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1.
Sci Immunol ; 5(46)2020 04 10.
Article in English | MEDLINE | ID: mdl-32276965

ABSTRACT

Intestinal mononuclear phagocytes (MPs) are composed of heterogeneous dendritic cell (DC) and macrophage subsets necessary for the initiation of immune response and control of inflammation. Although MPs in the normal intestine have been extensively studied, the heterogeneity and function of inflammatory MPs remain poorly defined. We performed phenotypical, transcriptional, and functional analyses of inflammatory MPs in infectious Salmonella colitis and identified CX3CR1+ MPs as the most prevalent inflammatory cell type. CX3CR1+ MPs were further divided into three distinct populations, namely, Nos2 +CX3CR1lo, Ccr7 +CX3CR1int (lymph migratory), and Cxcl13 +CX3CR1hi (mucosa resident), all of which were transcriptionally aligned with macrophages and derived from monocytes. In follow-up experiments in vivo, intestinal CX3CR1+ macrophages were superior to conventional DC1 (cDC1) and cDC2 in inducing Salmonella-specific mucosal IgA. We next examined spatial organization of the immune response induced by CX3CR1+ macrophage subsets and identified mucosa-resident Cxcl13 +CX3CR1hi macrophages as the antigen-presenting cells responsible for recruitment and activation of CD4+ T and B cells to the sites of Salmonella invasion, followed by tertiary lymphoid structure formation and the local pathogen-specific IgA response. Using mice we developed with a floxed Ccr7 allele, we showed that this local IgA response developed independently of migration of the Ccr7 +CX3CR1int population to the mesenteric lymph nodes and contributed to the total mucosal IgA response to infection. The differential activity of intestinal macrophage subsets in promoting mucosal IgA responses should be considered in the development of vaccines to prevent Salmonella infection and in the design of anti-inflammatory therapies aimed at modulating macrophage function in inflammatory bowel disease.


Subject(s)
CX3C Chemokine Receptor 1/immunology , Immunoglobulin A/immunology , Intestinal Mucosa/immunology , Macrophages/immunology , Tertiary Lymphoid Structures/immunology , Animals , Female , Gastrointestinal Microbiome/immunology , Inflammation/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Salmonella enterica/immunology , Streptomycin
2.
Article in English | MEDLINE | ID: mdl-31557844

ABSTRACT

This study aimed to compare the mean scores of mobile phone use, mobile phone addiction, and depressive symptoms at three-time points among Korean adolescents according to gender and to examine the differences in the long-term relationships among the three abovementioned variables between Korean boys and girls in a four-year period. Data for 1794 adolescents (897 boys and 897 girls) were obtained from three waves of the second panel of the Korean Children and Youth Panel Survey. Multigroup structural equation modeling was used for data analyses. The study findings showed that at each of the three-time points, Korean girls tended to use their mobile phones more frequently and were at a higher risk of mobile phone addiction and depressive symptoms than Korean boys. Significant changes were observed in the longitudinal relationships among phone use, mobile phone addiction, and depressive symptoms in Korean adolescents across time periods, but no gender differences were found in the strengths of these relationships. These findings contribute to expanding the knowledge base of mobile phone addiction and depressive symptoms among Korean adolescents.


Subject(s)
Behavior, Addictive/epidemiology , Cell Phone Use/statistics & numerical data , Depression/epidemiology , Depressive Disorder/epidemiology , Adolescent , Behavior, Addictive/etiology , Cell Phone/statistics & numerical data , Cell Phone Use/adverse effects , Depression/etiology , Depressive Disorder/etiology , Female , Humans , Male , Republic of Korea/epidemiology , Sex Factors , Surveys and Questionnaires
3.
Lab Chip ; 19(18): 3140, 2019 Sep 10.
Article in English | MEDLINE | ID: mdl-31468052

ABSTRACT

Correction for 'Immature dendritic cells navigate microscopic mazes to find tumor cells' by Eujin Um et al., Lab Chip, 2019, 19, 1665-1675.

4.
Lab Chip ; 19(9): 1665-1675, 2019 04 23.
Article in English | MEDLINE | ID: mdl-30931468

ABSTRACT

Dendritic cells (DCs) are potent antigen-presenting cells with high sentinel ability to scan their neighborhood and to initiate an adaptive immune response. Whereas chemotactic migration of mature DCs (mDCs) towards lymph nodes is relatively well documented, the migratory behavior of immature DCs (imDCs) in tumor microenvironments is still poorly understood. Here, microfluidic systems of various geometries, including mazes, are used to investigate how the physical and chemical microenvironment influences the migration pattern of imDCs. Under proper degree of confinement, the imDCs are preferentially recruited towards cancer vs. normal cells, accompanied by increased cell speed and persistence. Furthermore, a systematic screen of cytokines, reveals that Gas6 is a major chemokine responsible for the chemotactic preference. These results and the accompanying theoretical model suggest that imDC migration in complex tissue environments is tuned by a proper balance between the strength of the chemical gradients and the degree of spatial confinement.


Subject(s)
Cell Movement , Dendritic Cells/cytology , Animals , Cell Line , Chemotaxis , Cytokines/metabolism , Dendritic Cells/metabolism , Mice , Mice, Inbred BALB C
5.
J Periodontal Res ; 54(1): 53-62, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30298515

ABSTRACT

BACKGROUND AND OBJECTIVES: Proteome analysis of periodontal ligament stem cells (PDLSCs) could be used to study the function of PDL tissue. We used a label-free quantitative proteomic technique to investigate differentially expressed proteins (DEPs) in human PDLSCs (hPDLSCs) compared to human bone marrow mesenchymal stem cells (hBMSCs) and identify proteins specific to hPDLSCs. MATERIAL AND METHODS: hPDLSCs (n = 3) and hBMSCs (n = 3) were cultured and harvested for protein extraction and trypsin digestion. The proteomes of both cell types were analyzed by nano-liquid chromatography/tandem mass spectrometry. DEPs in hPDLSCs compared to hBMSCs were detected by label-free quantification and evaluated through signal transduction pathway and gene ontology (GO) analysis. RESULTS: In total, 690 and 771 proteins were identified from hPDLSCs and hBMSCs, of which 561 proteins were in common and 124 DEPs were found between hPDLSCs and hBMSCs. Fifty-eight proteins were expressed at significantly higher levels in hPDLSCs, whereas 66 proteins were expressed at lower levels compared to hBMSCs. The more highly expressed proteins were associated with translation and initiating protein synthesis, and lower expressed proteins were related to cell aging and metabolic processes. Proteins unique to hPDLSCs and hBMSCs were associated with translation and metabolic processes, respectively. CONCLUSION: Our results demonstrate evidence of distinct differences in protein expression between hPDLSCs and hBMSCs by using label-free quantitative proteomic analysis which was the first attempt in this field. DEPs included previously reported hPDLSC marker proteins and novel marker candidates, such as microtubule-associated protein, CTP synthase 1 and stathmin, which could be the markers for developing periodontal disease diagnostics and therapies.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Stem Cells/metabolism , Tandem Mass Spectrometry , Apoptosis Regulatory Proteins , Biomarkers/metabolism , Carbon-Nitrogen Ligases/metabolism , Cells, Cultured , Chromatography, Liquid , Humans , Mesenchymal Stem Cells/metabolism , Microtubule-Associated Proteins/metabolism , Periodontal Diseases/diagnosis , Stathmin/metabolism , Tumor Suppressor Proteins/metabolism
6.
Proc Natl Acad Sci U S A ; 114(18): E3709-E3718, 2017 05 02.
Article in English | MEDLINE | ID: mdl-28420791

ABSTRACT

According to current dogma, there is little or no ongoing neurogenesis in the fully developed adult enteric nervous system. This lack of neurogenesis leaves unanswered the question of how enteric neuronal populations are maintained in adult guts, given previous reports of ongoing neuronal death. Here, we confirm that despite ongoing neuronal cell loss because of apoptosis in the myenteric ganglia of the adult small intestine, total myenteric neuronal numbers remain constant. This observed neuronal homeostasis is maintained by new neurons formed in vivo from dividing precursor cells that are located within myenteric ganglia and express both Nestin and p75NTR, but not the pan-glial marker Sox10. Mutation of the phosphatase and tensin homolog gene in this pool of adult precursors leads to an increase in enteric neuronal number, resulting in ganglioneuromatosis, modeling the corresponding disorder in humans. Taken together, our results show significant turnover and neurogenesis of adult enteric neurons and provide a paradigm for understanding the enteric nervous system in health and disease.


Subject(s)
Apoptosis , Enteric Nervous System/metabolism , Nestin/metabolism , Neurogenesis , Receptors, Nerve Growth Factor/metabolism , SOXE Transcription Factors/metabolism , Animals , Humans , Mice , Mice, Transgenic , Nestin/genetics , Receptors, Nerve Growth Factor/genetics , SOXE Transcription Factors/genetics
7.
Sci Rep ; 6: 30207, 2016 07 25.
Article in English | MEDLINE | ID: mdl-27451948

ABSTRACT

Breast cancer remains as a challenging disease with high mortality in women. Increasing evidence points the importance of understanding a crosstalk between breast cancers and immune cells, but little is known about the effect of breast cancer-derived factors on the migratory properties of dendritic cells (DCs) and their consequent capability in inducing T cell immune responses. Utilizing a unique 3D microfluidic device, we here showed that breast cancers (MCF-7, MDA-MB-231, MDA-MB-436 and SK-BR-3)-derived soluble factors increase the migration of DCs toward CCL19. The enhanced migration of DCs was mainly mediated via the highly activated JNK/c-Jun signaling pathway, increasing their directional persistence, while the velocity of DCs was not influenced, particularly when they were co-cultured with triple negative breast cancer cells (TNBCs or MDA-MB-231 and MDA-MB-436). The DCs up-regulated inflammatory cytokines IL-1ß and IL-6 and induced T cells more proliferative and resistant against activation-induced cell death (AICD), which secret high levels of inflammatory cytokines IL-1ß, IL-6 and IFN-γ. This study demonstrated new possible evasion strategy of TNBCs utilizing their soluble factors that exploit the directionality of DCs toward chemokine responses, leading to the building of inflammatory milieu which may support their own growth.


Subject(s)
Breast Neoplasms/metabolism , Chemokine CCL19/metabolism , Chemotaxis/physiology , Dendritic Cells/metabolism , Cell Line, Tumor , Female , Humans , Inflammation/metabolism , Interferon-gamma/metabolism , Interleukin-1beta/metabolism , Interleukin-6/metabolism , MCF-7 Cells , T-Lymphocytes/metabolism
8.
ACS Nano ; 10(8): 7339-50, 2016 08 23.
Article in English | MEDLINE | ID: mdl-27390910

ABSTRACT

In cancer immunotherapy, robust and efficient activation of cytotoxic CD8(+) T cell immune responses is a promising, but challenging task. Dendritic cells (DCs) are well-known professional antigen presenting cells that initiate and regulate antigen-specific cytotoxic CD8(+) T cells that kill their target cells directly as well as secrete IFN-γ, a cytokine critical in tumor rejection. Here, we employed recently established protein cage nanoparticles, encapsulin (Encap), as antigenic peptide nanocarriers by genetically incorporating the OT-1 peptide of ovalbumin (OVA) protein to the three different positions of the Encap subunit. With them, we evaluated their efficacy in activating DC-mediated antigen-specific T cell cytotoxicity and consequent melanoma tumor rejection in vivo. DCs efficiently engulfed Encap and its variants (OT-1-Encaps), which carry antigenic peptides at different positions, and properly processed them within phagosomes. Delivered OT-1 peptides were effectively presented by DCs to naïve CD8(+) T cells successfully, resulting in the proliferation of antigen-specific cytotoxic CD8(+) T cells. OT-1-Encap vaccinations in B16-OVA melanoma tumor bearing mice effectively activated OT-1 peptide specific cytotoxic CD8(+) T cells before or even after tumor generation, resulting in significant suppression of tumor growth in prophylactic as well as therapeutic treatments. A large number of cytotoxic CD8(+) T cells that actively produce both intracellular and secretory IFN-γ were observed in tumor-infiltrating lymphocytes collected from B16-OVA tumor masses originally vaccinated with OT-1-Encap-C upon tumor challenges. The approaches we describe herein may provide opportunities to develop epitope-dependent vaccination systems that stimulate and/or modulate efficient and epitope-specific cytotoxic T cell immune responses in nonpathogenic diseases.


Subject(s)
Dendritic Cells , Drug Carriers , Lymphocyte Activation , Nanoparticles , T-Lymphocytes, Cytotoxic , Animals , CD8-Positive T-Lymphocytes , Mice , Mice, Inbred C57BL , Ovalbumin
9.
Immunol Lett ; 172: 21-8, 2016 04.
Article in English | MEDLINE | ID: mdl-26850563

ABSTRACT

T follicular helper (Tfh) cells, a true B cell helper, have a critical role in enhancing humoral immune responses. However, the initial differentiation of Tfh cells by dendritic cells (DCs), the most potent antigen presenting cells, has not been clearly understood, particularly in the knowledge of the two major conventional dendritic cell subsets, CD8α(+) DCs or CD8α(-) DCs. Here we demonstrated that the localization of CD8α(-) DCs in the marginal zone (MZ) bridging channels is closely associated with the induction of CXCR5(+)CCR7(low) Tfh cells. We also showed that the major source of IL-6 for inducing Tfh cells is provided from the activated CD4(+) T cells induced by CD8α(-) DCs, and IL-6 directly secreted from the DC subsets seems minor. CD8α(-) DCs were superior in inducing functional Tfh cells over other antigen presenting cells including B cells. We here observed the unknown intrinsic features of the DC subsets, suggesting the potential of utilizing the CD8α(-) DC subset as therapeutic vaccine for the regulation of humoral immune responses.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Immunotherapy, Adoptive/methods , Animals , Antigen Presentation , CD8 Antigens/metabolism , Cells, Cultured , Dendritic Cells/transplantation , Germinal Center/immunology , Immunity, Humoral , Interleukin-6/metabolism , Lymphocyte Activation , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Receptors, CCR7/metabolism , Receptors, CXCR5/metabolism
10.
Cell Rep ; 11(12): 1929-40, 2015 Jun 30.
Article in English | MEDLINE | ID: mdl-26095362

ABSTRACT

Recent studies on T follicular helper (Tfh) cells have significantly advanced our understanding of T cell-dependent B cell responses. However, little is known about the early stage of Tfh cell commitment by dendritic cells (DCs), particularly by the conventional CD8α(+) and CD8α(-) DC subsets. We show that CD8α(-) DCs localized at the interfollicular zone play a pivotal role in the induction of antigen-specific Tfh cells by upregulating the expression of Icosl and Ox40l through the non-canonical NF-κB signaling pathway. Tfh cells induced by CD8α(-) DCs function as true B cell helpers, resulting in significantly increased humoral immune responses against various human pathogenic antigens, including Yersinia pestis LcrV, HIV Gag, and hepatitis B surface antigen. Our findings uncover a mechanistic role of CD8α(-) DCs in the initiation of Tfh cell differentiation and thereby provide a rationale for investigating CD8α(-) DCs in enhancing antigen-specific humoral immune responses for improving vaccines and therapeutics.


Subject(s)
Dendritic Cells/immunology , Immunity, Humoral/genetics , Lymphocyte Activation/immunology , T-Lymphocytes, Helper-Inducer/immunology , Animals , Antigen Presentation/immunology , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Hepatitis B Surface Antigens/immunology , Hepatitis B virus/immunology , Hepatitis B virus/pathogenicity , Humans , Mice , NF-kappa B/genetics , NF-kappa B/immunology , Signal Transduction/immunology , Yersinia pestis/immunology , Yersinia pestis/pathogenicity
11.
Cell Biol Int ; 39(9): 1080-6, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25976739

ABSTRACT

Dendritic cells (DCs) are the most potent antigen-presenting cells that play a crucial role in the initiation of an immune response. As DC-based therapeutic applications is increasing, large-scale DC production is required for transplantation. Human umbilical cord blood (UCB) has been shown to contain a rare and precious population of hematopoietic stem cells (HSCs), which can give rise to DCs. The CD34 antigen has been widely used as a cell surface marker to identify HSCs. In this study, we used CD34 antibody to isolate CD34(+) and CD34(-) cells and compared the ability to differentiate into DCs. We used a two-step method combined with the magnetic bead sorting system to isolate CD34(+) and CD34(-) cells from human UCB. Analysis of cellular properties and functionality using a migration assay and T cell proliferation assay revealed no significant differences between CD34(+) cells and CD34(-) cells in their ability to generate DCs.


Subject(s)
Dendritic Cells/cytology , Fetal Blood/cytology , Hematopoietic Stem Cells/cytology , Antigens, CD34/immunology , Cell Differentiation/immunology , Cells, Cultured , Dendritic Cells/immunology , Hematopoietic Stem Cells/immunology , Humans , Lymphocyte Activation
12.
Nanomedicine ; 10(3): 561-9, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24262997

ABSTRACT

We utilized ferritin protein cage nanoparticles (FPCN) as antigen delivery nanoplatforms for DC-based vaccine development and investigated DC-mediated antigen-specific immune responses. Antigenic peptides, OT-1 (SIINFEKL) or OT-2 (ISQAVHAAHAEINEAGR) which are derived from ovalbumin, were genetically introduced either onto the exterior surface or into the interior cavity of FPCN. FPCN carrying antigenic peptides (OT-1-FPCN and OT-2-FPCN) were effectively delivered to DCs and processed within endosomes. Delivered antigenic peptides, OT-1 or OT-2, to DCs successfully induced antigen-specific CD8(+) or CD4(+) T cell proliferations both in vitro and in vivo. Naïve mice immunized with OT-1-FPCN efficiently differentiated OT-1 specific CD8(+) T cells into functional effector cytotoxic T cells resulting in selective killing of antigen-specific target cells. Effective differentiation of proliferated OT-2 specific CD4(+) T cells into functional CD4(+) Th1 and Th2 cells was confirmed with the productions of IFN-γ/IL-2 and IL-10/IL-13 cytokines, respectively. FROM THE CLINICAL EDITOR: In this study, the authors utilized ferritin protein cage nanoparticles as antigen delivery nanoplatforms for dendritic cell-based vaccine development and investigated DC-mediated antigen-specific immune responses using strong model antigens derived from ovalbumin, suggesting potential future clinical applicability of this or similar techniques.


Subject(s)
Antigens/administration & dosage , Cancer Vaccines/administration & dosage , Dendritic Cells/immunology , Ferritins/chemistry , Nanoparticles/chemistry , Ovalbumin/administration & dosage , Amino Acid Sequence , Animals , Antigens/chemistry , Antigens/immunology , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Cancer Vaccines/chemistry , Cancer Vaccines/immunology , Cells, Cultured , Cytokines/immunology , Dendritic Cells/cytology , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Ovalbumin/chemistry , Ovalbumin/immunology , Peptide Fragments/administration & dosage , Peptide Fragments/chemistry , Peptide Fragments/immunology , Th1 Cells/cytology , Th1 Cells/immunology , Th2 Cells/cytology , Th2 Cells/immunology
13.
Antimicrob Agents Chemother ; 57(12): 5889-900, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24041884

ABSTRACT

Despite the important role of the antimalarial artesunate and its active metabolite dihydroartemisinin (DHA) in malaria treatment efforts, there are limited data on the pharmacokinetics of these agents in pediatric patients. This study evaluated the effects of body size and gender on the pharmacokinetics of artesunate-DHA using data from pediatric and adult malaria patients. Nonlinear mixed-effects modeling was used to obtain a base model consisting of first-order artesunate absorption and one-compartment models for artesunate and for DHA. Various methods of incorporating effects of body size descriptors on clearance and volume parameters were tested. An allometric scaling model for weight and a linear body surface area (BSA) model were deemed optimal. The apparent clearance and volume of distribution of DHA obtained with the allometric scaling model, normalized to a 38-kg patient, were 63.5 liters/h and 65.1 liters, respectively. Estimates for the linear BSA model were similar. The 95% confidence intervals for the estimated gender effects on clearance and volume parameters for artesunate fell outside the predefined no-relevant-clinical-effect interval of 0.75 to 1.25. However, the effect of gender on apparent DHA clearance was almost entirely contained within this interval, suggesting a lack of an influence of gender on this parameter. Overall, the pharmacokinetics of artesunate and DHA following oral artesunate administration can be described for pediatric patients using either an allometric scaling or linear BSA model. Both models predict that, for a given artesunate dose in mg/kg of body weight, younger children are expected to have lower DHA exposure than older children or adults.


Subject(s)
Antimalarials/pharmacokinetics , Artemisinins/pharmacokinetics , Models, Statistical , Plasmodium falciparum/drug effects , Administration, Oral , Adult , Age Factors , Antimalarials/pharmacology , Artemisinins/metabolism , Artemisinins/pharmacology , Artesunate , Body Size , Body Weight , Child , Child, Preschool , Computer Simulation , Drug Administration Schedule , Drug Dosage Calculations , Female , Half-Life , Humans , Malaria, Falciparum/drug therapy , Malaria, Falciparum/microbiology , Male , Microbial Sensitivity Tests , Plasmodium falciparum/growth & development , Sex Factors
14.
Malar J ; 12: 70, 2013 Feb 21.
Article in English | MEDLINE | ID: mdl-23433102

ABSTRACT

BACKGROUND: Pyronaridine-artesunate (PA) is indicated for the treatment of acute uncomplicated Plasmodium falciparum and Plasmodium vivax malaria. METHODS: Individual patient data on safety outcomes were integrated from six randomized clinical trials conducted in Africa and Asia in patients with microscopically confirmed P. falciparum (five studies) or P. vivax (one study) malaria. Efficacy against P. falciparum was evaluated across three Phase III clinical trials. RESULTS: The safety population included 2,815 patients randomized to PA, 1,254 to comparators: mefloquine + artesunate (MQ + AS), artemether-lumefantrine (AL), or chloroquine. All treatments were generally well tolerated. Adverse events occurred in 57.2% (1,611/2,815) of patients with PA versus 51.5% (646/1,254) for comparators, most commonly (PA; comparators): headache (10.6%; 9.9%), cough (5.9%; 5.6%) and anaemia (4.5%; 2.9%). Serious averse events were uncommon for all treatments (0-0.7%). Transient increases in alanine aminotransferase and aspartate aminotransferase were observed with PA but did not lead to any clinical sequelae. For P. falciparum malaria, day-28 PCR-corrected adequate clinical and parasitological response with PA was 93.6% ([1,921/2,052] 95% CI 92.6, 94.7) in the intent-to-treat population and 98.5% ([1,852/1,880] 95% CI 98.0, 99.1) in the per-protocol population. Median parasite clearance time was 24.1 h with PA, 31.9 h with MQ + AS, and 24.0 h with AL. Median fever clearance time was 15.5 h with PA, 15.8 h with MQ + AS, and 14.0 h with AL. By day 42, P. falciparum gametocytes had declined to near zero for all treatments. CONCLUSIONS: Pyronaridine-artesunate was well tolerated with no safety concerns with the exception of mostly mild transient rises in transaminases. Efficacy was high and met the requirements for use as first-line therapy. Pyronaridine-artesunate should be considered for inclusion in malaria treatment programmes. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00331136; NCT00403260; NCT00422084; NCT00440999; NCT00541385; NCT01594931.


Subject(s)
Antimalarials/administration & dosage , Antimalarials/adverse effects , Artemisinins/administration & dosage , Artemisinins/adverse effects , Malaria/drug therapy , Naphthyridines/administration & dosage , Naphthyridines/adverse effects , Adolescent , Adult , Africa , Artesunate , Asia , Child , Child, Preschool , Clinical Trials, Phase III as Topic , Drug Combinations , Drug-Related Side Effects and Adverse Reactions/epidemiology , Female , Humans , Infant , Malaria, Falciparum/drug therapy , Malaria, Vivax/drug therapy , Male , Middle Aged , Randomized Controlled Trials as Topic , Treatment Outcome , Young Adult
15.
Biomed Microdevices ; 15(4): 627-634, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23232700

ABSTRACT

This report presents a multilevel microfluidic platform for robust construction of hydrogel scaffold in microchannels and its application to three dimensional (3D) multicellular co-cultures and assays. A new rapid prototyping method based on soft lithography using multi-layered adhesive tapes is also introduced. We have successfully cultured MCF-7 breast cancer cell line more than 11 days with > 98 % viability, and co-cultured MDA-MB-231 breast cancer cells and NIH/3T3 fibroblasts in separate compartments. This multilevel microfluidic device with a cell-laden hydrogel microstructure has also been applied for anticancer drug assays in multicellular niches. Here we tested the effect of estrogen receptor (ER) antagonist drug, tamoxifen, on the growth of ER positive MCF-7 cells in microchannels. The inhibitory effect of tamoxifen on the growth of MCF-7 cells was diminished when they were co-cultured with ER negative MDA-MB-231 cells. The rapid prototyped multilevel microfluidic devices would provide simple, easy to use, low cost, robust, and reproducible cell-based assay platforms for potential end-users such as biologists and pharmacists.


Subject(s)
Coculture Techniques/instrumentation , Drug Screening Assays, Antitumor/instrumentation , Microfluidic Analytical Techniques/instrumentation , Adhesives/chemistry , Animals , Cell Line , Fibroblasts/cytology , Humans , Mice , Time Factors
16.
Malar J ; 11: 364, 2012 Oct 31.
Article in English | MEDLINE | ID: mdl-23113947

ABSTRACT

BACKGROUND: Children are most vulnerable to malaria. A pyronaridine-artesunate pediatric granule formulation is being developed for the treatment of uncomplicated Plasmodium falciparum malaria. METHODS: This phase III, multi-center, comparative, open-label, parallel-group, controlled clinical trial included patients aged ≤12 years, bodyweight ≥5 to <25 kg, with a reported history of fever at inclusion or in the previous 24 h and microscopically-confirmed uncomplicated P. falciparum malaria. Patients were randomized (2:1) to pyronaridine-artesunate granules (60/20 mg) once daily or artemether-lumefantrine crushed tablets (20/120 mg) twice daily, both dosed by bodyweight, orally (liquid suspension) for three days. RESULTS: Of 535 patients randomized, 355 received pyronaridine-artesunate and 180 received artemether-lumefantrine. Day-28 adequate clinical and parasitological response (ACPR), corrected for re-infection using polymerase chain reaction (PCR) genotyping (per-protocol population) was 97.1% (329/339; 95% CI 94.6, 98.6) for pyronaridine-artesunate; 98.8% (165/167; 95% CI 95.7, 99.9) for artemether-lumefantrine. The primary endpoint was achieved: pyronaridine-artesunate PCR-corrected day-28 ACPR was statistically significantly >90% (P < .0001). Pyronaridine-artesunate was non-inferior to artemether-lumefantrine: treatment difference -1.8% (95% CI -4.3 to 1.6). The incidence of drug-related adverse events was 37.2% (132/355) with pyronaridine-artesunate, 44.4% (80/180) with artemether-lumefantrine. Clinical biochemistry results showed similar mean changes versus baseline in the two treatment groups. From day 3 until study completion, one patient in each treatment group had peak alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN) and peak total bilirubin >2xULN (i.e. within the Hy's law definition). CONCLUSIONS: The pyronaridine-artesunate pediatric granule formulation was efficacious and was non-inferior to artemether-lumefantrine. The adverse event profile was similar for the two comparators. Pyronaridine-artesunate should be considered for inclusion in paediatric malaria treatment programmes. TRIAL REGISTRATION: ClinicalTrials.gov: identifier NCT00541385.


Subject(s)
Antimalarials/administration & dosage , Artemisinins/administration & dosage , Ethanolamines/administration & dosage , Fluorenes/administration & dosage , Malaria, Falciparum/drug therapy , Naphthyridines/administration & dosage , Antimalarials/adverse effects , Artemether, Lumefantrine Drug Combination , Artesunate , Child , Child, Preschool , Dosage Forms , Drug Combinations , Female , Humans , Infant , Malaria, Falciparum/parasitology , Male , Parasite Load , Recurrence , Tablets , Treatment Outcome
17.
Malar J ; 11: 270, 2012 Aug 09.
Article in English | MEDLINE | ID: mdl-22877082

ABSTRACT

Pyronaridine was synthesized in 1970 at the Institute of Chinese Parasitic Disease and has been used in China for over 30 years for the treatment of malaria. Pyronaridine has high potency against Plasmodium falciparum, including chloroquine-resistant strains. Studies in various animal models have shown pyronaridine to be effective against strains resistant to other anti-malarials, including chloroquine. Resistance to pyronaridine appears to emerge slowly and is further retarded when pyronaridine is used in combination with other anti-malarials, in particular, artesunate. Pyronaridine toxicity is generally less than that of chloroquine, though evidence of embryotoxicity in rodents suggests use with caution in pregnancy. Clinical pharmacokinetic data for pyronaridine indicates an elimination T1/2 of 13.2 and 9.6 days, respectively, in adults and children with acute uncomplicated falciparum and vivax malaria in artemisinin-combination therapy. Clinical data for mono or combined pyronaridine therapy show excellent anti-malarial effects against P. falciparum and studies of combination therapy also show promise against Plasmodium vivax. Pyronaridine has been developed as a fixed dose combination therapy, in a 3:1 ratio, with artesunate for the treatment of acute uncomplicated P. falciparum malaria and blood stage P. vivax malaria with the name of Pyramax® and has received Positive Opinion by European Medicines Agency under the Article 58 procedure.


Subject(s)
Antimalarials/adverse effects , Antimalarials/therapeutic use , Malaria, Falciparum/drug therapy , Malaria, Vivax/drug therapy , Naphthyridines/adverse effects , Naphthyridines/therapeutic use , Antimalarials/pharmacokinetics , Antimalarials/pharmacology , China , Drug Therapy, Combination/methods , Drug-Related Side Effects and Adverse Reactions/epidemiology , Humans , Naphthyridines/pharmacokinetics , Naphthyridines/pharmacology , Plasmodium falciparum/drug effects , Plasmodium vivax/drug effects , Treatment Outcome
18.
N Engl J Med ; 366(14): 1298-309, 2012 Apr 05.
Article in English | MEDLINE | ID: mdl-22475593

ABSTRACT

BACKGROUND: Pyronaridine-artesunate is an artemisinin-based combination therapy under evaluation for the treatment of Plasmodium falciparum and P. vivax malaria. METHODS: We conducted a phase 3, open-label, multicenter, noninferiority trial that included 1271 patients between 3 and 60 years of age from Asia (81.3%) or Africa (18.7%) with microscopically confirmed, uncomplicated P. falciparum malaria. Patients underwent randomization for treatment with a fixed-dose combination of 180 mg of pyronaridine and 60 mg of artesunate or with 250 mg of mefloquine plus 100 mg of artesunate. Doses were calculated according to body weight and administered once daily for 3 days. RESULTS: Pyronaridine-artesunate was noninferior to mefloquine plus artesunate for the primary outcome: adequate clinical and parasitologic response in the per-protocol population on day 28, corrected for reinfection with the use of polymerase-chain-reaction (PCR) genotyping. For this outcome, efficacy in the group receiving pyronaridine-artesunate was 99.2% (743 of 749 patients; 95% confidence interval [CI], 98.3 to 99.7) and that in the group receiving mefloquine plus artesunate was 97.8% (360 of 368 patients; 95% CI, 95.8 to 99.1), with a treatment difference of 1.4 percentage points (95% CI, 0.0 to 3.5; P=0.05). In the intention-to-treat population, efficacy on day 42 in the group receiving pyronaridine-artesunate was 83.1% (705 of 848 patients; 95% CI, 80.4 to 85.6) and that in the group receiving mefloquine plus artesunate was 83.9% (355 of 423 patients; 95% CI, 80.1 to 87.3). In Cambodia, where there were 211 study patients, the median parasite clearance time was prolonged for both treatments: 64 hours versus 16.0 to 38.9 hours in other countries (P<0.001, on the basis of Kaplan-Meier estimates). Kaplan-Meier estimates of the recrudescence rate in the intention-to-treat population in Cambodia until day 42 were higher with pyronaridine-artesunate than with mefloquine plus artesunate (10.2% [95% CI, 5.4 to 18.6] vs. 0%; P=0.04 as calculated with the log-rank test), but similar for the other countries combined (4.7% [95% CI, 3.3 to 6.7] and 2.8% [95% CI, 1.5 to 5.3], respectively; P=0.24). Elevated levels of aminotransferases were observed in those receiving pyronaridine-artesunate. Two patients receiving mefloquine plus artesunate had seizures. CONCLUSIONS: Fixed-dose pyronaridine-artesunate was efficacious in the treatment of uncomplicated P. falciparum malaria. In Cambodia, extended parasite clearance times were suggestive of in vivo resistance to artemisinin. (Funded by Shin Poong Pharmaceutical Company and the Medicines for Malaria Venture; ClinicalTrials.gov number, NCT00403260.).


Subject(s)
Antimalarials/therapeutic use , Artemisinins/therapeutic use , Malaria, Falciparum/drug therapy , Mefloquine/therapeutic use , Naphthyridines/therapeutic use , Adolescent , Adult , Africa , Antimalarials/administration & dosage , Antimalarials/adverse effects , Artemisinins/administration & dosage , Artemisinins/adverse effects , Artesunate , Asia , Child , Child, Preschool , Drug Combinations , Drug Resistance , Female , Humans , Intention to Treat Analysis , Kaplan-Meier Estimate , Male , Mefloquine/administration & dosage , Mefloquine/adverse effects , Middle Aged , Naphthyridines/administration & dosage , Naphthyridines/adverse effects , Proportional Hazards Models , Young Adult
19.
Am J Trop Med Hyg ; 86(3): 489-495, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22403324

ABSTRACT

A multiple dose, parallel group study was conducted to assess for a drug-drug interaction between the pyronaridine/artesunate (PA) combination antimalarial and ritonavir. Thirty-four healthy adults were randomized (1:1) to receive PA for 3 days or PA with ritonavir (100 mg twice daily for 17 days, PA administered on Days 8-10). Pharmacokinetic parameters for pyronaridine, artesunate, and its active metabolite dihydroartemisinin (DHA) were obtained after the last PA dose and for ritonavir on Days 1 and 10. Ritonavir coadministration did not markedly change pyronaridine pharmacokinetics but resulted in a 27% increase in artesunate area under the curve (AUC) and a 38% decrease in DHA AUC. Ritonavir exposure was increased 3.2-fold in the presence of PA. The only relevant safety observations were increases in liver enzymes, only reaching a clinically significant grade in the PA + ritonavir arm. It was concluded that coadministered ritonavir and PA interact to alter exposure to artesunate, DHA, and ritonavir itself.


Subject(s)
Antimalarials/administration & dosage , Artemisinins/administration & dosage , HIV Protease Inhibitors/administration & dosage , Naphthyridines/administration & dosage , Ritonavir/administration & dosage , Adolescent , Adult , Antimalarials/pharmacokinetics , Area Under Curve , Artemisinins/pharmacokinetics , Artesunate , Drug Interactions , Female , HIV Protease Inhibitors/pharmacokinetics , Humans , Male , Middle Aged , Naphthyridines/pharmacokinetics , Ritonavir/pharmacokinetics , Young Adult
20.
Malar J ; 10: 263, 2011 Sep 13.
Article in English | MEDLINE | ID: mdl-21914160

ABSTRACT

Artesunate (AS) is a clinically versatile artemisinin derivative utilized for the treatment of mild to severe malaria infection. Given the therapeutic significance of AS and the necessity of appropriate AS dosing, substantial research has been performed investigating the pharmacokinetics of AS and its active metabolite dihydroartemisinin (DHA). In this article, a comprehensive review is presented of AS clinical pharmacokinetics following administration of AS by the intravenous (IV), intramuscular (IM), oral or rectal routes. Intravenous AS is associated with high initial AS concentrations which subsequently decline rapidly, with typical AS half-life estimates of less than 15 minutes. AS clearance and volume estimates average 2 - 3 L/kg/hr and 0.1 - 0.3 L/kg, respectively. DHA concentrations peak within 25 minutes post-dose, and DHA is eliminated with a half-life of 30 - 60 minutes. DHA clearance and volume average between 0.5 - 1.5 L/kg/hr and 0.5 - 1.0 L/kg, respectively. Compared to IV administration, IM administration produces lower peaks, longer half-life values, and higher volumes of distribution for AS, as well as delayed peaks for DHA; other parameters are generally similar due to the high bioavailability, assessed by exposure to DHA, associated with IM AS administration (> 86%). Similarly high bioavailability of DHA (> 80%) is associated with oral administration. Following oral AS, peak AS concentrations (Cmax) are achieved within one hour, and AS is eliminated with a half-life of 20 - 45 minutes. DHA Cmax values are observed within two hours post-dose; DHA half-life values average 0.5 - 1.5 hours. AUC values reported for AS are often substantially lower than those reported for DHA following oral AS administration. Rectal AS administration yields pharmacokinetic results similar to those obtained from oral administration, with the exceptions of delayed AS Cmax and longer AS half-life. Drug interaction studies conducted with oral AS suggest that AS does not appreciably alter the pharmacokinetics of atovaquone/proguanil, chlorproguanil/dapsone, or sulphadoxine/pyrimethamine, and mefloquine and pyronaridine do not alter the pharmacokinetics of DHA. Finally, there is evidence suggesting that the pharmacokinetics of AS and/or DHA following AS administration may be altered by pregnancy and by acute malaria infection, but further investigation would be required to define those alterations precisely.


Subject(s)
Antimalarials/pharmacokinetics , Artemisinins/pharmacokinetics , Administration, Oral , Administration, Rectal , Antimalarials/administration & dosage , Artemisinins/administration & dosage , Artesunate , Biological Availability , Half-Life , Humans , Injections, Intramuscular , Injections, Intravenous , Metabolic Clearance Rate , Time Factors
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