RIG-I Activation by a Designer Short RNA Ligand Protects Human Immune Cells against Dengue Virus Infection without Causing Cytotoxicity.

Virus-derived double-stranded RNA (dsRNA) molecules containing a triphosphate group at the 5' end are natural ligands of retinoic acid-inducible gene I (RIG-I). The cellular pathways and proteins induced by RIG-I are an essential part of the innate immune response against viral infections. Starting from a previously published RNA scaffold (3p10L), we characterized an optimized small dsRNA hairpin (called 3p10LG9, 25 nucleotides [nt] in length) as a highly efficient RIG-I activator. Dengue virus (DENV) infection in cell lines and primary human skin cells could be prevented and restricted through 3p10LG9-mediated activation of RIG-I. This antiviral effect was RIG-I and interferon signal dependent. The effect was temporary and was reversed above a saturating concentration of RIG-I ligand. This finding revealed an effective feedback loop that controls potentially damaging inflammatory effects of the RIG-I response, at least in immune cells. Our results show that the small RIG-I activator 3p10LG9 can confer short-term protection against DENV and can be further explored as an antiviral treatment in humans.IMPORTANCE Short hairpin RNA ligands that activate RIG-I induce antiviral responses in infected cells and prevent or control viral infections. Here, we characterized a new short hairpin RNA molecule with high efficacy in antiviral gene activation and showed that this molecule is able to control dengue virus infection. We demonstrate how structural modifications of minimal RNA ligands can lead to increased potency and a wider window of RIG-I-activating concentrations before regulatory mechanisms kick in at high concentrations. We also show that minimal RNA ligands induce an effective antiviral response in human skin dendritic cells and macrophages, which are the target cells of initial infection after the mosquito releases virus into the skin. Using short hairpin RNA as RIG-I ligands could therefore be explored as antiviral therapy.

Macrophages are more potent immune suppressors ex vivo than immature myeloid-derived suppressor cells induced by metastatic murine mammary carcinomas.

Myeloid-derived suppressor cells (MDSCs) are emerging as potential promoters of metastatic tumor growth, and there is interest in targeting immature MDSCs by inducing their differentiation into more mature myeloid cells. We used all-trans retinoic acid (ATRA) to differentiate MDSCs in mice bearing metastatic 4T1 or 4TO7 murine mammary tumors, and assessed the immune-suppressive mechanisms and potencies of different myeloid cell subpopulations. Metastatic mammary tumors induced the accumulation of distinct populations of immature CD11b(+)Gr1(+)F4/80(-)Ly6C(mid)Ly6G(+) MDSCs ("Gr1(+) cells") and mature CD11b(+)Gr1(-)F4/80(+) cells ("F4/80(+) cells") in metastatic target organs. ATRA triggered the differentiation of Gr1(+) cells into F4/80(+) cells in the lungs and, unexpectedly, enhanced pulmonary metastatic tumor growth. We found that F4/80(+)Ly6C(-)Ly6G(-) mature macrophages (Ms) were up to 30-fold more potent immune suppressors than Gr1(+) cells on a per-cell basis, which we postulate may contribute to the increased metastatic growth observed with ATRA treatment. F4/80(+) cells and Gr1(+) cells used different reactive oxygen species (ROS)-mediated mechanisms of immunosuppression ex vivo, with F4/80(+) cells producing higher levels of ROS, which is consistent with their superior immunosuppressive abilities. These data highlight the potent immunosuppressive functions of Ms, reveal that Ms can suppress T cell responses via ROS production, and suggest that ROS inhibitors may be useful in promoting antitumor immune responses. Our findings also caution against using ATRA to modulate myeloid cell differentiation and function to treat breast cancer metastases in the lung, and support the development of therapeutic strategies to enhance antitumor immunity by targeting myeloid cells as a collective group.

A low carbohydrate, high protein diet combined with celecoxib markedly reduces metastasis.

We recently demonstrated that both murine and human carcinomas grow significantly slower in mice on low carbohydrate (CHO), high protein diets than on isocaloric Western diets and that a further reduction in tumor growth rates occur when the low CHO diets are combined with the cyclooxygenase-2 inhibitor, celecoxib. Following upon these studies, we asked herein what effect low CHO, high protein diets, with or without celecoxib, might have on tumor metastasis. In the highly metastatic 4T1 mouse mammary tumor model, a 15% CHO, high protein diet supplemented with celecoxib (1 g/kg chow) markedly reduced lung metastases. Moreover, in longer-term studies using male Transgenic Adenocarcinoma of the Mouse Prostate mice, which are predisposed to metastatic prostate cancer, the 15% CHO diet, with and without celecoxib (0.3 g/kg chow), gave the lowest incidence of metastases, but a more moderate 25% CHO diet containing celecoxib led to the best survival. Metabolic studies with 4T1 tumors suggested that the low CHO, high protein diets may be forcing tumors to become dependent on amino acid catabolism for survival/growth. Taken together, our results suggest that a combination of a low CHO, high protein diet with celecoxib substantially reduces metastasis.

Hormone-sensing cells require Wip1 for paracrine stimulation in normal and premalignant mammary epithelium.

INTRODUCTION: The molecular circuitry of different cell types dictates their normal function as well as their response to oncogene activation. For instance, mice lacking the Wip1 phosphatase (also known as PPM1D; protein phosphatase magnesium-dependent 1D) have a delay in HER2/neu (human epidermal growth factor 2), but not Wnt1-induced mammary tumor formation. This suggests a cell type-specific reliance on Wip1 for tumorigenesis, because alveolar progenitor cells are the likely target for transformation in the MMTV(mouse mammary tumor virus)-neu but not MMTV-wnt1 breast cancer model. METHODS: In this study, we used the Wip1-knockout mouse to identify the cell types that are dependent on Wip1 expression and therefore may be involved in the early stages of HER2/neu-induced tumorigenesis. RESULTS: We found that alveolar development during pregnancy was reduced in Wip1-knockout mice; however, this was not attributable to changes in alveolar cells themselves. Unexpectedly, Wip1 allows steroid hormone-receptor-positive cells but not alveolar progenitors to activate STAT5 (signal transducer and activator of transcription 5) in the virgin state. In the absence of Wip1, hormone-receptor-positive cells have significantly reduced transcription of RANKL (receptor activator of nuclear factor kappa-B ligand) and IGF2 (insulin-like growth factor 2), paracrine stimulators of alveolar development. In the MMTV-neu model, HER2/neu activates STAT5 in alveolar progenitor cells independent of Wip1, but HER2/neu does not override the defect in STAT5 activation in Wip1-deficient hormone-sensing cells, and paracrine stimulation remains attenuated. Moreover, ERK (extracellular signal-regulated kinase) activation by HER2/neu in hormone-sensing cells is also Wip1 dependent. CONCLUSIONS: We identified Wip1 as a potentiator of prolactin and HER2/neu signaling strictly in the molecular context of hormone-sensing cells. Furthermore, our findings highlight that hormone-sensing cells convert not only estrogen and progesterone but also prolactin signals into paracrine instructions for mammary gland development. The instructive role of hormone-sensing cells in premalignant development suggests targeting Wip1 or prolactin signaling as an orthogonal strategy for inhibiting breast cancer development or relapse.

SHIP represses Th2 skewing by inhibiting IL-4 production from basophils.

We report that SHIP(-/-) mice, compared to SHIP(+/+) mice, are Th2 skewed with elevated serum IgE and twice as many splenic CD4(+) Th2 cells that, when stimulated with anti-CD3, produce more IL-4 and less IFN-γ. Exploring the reason for this Th2 skewing, we found that freshly isolated SHIP(-/-) splenic and bone marrow basophils are present in elevated numbers and secrete far more IL-4 in response to IL-3 or to FcεRI stimulation than do WT basophils. These SHIP(-/-) basophils markedly skew wild-type macrophage colony stimulating factor-derived macrophages toward an M2 phenotype, stimulate OT-II CD4(+) Th cells to differentiate into Th2 cells, and trigger SHIP(+/+) B cells to become IgE-producing cells. All these effects are completely abrogated with neutralizing anti-IL-4 Ab. Exploring the cell signaling pathways responsible for hyperproduction of IL-4 by SHIP(-/-) basophils, we found that IL-3-induced activation of the PI3K pathway is significantly enhanced and that PI3K inhibitors, especially a p110α inhibitor, dramatically suppresses IL-4 production from these cells. In vivo studies, in which basophils were depleted from mast cell-deficient SHIP(+/+) and SHIP(-/-) mice, confirmed the central role that basophils play in the Th2 skewing of naive SHIP-deficient mice. Taken together, these studies demonstrate that SHIP is a potent negative regulator of IL-4 production from basophils and thus may be a novel therapeutic target for Th1- and Th2-related diseases.

Morphology and thermodynamic properties of a copolymer with an electronically conducting block: poly(3-ethylhexylthiophene)-block-poly(ethylene oxide).

We report on the synthesis and morphology of a block copolymer, poly(3-(2'-ethylhexyl)thiophene)-b-poly(ethylene oxide) (P3EHT-b-PEO), that conducts both electrons and ions. We show that in the melt state the P3EHT-b-PEO chains self-assemble to produce traditional nanoscale morphologies such as lamellae and gyroid. This is in contrast to a majority of previous studies on copolymers with electronically conducting blocks wherein a nanofibrillar morphology is obtained. Our approach enables estimation of the Flory-Huggins interaction parameter, χ. The segregation strength between the two blocks is controlled through the addition of lithium bis(trifluoromethanesulfonyl)imide (LiTFSI). For the salt-free sample, the gyroid morphology, obtained in the melt state, is transformed into lamellae below the melting temperature of the P3EHT block. This is due to the "breaking out" of the crystalline phase. For the salt-containing sample, P3EHT-b-PEO has a lamellar morphology in both melt and crystalline states (confined crystallization).

Discourse markers in TV interviews: A corpus-based comparative study of Chinese and the western media.

This article, which is part of an on-going large-scale study, quantitatively explores and compares the frequency, patterns, and positions of the three most frequently used discourse markers (DMs): so, and, but in TV interviews. The data comprise three corpora consisting of three media programs from China, the US, and the UK. Results show that there is a statistically significant difference in the frequency of the DM so and the DM and, with each DM having the highest frequency in a specific corpus. Four co-occurring strings ("and so," "and but," "so but," "but so") are identified in the three corpora with the DM co-occurrence "and so" having the highest frequency in the American program, supporting the claim that this combination is a typical use in American English. The general positional distribution of the three DMs is similar with the highest tendency in the initial position, which can be attributed to the program's interactivity. The findings will enhance our understanding of the three DMs used in media discourse and should be of practical significance to media hosts and guests in achieving better bilateral communication.

Poly(3-alkylthiophene) diblock copolymers with ordered microstructures and continuous semiconducting pathways.

Conjugated rod-coil diblock copolymers self-assemble due to a balance of liquid crystalline (rod-rod) and enthalpic (rod-coil) interactions. Previous work has shown that while classical block copolymers self-assemble into a wide variety of nanostructures, when rod-rod interactions dominate self-assembly in rod-coil block copolymers, lamellar structures are preferred. Here, it is demonstrated that other, potentially more useful, nanostructures can be formed when these two interactions are more closely balanced. In particular, hexagonally packed polylactide (PLA) cylinders embedded in a semiconducting poly(3-alkylthiophene) (P3AT) matrix can be formed. This microstructure has been long-sought as it provides an opportunity to incorporate additional functionalities into a majority phase nanostructured conjugated polymer, for example in organic photovoltaic applications. Previous efforts to generate this phase in polythiophene-based block copolymers have failed due to the high driving force for P3AT crystallization. Here, we demonstrate that careful design of the P3AT moiety allows for a balance between crystallization and microphase separation due to chemical dissimilarity between copolymer blocks. In addition to hexagonally packed cylinders, P3AT-PLA block copolymers form nanostructures with long-range order at all block copolymer compositions. Importantly, the conjugated moiety of the P3AT-PLA block copolymers retains the crystalline packing structure and characteristic high time-of-flight charge transport of the homopolymer polythiophene (µ(h) ~10(-4) cm(2) V(-1) s(-1)) in the confined geometry of the block copolymer domains.

SHIP prevents lipopolysaccharide from triggering an antiviral response in mice.

Gram-negative bacterial infections, unlike viral infections, do not typically protect against subsequent viral infections. This is puzzling given that lipopolysaccharide (LPS) and double-stranded (ds) RNA both activate the TIR domain-containing adaptor-inducing interferon beta (TRIF) pathway and, thus, are both capable of eliciting an antiviral response by stimulating type I interferon (IFN) production. We demonstrate herein that SH2-containing inositol-5'-phosphatase (SHIP) protein levels are dramatically increased in murine macrophages via the MyD88-dependent pathway, by up-regulating autocrine-acting transforming growth factor-beta (TGFbeta). The increased SHIP then mediates, via inhibition of the phosphatidylinositol-3-kinase (PI3K) pathway, cytosine-phosphate-guanosine (CPG)- and LPS-induced tolerance and cross-tolerance and restrains IFN-beta production induced by a subsequent exposure to LPS or dsRNA. Intriguingly, we found, using isoform-specific PI3K inhibitors, that LPS- or cytosine-phosphate-guanosine-induced interleukin-6 (IL-6) is positively regulated by p110alpha, -gamma, and -delta but negatively regulated by p110beta. This may explain some of the controversy concerning the role of PI3K in Toll-like receptor-induced cytokine production. Consistent with our in vitro findings, SHIP(-/-) mice overproduce IFN-beta in response to LPS, and this leads to antiviral hypothermia. Thus, up-regulation of SHIP in response to Gram-negative bacterial infections probably explains the inability of such infections to protect against subsequent viral infections.

SHIP represses the generation of IL-3-induced M2 macrophages by inhibiting IL-4 production from basophils.

There is a great deal of interest in determining what regulates the generation of classically activated (M1) vs alternatively activated (M2) macrophages (Mphis) because of the opposing effects that these two Mphi subsets have on tumor progression. We show herein that IL-3 and, to a lesser extent, GM-CSF skew murine Mphi progenitors toward an M2 phenotype, especially in the absence of SHIP. Specifically, the addition of these cytokines, with or without M-CSF, to adherence- or lineage-depleted (Lin(-)) SHIP(-/-) bone marrow (BM) cells induces high levels of the M2 markers, arginase I, and Ym1 in the resulting mature Mphis. These in vitro-derived mature Mphis also display other M2 characteristics, including an inability to enhance anti-CD3-stimulated splenic T cell secretion of IFN-gamma and low IL-12 and high IL-10 production in response to LPS. Not surprisingly, given that IL-3 and GM-CSF utilize STAT5 to trigger many downstream signaling pathways, this M2 phenotype is suppressed when STAT5(-/-) BM cells are used. Unexpectedly, however, this M2 phenotype is also suppressed when STAT6(-/-) BM cells are used, suggesting that IL-4- or IL-13-induced signaling might be involved. Consistent with this, we found that IL-3 and GM-CSF stimulate the production of IL-4, especially from SHIP(-/-) Lin(-) BM cells, and that neutralizing anti-IL-4 Abs block IL-3-induced M2 skewing. Moreover, we found that basophil progenitors within the Lin(-) BM are responsible for this IL-3- and GM-CSF-induced IL-4 production, and that SHIP represses M2 skewing not by preventing skewing within Mphis themselves but by inhibiting IL-4 production from basophils.

Optical Trapping and Manipulating with a Silica Microring Resonator in a Self-Locked Scheme.

Based on the gradient force of evanescent waves in silica waveguides and add-drop micro-ring resonators, the optical trapping and manipulation of micro size particles is demonstrated in a self-locked scheme that maintains the on-resonance system even if there is a change in the ambient temperature or environment. The proposed configuration allows the trapping of particles in the high Q resonator without the need for a precise wavelength adjustment of the input signal. On the one hand, a silicon dioxide waveguide having a lower refractive index and relatively larger dimensions facilitates the coupling of the laser with a single-mode fiber. Furthermore, the experimental design of the self-locked scheme reduces the sensitivity of the ring to the environment. This combination can trap the micro size particles with a high stability while manipulating them with high accuracy.

Temporal release of a three-component protein subunit vaccine from polymer multilayers.

Sustained antigen and adjuvant availability have been shown to improve antiviral immune responses following vaccination. Transcutaneous delivery of vaccines using microneedles has also shown promise and may be particularly relevant for mosquito-borne viruses. We aim to combine these traits to create a three-component Protein Subunit vaccine on Microneedle Arrays (PSMNs) for transcutaneous delivery using layer-by-layer (LbL) assembly. Polymer multilayer thin films were generated to co-deliver a model combination of three chemically distinct vaccine components, a dengue virus Envelope protein Domain III (EDIII) subunit antigen and two adjuvants, a double-stranded RNA (Poly (inosinic:cytidylic acid) (PolyI:C)) and an amphiphilic hexapeptide, Pam3CSK4. Following application of PSMNs to the skin, implanted thin films facilitated sustained and temporal release of individual vaccine components from polymer multilayers. By modulating LbL composition and architecture, component release profiles in the skin could be independently tuned to allow release of adjuvants and antigen from days up to two weeks. Uptake of antigen and adjuvant from implanted vaccine films by antigen-presenting cells was demonstrated using in vivo mouse and ex vivo human skin models. Overall, we believe that such modular vaccine strategies offer design principles for enhancing the immunogenicity of protein subunit vaccines.

Iliac artery dissection - A rare complication of renal transplantation: A case report and literature review.

External iliac artery dissection is a rare and under-reported vascular complication after renal transplantation. The etiology is yet to be fully understood. The presentation, investigation and management of this condition are highly variable. Here we report a 52-year-old man successfully treated by endovascular stenting with nitinol stents for an external iliac artery dissection proximal to the anastomosis.

Distinct fibroblast functional states drive clinical outcomes in ovarian cancer and are regulated by TCF21.

Recent studies indicate that cancer-associated fibroblasts (CAFs) are phenotypically and functionally heterogeneous. However, little is known about CAF subtypes, the roles they play in cancer progression, and molecular mediators of the CAF "state." Here, we identify a novel cell surface pan-CAF marker, CD49e, and demonstrate that two distinct CAF states, distinguished by expression of fibroblast activation protein (FAP), coexist within the CD49e+ CAF compartment in high-grade serous ovarian cancers. We show for the first time that CAF state influences patient outcomes and that this is mediated by the ability of FAP-high, but not FAP-low, CAFs to aggressively promote proliferation, invasion and therapy resistance of cancer cells. Overexpression of the FAP-low-specific transcription factor TCF21 in FAP-high CAFs decreases their ability to promote invasion, chemoresistance, and in vivo tumor growth, indicating that it acts as a master regulator of the CAF state. Understanding CAF states in more detail could lead to better patient stratification and novel therapeutic strategies.

Derivation and characterization of murine alternatively activated (M2) macrophages.

Diversity in macrophage responsiveness to inflammatory stimuli has resulted in the description of a new paradigm wherein macrophages are referred to as polarized into one of two distinct phenotypes, classically activated (M1) macrophages and alternatively activated (M2) macrophages. Classically activated, M1 or "killer" macrophages are thought to play a critical role in destroying foreign organisms and tumor cells, while alternatively activated M2 or "healer" macrophages are thought to be important in debris scavenging, wound healing, and angiogenesis. M2 macrophages may also play key roles in chronic infections, tumorigenesis, and tumor metastasis. It is therefore important to establish models of M1 and M2 polarized macrophages to study their characteristics and amenability to manipulation. M1 macrophages are typically derived from myeloid progenitors with murine macrophage-colony-stimulating factor (M-CSF, also known as CSF-1), while M2 macrophages are thought to be derived from mature M1 macrophages by treatment with interleukin-4 (IL-4) or IL-13. M2 macrophages can also be isolated from SH2-containing inositol 5'-phosphatase (SHIP)-/- mice by harvesting macrophages from peritoneal lavage fluids or they can be derived from SHIP-/- bone marrow aspirate cells with addition of 5% human serum. Upon stimulation with lipopolysaccharide (LPS), M1 macrophages produce high levels of proinflammatory cytokines, low levels of anti-inflammatory cytokines, and high levels of inducible nitric oxide synthase (iNOS), which leads to nitric oxide (NO) production. M2 macrophages, on the other hand, express high levels of M2 markers Ym1 and arginase I (ArgI) and, upon stimulation with LPS, produce relatively lower levels of proinflammatory cytokines and NO and higher levels of anti-inflammatory cytokines. In this chapter, we describe methods used in our laboratory to generate and characterize alternatively activated (M2) macrophages.

A hierarchical classification of adolescent idiopathic scoliosis: Identifying the distinguishing features in 3D spinal deformities.

This study aimed to identify the differentiating parameters of the spinal curves' 2D projections through a hierarchical classification of the 3D spinal curve in adolescent idiopathic scoliosis (AIS). A total number of 103 right thoracic left lumbar pre-operative AIS patients were included retrospectively and consecutively. A total number of 20 non-scoliotic adolescents were included as the control group. All patients had biplanar X-rays and 3D reconstructions of the spine. The 3D spinal curve was calculated by interpolating the center of vertebrae and was isotropically normalized. A hierarchical classification of the normalized spinal curves was developed to group the patients based on the similarity of their 3D spinal curve. The spinal curves' 2D projections and clinical spinal measurements in the three anatomical planes were then statistically compared between these groups and between the scoliotic subtypes and the non-scoliotic controls. A total of 5 patient groups of right thoracic left lumbar AIS patients were identified. The characteristics of the posterior-anterior and sagittal views of the spines were: Type 1: Normal sagittal profile and S shape axial view. T1 is leveled or tilted to the right in the posterior view. Type 2: Hypokyphotic and a V shape axial view. T1 is tilted to the left in the posterior view. Type 3: Hypokyphotic (only T5-T10) and frontal imbalance, S shape axial view. T1 is leveled or tilted to the right, and 3 frontal curves. Type 4: Flat sagittal profile (T1-L2), slight frontal imbalance with a V shape axial view, T1 tilted to the left. Type 5: flat sagittal profile and forward trunk shift with a proximal kyphosis and S shape axial view. T1 is leveled or tilted to the right. In conclusion, a hierarchical classification of the 3D scoliotic spine allowed identifying various distinguishing features of the spinal curves in patients with a right thoracic curve in an orderly fashion. The subtypes' characteristics resulting from this 3D classification can be identified from the pairs of the frontal and sagittal spinal curves i.e. X-rays in right thoracic AIS patients.

Structure-guided design of immunomodulatory RNAs specifically targeting the cytoplasmic viral RNA sensor RIG-I.

The cytoplasmic immune sensor RIG-I detects viral RNA and initiates an antiviral immune response upon activation. It has become a potential target for vaccination and immunotherapies. To develop the smallest but potent immunomodulatory RNA (immRNAs) species, we performed structure-guided RNA design and used biochemical, structural, and cell-based methods to select and characterize the immRNAs. We demonstrated that inserting guanosine at position 9 to the 10mer RNA hairpin (3p10LG9) activates RIG-I more robustly than the parental RNA. 3p10LG9 interacts strongly with the RIG-I helicase-CTD RNA sensing module and disrupts the auto-inhibitory interaction between the HEL2i and CARDs domains. We further showed that 3p10LA9 has a stronger cellular activity than 3p10LG9. Collectively, purine insertion at position 9 of the immRNA species triggered more robust activation of RIG-1.

Dengue Mosaic Vaccines Enhance Cellular Immunity and Expand the Breadth of Neutralizing Antibody Against All Four Serotypes of Dengue Viruses in Mice.

An estimated 400 million people in the world are infected with any of the four types of dengue virus (DENV) annually. The only licensed dengue vaccine cannot effectively prevent infection with all of the four DENVs, especially in those immunologically naïve at baseline. In this study, we explored a mosaic vaccine approach, which utilizes an artificial recombinant sequence for each serotype to achieve maximum coverage of variant epitopes in the four DENVs. We determined the immunogenicity and cross-reactivity of DNA plasmids encoding individual mosaic sequences or the natural sequences in mice. We show that the mosaic vaccines, particularly those targeting DENV serotype 1 and 2, improved vaccine immunogenicity by increasing the percentage of antigen-specific IFNγ- or TNFα-secreting CD4 and CD8 T cells, and titers of neutralizing antibodies. The mosaic vaccine diversified and broadened anti-dengue T cell responses and cross-reactive neutralizing antibodies against all four serotypes. The mosaic vaccines also induced higher level of antigen-specific B cell responses. These results suggest that mosaic vaccines comprising of DENV serotype 1 and 2 variant epitopes could stimulate strong and broad immune responses against all four serotypes.

N-Glycoproteomics of Patient-Derived Xenografts: A Strategy to Discover Tumor-Associated Proteins in High-Grade Serous Ovarian Cancer.

High-grade serous ovarian carcinoma (HGSC) is the most common and lethal subtype of gynecologic malignancy in women. The current standard of treatment combines cytoreductive surgery and chemotherapy. Despite the efficacy of initial treatment, most patients develop cancer recurrence, and 70% of patients die within 5 years of initial diagnosis. CA125 is the current FDA-approved biomarker used in the clinic to monitor response to treatment and recurrence, but its impact on patient survival is limited. New strategies for the discovery of HGSC biomarkers are urgently needed. Here, we describe a proteomics strategy to detect tumor-associated proteins in serum of HGSC patient-derived xenograft models. We demonstrate proof-of-concept applicability using two independent, longitudinal serum cohorts from HGSC patients.

Erratum: Author Correction: Mimicking immune signatures of flavivirus infection with targeted adjuvants improves dengue subunit vaccine immunogenicity.

[This corrects the article DOI: 10.1038/s41541-019-0119-3.].