies are needed to highlight whether and how decreased humanin levels play an important role in GDM.
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http://dx.doi.org/10.1080/09513590.2018.1482869DOI Listing
December 2018