Rectal delivery of 89Zr-labeled infliximab-loaded nanoparticles enables PET imaging-guided localized therapy of inflammatory bowel disease.

Inflammatory bowel diseases (IBDs) like Crohn's disease and ulcerative colitis involve chronic gastrointestinal inflammation. The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) drives IBD pathogenesis. Anti-TNF-α therapies using monoclonal antibodies (mAbs) like infliximab (INF) help treat IBD but have limitations. We developed inflammation-targeting polyphenol-poloxamer nanoparticles loaded with the anti-inflammatory mAb INF (INF@PPNP) as a novel IBD therapy. Characterization showed that INF@PPNP had favorable stability and purity. Radiolabeling INF@PPNP with 89Zr enabled tracking localization with positron emission tomography (PET) imaging. Rectal administration of 89Zr-INF@PPNP led to colon delivery with remarkably reduced systemic exposure versus intravenous INF revealed by non-invasive PET imaging. 89Zr-INF@PPNP retention at inflamed foci indicated prolonged INF@PPNP action. INF@PPNP rectally achieved similar anti-inflammatory effects as intravenously injected INF, demonstrating the high therapeutic potential. Our findings support the use of nanoparticle-based rectal administration for localized drug delivery, prolonging drug activity and minimizing systemic exposure, ultimately offering an effective approach for treating IBD.

Recent advances in electrochemical proximity ligation assay.

Proximity ligation assay (PLA) is a vigorously developed homogeneous immunoassay assisted by DNA combining dual recognition of target protein by pairs of proximity probes, in which the detection of protein is tactfully converted to the detection of DNA. The booming developments in PLA have enabled a variety of ultrasensitive assays for the detection of protein and this concept of PLA is also extended to the detection of nucleic acids and some small molecule. The association between PLA and electrochemical method, defined as electrochemical proximity ligation assay (ECPLA), has gained much interests in disease diagnosis, food safety and environmental assays with the advantages, such as broad range of targets, simplicity, low cost and rapid response. In this review, we took a different perspective to present the history of PLA, the classical ECPLA biosensing methodology as well as the developments of ECPLA based on several key parameters, such as sensitivity, selectivity, reusability and generalization. In addition, the developments of PLA with electrochemiluminescence as readout are also presented. Finally, perspective and some unresolved challenges in ECPLA that can potentially be addressed have also been discussed.

Overexpression of Interferon-Inducible Protein 16 Promotes Progression of Human Pancreatic Adenocarcinoma Through Interleukin-1ß-Induced Tumor-Associated Macrophage Infiltration in the Tumor Microenvironment.

Activation of inflammasomes has been reported in human pancreatic adenocarcinoma (PAAD); however, the expression pattern and functional role of inflammasome-related proteins in PAAD have yet to be identified. In this study, we systemically examined the expression and role of different inflammasome proteins by retrieving human expression data. Several genes were found to be differentially expressed; however, only interferon-inducible protein 16 (IFI16) expression was found to be adversely correlated with the overall survival of PAAD patients. Overexpression of IFI16 significantly promoted tumor growth, increased tumor size and weight in the experimental PAAD model of mice, and specifically increased the population of tumor-associated macrophages (TAMs) in the tumor microenvironment. Depletion of TAMs by injection of liposome clodronate attenuated the IFI16 overexpression-induced tumor growth in PAAD. In vitro treatment of conditioned medium from IFI16-overexpressing PAAD cells induced maturation, proliferation, and migration of bone marrow-derived monocytes, suggesting that IFI16 overexpression resulted in cytokine secretion that favored the TAM population. Further analysis suggested that IFI16 overexpression activated inflammasomes, thereby increasing the release of IL-1ß. Neutralization of IL-1ß attenuated TAM maturation, proliferation, and migration induced by the conditioned medium from IFI16-overexpressing PAAD cells. Additionally, knockdown of IFI16 could significantly potentiate gemcitabine treatment in PAAD, which may be associated with the reduced infiltration of TAMs in the tumor microenvironment. The findings of our study shed light on the role of IFI16 as a potential therapeutic target for PAAD.

Electrochemiluminescence Imaging for the Morphological and Quantitative Analysis of Living Cells under External Stimulation.

In this work, a simple electrochemiluminescence (ECL) imaging method based on the cell shield of the ECL emission was developed for the morphological and quantitative analysis of living cells under external stimulation. ECL images of MCF-7 cells cultured on or captured at the glassy carbon electrode (GCE) surface in a solution of tris(2,2'-bipyridyl)ruthenium(II)-tri-n-propylamine were recorded. Important morphological characteristics of living cells, including cell shape, cell area, average cell boundary, and junction distance between two adjacent cells, were directly obtained using the developed negative ECL imaging method. The ECL images revealed gradual morphological changes in cells on the GCE surface. During the course of H2O2 stimulation of cells on the GCE surface, cells shrunk, rounded up, disengaged from surrounding cells, and finally detached from the electrode surface. During the course of electrical stimulation (0.8 V), the cells on the GCE surface exhibited aggregation as demonstrated by increases in the average cell boundary and decreases in the junction distance between two adjacent cells. Additionally, a quantitative method for the sensitive determination of MCF-7 cells with a limit of detection of 29 cells/mL was developed using the negative ECL imaging strategy. This work demonstrates that the proposed negative ECL imaging strategy is a promising approach to assess important morphological characteristics of living cells during the course of external stimulation and to obtain quantitative information on cell concentrations in solution.

Synthesis of multiple-color emissive carbon dots towards white-light emission.

Multiple-color emissive carbon dots (C-dots) are gaining increasing attention in various fields. Herein, we report a facile solvothermal method for the synthesis of multiple-color emissive C-dots with the aim of white-light emission. Under single ultraviolet-light excitation, three C-dots emit a easily controlled fluorescent emission wavelength at 440 nm, 500 nm and 610 nm by using different three amines (either ammonium hydroxide, ethylenediamine or p-phenylenediamine, respectively) and pyromellitic dianhydride as molecular precursors while another three C-dots emit a controllable fluorescent emission wavelength at 500 nm, 550 nm and 585 nm by using same three amines and naphthalene-1,4,5,8-tetracarboxylic dianhydride as molecular precursors. The maximum fluorescence wavelength of these C-dots is red-shifted by changing three different amines molecular precursors from ammonium hydroxide, ethylenediamine, to p-phenylenediamine. Furthermore, these C-dots have shown promising applications in the fields of white-light-emitting diodes devices and color printing.

A "switch-on" photoluminescent and electrochemiluminescent multisignal probe for hypochlorite via a cyclometalated iridium complex.

A new cyclometalated iridium complex, [(bt)2Ir(bpy-Fc)]PF6 (bt = 2-phenylbenzothiazole, bpy-Fc = 4-ferrocenecarbonyl hydrazinocarbonyl-4'-methyl- 2,2'-bipyridine) (probe 1) was designed and synthesized for rapid photoluminescent (PL) and electrochemiluminescent (ECL) sensing of hypochlorite (ClO-). Probe 1 exhibits weak PL and ECL emissions attributed to its electron transfer process. In the presence of ClO-, the cleavage of the hydrazine-linked Fc moiety in probe 1 led to the enhancement of both PL and ECL. The photophysical and ECL properties of probe 1 were investigated and the proposed mechanism of the luminescence enhancement was confirmed by 1H nuclear magnetic resonance spectroscopy, and PL and ECL investigations. In addition, the role of the Fc group in probe 1 in intra- and intermolecular electron transfer processes in the absence and presence of ClO- is demonstrated for both PL and ECL processes. Further, a "switch-on" multi-signal method was developed for sensitive and selective detection of ClO- with detection limits of 466 nM and 302 nM via PL and ECL techniques, respectively. Further, probe 1 was successfully applied for PL imaging of ClO- in living macrophage cells. This work demonstrates that cyclometalated iridium complex bearing recognition and quenching groups is a promising "switch-on" probe in aqueous solutions to image living cells with high sensitivity and selectivity for biomedical applications.

Cyclometalated Iridium Complex as Off-On-Off Reversible Photoluminescence Probe for Redox Cycle HSO3-/H2O2 in Living Cells.

The development of new methods for the detection of redox cycle is important for biological and clinical diagnoses. Here, a new cyclometalated iridium complex, (4-(2-pyridyl) benzaldehyde)2Ir (5-chloro-1,10-phenanthroline) ([(4-pba)2Ir(5-Cl-phen)]PF6, probe 1), has been synthesized and applied to rapid, sensitive, and reversible detection and imaging of redox cycle HSO3-/H2O2 in living cells. The probe 1 is synthesized by using 4-(2-pyridyl) benzaldehyde as main ligand and 5-chloro-1,10-phenanthroline as ancillary ligand. Probe 1 exhibited "off-on-off" photoluminescence (PL) signal change in response to HSO3- and H2O2 in aqueous solution within 1 min. The change of PL intensity is proportional to HSO3- concentration from 40 µM to 300 µM and to H2O2 concentration from 40 µM to 260 µM. The detection limit is 10 µM for HSO3- and 20 µM for H2O2. Additionally, probe 1 was applied to detect HSO3- in food samples with satisfactory results. More importantly, PL imaging of HeLa cells indicates that probe 1 is able to image redox cycle HSO3-/H2O2 in living cells.

Observing Transient Bipolar Electrochemical Coupling on Single Nanoparticles Translocating through a Nanopore.

We report the observation of transient bipolar electrochemical coupling on freely moving 40 nm silver nanoparticles. The use of an asymmetric nanoelectrochemical environment at the nanopore orifice, for example, an acid inside the pipette and halide ions in the bulk, enabled us to observe unusually large current blockages of single Ag nanoparticles. We attribute these current blockages to the formation of H2 nanobubbles on the surface of Ag nanoparticles due to the coupled faradaic reactions, in which the reduction of protons and water is coupled to the oxidation of Ag and water under potentials higher than 1 V. The appearance of large current blockages was strongly dependent on the applied voltage and the choice of anions in the bulk solution. The correlation between large current blockages with the oxidation of Ag nanoparticles and their nanopore translocation was further supported by simultaneous fluorescence and electric recordings. This study demonstrates that transient bipolar electrochemistry can take place on small metal nanoparticles below 50 nm when they pass through nanopores where the electric field is highly localized. The use of a nanopore and the resistive-pulse sensing method to study transient bipolar electrochemistry of nanoparticles may be extended to future studies in ultrafast electrochemistry, nanocatalyst screening, and gas nucleation on nanoparticles.

Ultrasensitive Electrochemiluminescence Aptasensor for Assessment of Protein Heterogeneity in Small Cell Population.

Development of sensitive method for assay of proteins secreted from small cell population is important for the assessment of cellular heterogeneity. Here, we developed an ultrasensitive electrochemiluminescence (ECL) aptasensor for secreted protein in small cell population of RAW 264.7 cells for cellular heterogeneity assessment. Tumor necrosis factor-alpha (TNF-α) was chosen as target secreted protein, and specific anti-TNF-α aptamer was chosen as molecule recognition element, while dichlorotris (1,10-phenanthroline) ruthenium(II) hydrate (Ru(phen)32+) was chosen as ECL signal compound. An ECL signal probe was prepared by combining aptamer, Ru(phen)32+, and graphene oxide (GO) through electrostatic interaction and π-π stacking interaction. An aptasensor was fabricated by self-assembly specific aptamer on gold nanoparticles modified electrode for the detection of TNF-α using sandwich assay. High sensitivity and good selectivity were obtained for TNF-α. Parallel analysis was conducted to detect TNF-α secreted by RAW 264.7 cells stimulated by either lipopolysaccharides (LPS) or lupeol for assessing the cell heterogeneity in small cell population and for estimating the intracellular signal transduction in inflammation. Compared to ELISA, our ECL method offers both high sensitivity and good accuracy. The distinct heterogeneity among the secreted protein in small cell population, for the first time, was observed and further correlated to the cell's nature of cluster growth. The developed ECL method incorporating the amplification of nanomaterial and selectivity of aptamer is promising for sensitive and selective analysis of biomolecules in small cell population.

Rapid "turn-on" photoluminescence detection of bisulfite in wines and living cells with a formyl bearing bis-cyclometalated Ir(iii) complex.

A new photoluminescence (PL) probe based on a formyl bearing bis-cyclometalated Ir(iii) complex, [Ir(ppy)2phen-CHO]+PF6- (1), is synthesized and applied to the selective detection of a bisulfite anion (HSO3-). Probe 1 is prepared using 2-phenylpyridine (ppy) as the C^N main ligand and 1,10-phenanthroline-5-carboxaldehyde (phen-CHO) as the N^N ancillary ligand. Probe 1 displayed excellent selective PL enhancement in response to HSO3- in acetic acid-sodium acetate buffer solution (pH = 5.0). The increase of PL signal is directly proportional to the concentration of HSO3- in the range of 2 µM to 45 µM with a detection limit of 0.9 µM using 50 µM probe 1 and in the range of 0.5 µM to 6 µM with a detection limit of 0.3 µM using 10 µM probe 1. More importantly, probe 1 can respond to HSO3- rapidly within 40 s. Furthermore, probe 1 was successfully applied to detect HSO3- in real white wines and the bioimaging of HSO3- in living cells. The superior properties of probe 1 make it of great potential use for studying the effects of HSO3- in other biosystems.

Proximity Hybridization-Regulated Immunoassay for Cell Surface Protein and Protein-Overexpressing Cancer Cells via Electrochemiluminescence.

A simple electrochemiluminescence (ECL) immunoassay based on a proximity hybridization-regulated strategy was developed for highly sensitive and specific detection of cell surface protein and protein-overexpressing cancer cells. A biosensor was fabricated by self-assembling a thiolated capture ss-DNA3 (partially hybridize with ss-DNA1 and ss-DNA2) and blocking with 6-mercapto-1-hexanol on a gold electrode surface. Target protein was simultaneously bound by two ss-DNA-tagged antibody probes (DNA1-Ab1 and DNA2-Ab2), while DNA1 and DNA2 were brought in sufficient proximity and hybridized with capture DNA3 on the surface of the biosensor. After ECL signal reagent Ru(phen)32+ was intercalated into the hybridized ds-DNAs, ECL measurement was performed in the coreactant solution. A "signal on" proximity hybridization-regulated ECL immunoassay for alpha-fetoprotein (AFP) was developed. The ECL intensity increased with the increase of AFP concentration in the range of 0.05-20.0 ng/mL with a detection limit of 6.2 pg/mL. Moreover, the developed ECL method was successfully used to detect AFP-overexpressing cancer cells (MCF-7 cancer cells as model) with a detection limit of 620 cells/mL (∼60 MCF-7 cells in 100 µL of cell suspension) and discriminate AFP expression on different types of the living cell surface. This work for the first time reports a proximity hybridization-regulated ECL immunoassay for the detection of the cell surface protein on a living cell surface with good specificity and sensitivity. This simple, specific, and sensitive strategy is greatly promising for the detection of proteins and specific cells.

Gene expression profiling of brain metastatic cell from triple negative breast cancer: Understanding the molecular events.

Brain metastatic triple negative breast cancer (BM-TNBC) is afflicted with unfavorable prognosis. However, the molecular events underlying BM-TNBC remain largely unknown. In the present study, we conducted gene expression microarray analysis using the triple negative breast cancer cell line MDA-MB-231 and its brain metastatic derivative (MDA-MB-231Brm). Results of microarray analysis showed that a total of 4296 genes were differentially expressed, of which 2433 genes were up-regulated and 1863 genes were down-regulated. Gene Ontology (GO), KEGG pathway and protein-protein interaction (PPI) analyses indicated differentially expressed genes functionally categorized as genes of signal transduction, multicellular organismal development, ion transport, nervous system development, plasma membrane, extracellular region, calcium ion binding, GTP binding neuroactive ligand-receptor interaction. The validity of the microarray results was verified by quantitative real-time PCR analysis of twelve representative genes. The present findings revealed molecular basis and events associated with brain metastasis in TNBC, which will potentially contribute to the understanding of underlying mechanism and develop therapeutic targets.

Aggregation-Induced Enhanced Electrochemiluminescence from Organic Nanoparticles of Donor-Acceptor Based Coumarin Derivatives.

Organic nanoparticles (NPs) from donor-acceptor based coumarin derivatives, 6-[4-(N,N-diphenylamino)phenyl]-3-ethoxycarbonyl coumarin (DPA-CM), with an average size of 5.82 nm, were synthesized by a facile reprecipitation method using water as a poor solvent and tetrahydrofuran as a good solvent. Red-shifted absorption, blue-shifted photoluminescence emission, and aggregation-induced enhanced electrochemiluminescence (ECL) emission were observed for the DPA-CM NPs in aqueous solution compared with the original DPA-CM in organic solution. The aggregation-induced enhanced ECL emission is ascribed to the combined effects of the small size of the DPA-CM NPs, the restricted conformational relaxation in the NPs, and the good stability of the cationic radical of DPA-CM. A strong and stable ECL emission is obtained at the DPA-CM NPs modified glassy carbon electrode in the presence of tri-n-propylamine, and the ECL intensity of the DPA-CM NPs modified electrode is quenched linearly in the range of 0.05-50 µM with detection limit of 0.04, 0.2, and 0.4 µM for ascorbic acid, uric acid, and dopamine, respectively. This work shows an example of donor-acceptor based organic NPs as ECL emitters and their analytical applications to monitor biomolecules.

Proximity hybridization-regulated electrogenerated chemiluminescence bioassay of α-fetoprotein via target-induced quenching mechanism.

A proximity hybridization-regulated electrogenerated chemiluminescence (PLA-ECL) bioassay was developed for the detection of α-fetoprotein (AFP) on basis of the sensitization of gold nanoparticles (AuNPs) and target-induced quenching mechanism. Ru(bpy)32+ was used as ECL signal while ferrocene (Fc) was used as ECL quencher. Ru(bpy)32+ was electrostatically adsorbed into the AuNPs/Nafion film prepared by casting the mixture of Nafion and AuNPs onto the surface of glassy carbon electrode (GCE) to form an ECL platform (Ru(bpy)32+/AuNPs/Nafion/GCE), which displayed strong ECL emissions. A recognition platform was fabricated by self-assembling a capture DNA via thiol-gold bond on the surface of Ru(bpy)32+/AuNPs/Nafion/GCE. After sandwich immunoassay and proximity hybridization assay among capture DNA, AFP, a pair of antibody-oligonucleotide conjugates and a signal probe (DNA-Fc), Fc in DNA-Fc was brought close to the surface of electrode in conjunction with target induced ECL quenching. The ECL intensity decreased with the increasing concentration of the AFP and AFP was monitored with a linear range of 0.05-50ng/mL along with a detection limit of 0.04ng/mL. The ECL bioassay is successfully applied to the detection of AFP in serum samples with one-step recognition, short operating time and good accuracy. This method displays great potential for point-of-care testing and commercial application.

Luminescence of ferrocene-modified pyrene derivatives for turn-on sensing of Cu2+ and anions.

Detection and identification of metal ions by fluorescent turn-on sensors are challenging due to the quenching effect of most of the tested metal ions. In the present work, three ferrocene-modified pyrene-based probes 2-4 were synthesized to act as turn-on fluorescent sensors for Cu2+. The measurements of fluorescence quantum yield and fluorescence lifetime reveal that ferrocenyl unit can efficiently reduce the fluorescence emission of pyrene moiety. Steady-state fluorescence measurements find that the three ferrocene-modified fluorophores exhibit selective turn-on responses to Cu2+. Moreover, this turn-on effect to Cu2+ is highly influenced by the type of the counter ion. It is found that the presence of Cl- or NO3- could realize the turn-on response to Cu2+, whereas, the presence of SO42- or Ac- could not induce any fluorescence enhancement to Cu2+. Control experiments with ferrocene-free pyrene-based probe 1 reveal that the ferrocenyl unit plays the key role in the turn-on response to Cu2+. The possible mechanism for the turn-on responses is attributed to the oxidation behavior of Cu2+ to the ferrocene unit, which is confirmed by the control experiments with sodium ascorbate. Cyclic voltammetry measurements show that Cu2+ can influence the redox behaviors of ferrocenyl derivatives, which is also highly dependent on the anion of the copper salts. The influence of anion on the turn-on responses to Cu2+ was further used for anion detection and fluorescent logic gate.

Simple and sensitive electrogenerated chemiluminescence peptide-based biosensor for detection of matrix metalloproteinase 2 released from living cells.

A simple and sensitive electrogenerated chemiluminescence biosensor was developed to monitor matrix metalloproteinase 2 (MMP-2) by employing a specific peptide (CGPLGVRGK) as a molecular recognition substrate. Bis(2,2'-bipyridine)-4'-methyl-4-carboxybipyridine-ruthenium N-succinimidyl ester-bis(hexafluorophosphate) (Ru(bpy)2(mcbpy-O-Su-ester)(PF6)2 (Ru1) was used as ECL-emitting species and covalently labeled onto the peptide through NH2-containing lysine on the peptide via acylation reaction to form Ru1-peptide as an ECL probe. An ECL peptide-based biosensor was fabricated by self-assembling the ECL probe onto the surface of gold electrode. MMP-2 can specifically cleave the Ru1-peptide on the electrode surface, which led the partly Ru1-peptide to leave the electrode surface and resulted in the decrease of the ECL intensity obtained from the resulted electrode in 0.1 M phosphate-buffered saline (pH 7.4) containing tri-n-propylamine. The decreased ECL intensity was piecewise linear to the concentration of MMP-2 in the range from 1 to 500 ng/mL. Moreover, the ECL biosensor is successfully applied to detection of MMP-2 secreted by living cell, such as HeLa cells. Additionally, the biosensor was also applied to the evaluation of matrix metalloproteinase inhibitors. The strategy presented here is promising for other disease-related matrix metalloproteinase assay and matrix metalloproteinase inhibitor profiling with sensitivity and simplicity. Graphical Abstract Detection of MMP-2 released from living cells by ECL peptide-based biosensor.

Electrogenerated chemiluminescence from heteroleptic iridium(III) complexes with multicolor emission.

Electrogenerated chemiluminescence (ECL) with different emission colors is important in the development of multichannel analytical techniques. In this report, five new heteroleptic iridium(III) complexes were synthesized, and their photophysical, electrochemical, and ECL properties were studied. Here, 2-(2,4-difluorophenyl)pyridine (dfppy, complex 1), 2-phenylbenzo[d]thiazole (bt, complex 2), and 2-phenylpyridine (ppy, complex 3) were used as the main ligands to tune the emission color, while avobenzone (avo) was used as the ancillary ligand. For comparison, complexes 4 and 5 with 2-phenylpyridine and 2-phenylbenzo[d]thiazole as the main ligand, respectively, and acetyl acetone (acac) as the ancillary ligand were also synthesized. All five iridium(III) complexes had strong intraligand absorption bands (π­π*) in the UV region (below 350 nm) and a featureless MLCT (d−π*) transition in the visible 400­500 nm range. Multicolored emissions were observed for these five iridium(III) complexes, including green, orange, and red for complexes 4, 5, 2, 1, 3, respectively. Density functional theory calculations indicate that the electronic density of the highest occupied molecular orbital is entirely located on the C^N ligands and the iridium atom, while the formation of the lowest unoccupied molecular orbital (LUMO) is complicated. The LUMO is mainly assigned to the ancillary ligand for complexes 1 and 3 but to the C^N ligand for complexes 2, 4, and 5. Cyclic voltammetry studies showed that all these complexes have a reversible oxidation wave, but no reduction waves were found in the electrochemical windows of CH2Cl2. The E1/2(ox) values of these complexes ranged from 0.642 to 0.978 V for complexes 3, 4, 2, 5, 1, (in increasing order) and are all lower than that of Ru(bpy)3(2+). Most importantly, when using tripropylamine as a coreactant, complexes 1­5 exhibited intense ECL signals with an emission wavelength centered at 616, 580, 663, 536, and 569 nm, respectively. In addition, complexes 1, 2, and 5 displayed approximately 2, 11, and 214 times higher ECL efficiencies than Ru(bpy)3(2+) under identical conditions.

Polyunsaturated fatty acid intake and risk of lung cancer: a meta-analysis of prospective studies.

BACKGROUND: Studies have reported inconsistent results for the existence of an association between polyunsaturated fatty acid (PUFA) intake and risk of lung cancer. The purpose of this study is to summarize the evidence regarding this relationship using a dose response meta-analytic approach. METHODOLOGY AND PRINCIPAL FINDINGS: We searched the PubMed, EmBase, and Cochrane Library electronic databases for related articles published through July 2013. Only prospective studies that reported effect estimates with 95% confidence intervals (CIs) of lung cancer incidence for greater than 2 categories of PUFA intake were included. We did random-effects meta-analyses of study-specific incremental estimates to determine the risk of lung cancer associated with a 5 g per day increase in PUFA intake. Overall, we included 8 prospective cohort studies reporting data on 1,268,442 individuals. High PUFA intake had little or no effect on lung cancer risk (risk ratio [RR], 0.91; 95% CI, 0.78-1.06; P = 0.230). Furthermore, the dose-response meta-analysis also suggested that a 5 g per day increase in PUFA has no significant effect on the risk of lung cancer (RR, 0.98; 95%CI: 0.96-1.01; P = 0.142). Finally, the findings of dose response curve suggested that PUFA intake of up to 15 g/d seemed to increase the risk of lung cancer. Furthermore, PUFA intake greater than 15 g/d was associated with a small beneficial effect and borderline statistical significance. Subgroup analyses for 5 g per day increment in PUFA indicated that the protective effect of PUFA was more evident in women (RR, 0.94; 95% CI, 0.87-1.01; P = 0.095) than in men (RR, 1.00; 95% CI, 0.98-1.02; P = 0.784). CONCLUSION/SIGNIFICANCE: Our study indicated that PUFA intake had little or no effect on lung cancer risk. PUFA intake might play an important role in lung cancer prevention in women.

Folate intake and the risk of breast cancer: a dose-response meta-analysis of prospective studies.

BACKGROUND: Previous observational studies regarding the existence of an association between folate intake and the risk of breast cancer have been inconsistent. This study aimed to summarize the evidence regarding this relationship using a dose-response meta-analytic approach. METHODOLOGY AND PRINCIPAL FINDINGS: We performed electronic searches of the PubMed, EmBase, and Cochrane Library databases to identify studies published through June 2013. Only prospective observational studies that reported breast cancer effect estimates with 95% confidence intervals (CIs) for more than 2 folate intake categories were included. We excluded traditional case-control studies because of possible bias from various confounding factors. Overall, we included 14 prospective studies that reported data on 677,858 individuals. Folate intake had little effect on the breast cancer risk (relative risk (RR) for highest versus lowest category = 0.97; 95% CI, 0.90-1.05; P = 0.451). Dose-response meta-analysis also suggested that a 100 µg/day increase in folate intake had no significant effect on the risk of breast cancer (RR = 0.99; 95% CI, 0.98-1.01; P = 0.361). Furthermore, we used restricted cubic splines to evaluate the nonlinear relationship between folate intake and the risk of breast cancer, and discovered a potential J-shaped correlation between folate intake and breast cancer risk (P = 0.007) and revealed that a daily folate intake of 200-320 µg was associated with a lower breast cancer risk; however, the breast cancer risk increased significantly with a daily folate intake >400 µg. CONCLUSION/SIGNIFICANCE: Our study revealed that folate intake had little or no effect on the risk of breast cancer; moreover, a dose-response meta-analysis suggested a J-shaped association between folate intake and breast cancer.

Association between folate intake and the risk of lung cancer: a dose-response meta-analysis of prospective studies.

BACKGROUND: Studies have reported inconsistent results regarding the existence of an association between folate intake and the risk of lung cancer. The purpose of this study was to summarize the evidence from prospective cohort studies regarding this relationship by using a dose-response meta-analytic approach. METHODOLOGY AND PRINCIPAL FINDINGS: In September 2013, we performed electronic searches in PubMed, Embase, and the Cochrane Library to identify studies examining the effect of folate intake on the incidence of lung cancer. Only prospective cohort studies that reported the effect estimates about the incidence of lung cancer with 95% confidence intervals (CIs) for more than 2 categories of folate intake were included. Overall, we examined 9 cohort studies reporting the data of 566,921 individuals. High folate intake had little effect on the risk of lung cancer (risk ratio [RR], 0.92; 95% CI, 0.84-1.01; P = 0.076). Dose-response meta-analysis also suggested that a 100 µg/day increase in folate intake had no significant effect on the risk of lung cancer (RR, 0.99; 95% CI, 0.97-1.01; P = 0.318). Subgroup analysis suggested that the potential protective effect of low folate intake (100-299 µg/day) was more evident in women than men, while the opposite was true of high folate intake (>400 µg/day). Finally, subgroup analyses of a 100 µg/day increment in folate intake indicated that its potential protective effect was more evident in men than in women. CONCLUSION/SIGNIFICANCE: Our study revealed that folate intake had little or no effect on the risk of lung cancer. Subgroup analyses indicated that an increased folate intake was associated with a reduced risk of lung cancer in men. Furthermore, low folate intake may be a protective factor for women, and high folate intake for men.