Why we need to pursue both universal and targeted prevention to reduce the incidence of affective and psychotic disorders: Systematic review and meta-analysis.

The effectiveness of universal preventive approaches in reducing the incidence of affective/psychotic disorders is unclear. We therefore aimed to synthesise the available evidence from randomised controlled trials. For studies reporting change in prevalence, we simulated all possible scenarios for the proportion of individuals with the disorder at baseline and at follow-up to exclude them. We then combined these data with studies directly measuring incidence and conducted random effects meta-analysis with relative risk (RR) to estimate the incidence in the intervention group compared to the control group. Eighteen studies (k=21 samples) were included investigating the universal prevention of depression in 66,625 individuals. No studies were available investigating universal prevention on the incidence of bipolar/psychotic disorders. 63 % of simulated scenarios showed a significant preventive effect on reducing the incidence of depression (k=9 - 19, RR=0.75-0.94, 95 %CIs=0.55-0.87,0.93-1.15, p=0.007-0.246) but did not survive sensitivity analyses. There is some limited evidence for the effectiveness of universal interventions for reducing the incidence of depression but not for bipolar/psychotic disorders.

Fish collagen peptides' modulating effect on human skin microbiota against pathogenic Staphylococcus aureus.

Aim: The current research aims to design effective strategies to enhance the body's immune system against pathogenic bacteria. Methods: Skin commensals were isolated, identified and cultured in fish collagen peptides (FCPs). Results: After culturing in FCP, the skin commensals were used in a dose-dependent manner for Staphylococcus aureus in a dual-culture test, which showed significant growth inhibition of the pathogenic bacteria, which concluded that FCP induced the immune defense system of skin microbiota against pathogenic strains. Conclusion: Results have validated that fish collagen peptide plays a vital role in the growth of selected human skin flora and induces more defensive immunity against pathogenic S. aureus bacteria in dual-culture experimentation.

Complement component C3 and the TLR co-receptor CD14 are not involved in angiotensin II induced cardiac remodelling.

Inflammation is centrally involved in the development of cardiac hypertrophy and the processes of remodelling. The complement system and Toll-like receptor (TLR) family, two upstream arms of the innate immune system, have previously been reported to be involved in cardiac remodelling. However, the role of complement component 3 (C3), TLR co-receptor CD14 and the synergy between them have not been addressed during pressure overload-induced cardiac remodelling. Here, we examined angiotensin II-induced cardiac hypertrophy and remodelling for 7 days in male C57Bl/6 J mice deficient in C3, CD14, or both (C3CD14), and WT controls. Angiotensin II infusion induced a mild concentric hypertrophic phenotype in WT mice with increased left ventricle weight, wall thicknesses and reduced ventricular internal diameter, associated with increased cardiac fibrosis. However, there were no differences between WT mice and mice deficient for C3, CD14 or C3CD14, as systolic blood pressure, cardiac function and structure and levels of fibrosis were comparable between WT mice and the three other genotypes. C5a did not change in angiotensin II treated mice, whereas Mac2 levels were increased in angiotensin II treated mice, but did not differ between genotypes. The inflammatory IL-6 response was comparable between WT and C3 deficient mice, however, it was decreased in CD14 and C3CD14 deficient mice. We conclude that deficiency in C3, CD14 or C3CD14 had no effect on cardiac remodelling following angiotensin II-induced pressure overload. This suggests that C3 and CD14 are not involved in angiotensin II-induced adverse cardiac remodelling.

Anti-angiogenesis Potential of Phytochemicals for the Therapeutic Management of Tumors.

The role of angiogeneses during the growth and progression of tumors is well documented. Likewise, a balance is generally maintained between the cellular proliferation and the apoptosis, therefore, the tumors can persist for years in a dormant phase. During the past few years, many hypotheses have been proposed relating to the importance of tumor angiogenesis for the development and spread of tumors and preventive or therapeutic capacity of angiogenesis inhibitors as a potential target for controlling the growth of cancerous tissue. The antiangiogenic based therapeutic approaches are considered as the most promising method for the control of tumors, as this therapeutic approach is less likely to attain the drug resistance. Further, the tumor vasculature is an important prognostic marker that can independently predict the pathological stages as well as the metastatic potential of tumors. Various biologically active phytochemicals have been extracted from the dietary sources and the plants that have engaged the scientist and pharmaceutical industries around the globe. The antioxidant, antiinflammatory, anti-proliferative and anti-angiogenic potential of these bioactive phytochemicals is evident from the in vitro studies using cell lines and investigations involving the animal models. The present review is focused on the promising role of anti-angiogenesis-based therapies for the management of tumors and the recent developments relating to the interplay of phytochemicals and angiogenesis for the suppression of tumor cells.

Modified Vaccinia Ankara-Vectored Vaccine Expressing Nucleoprotein and Matrix Protein 1 (M1) Activates Mucosal M1-Specific T-Cell Immunity and Tissue-Resident Memory T Cells in Human Nasopharynx-Associated Lymphoid Tissue.

BACKGROUND: Increasing evidence supports a critical role of CD8+ T-cell immunity against influenza. Activation of mucosal CD8+ T cells, particularly tissue-resident memory T (TRM) cells recognizing conserved epitopes would mediate rapid and broad protection. Matrix protein 1 (M1) is a well-conserved internal protein. METHODS: We studied the capacity of modified vaccinia Ankara (MVA)-vectored vaccine expressing nucleoprotein (NP) and M1 (MVA-NP+M1) to activate M1-specific CD8+ T-cell response, including TRM cells, in nasopharynx-associated lymphoid tissue from children and adults. RESULTS: After MVA-NP+M1 stimulation, M1 was abundantly expressed in adenotonsillar epithelial cells and B cells. MVA-NP+M1 activated a marked interferon γ-secreting T-cell response to M1 peptides. Using tetramer staining, we showed the vaccine activated a marked increase in M158-66 peptide-specific CD8+ T cells in tonsillar mononuclear cells of HLA-matched individuals. We also demonstrated MVA-NP+M1 activated a substantial increase in TRM cells exhibiting effector memory T-cell phenotype. On recall antigen recognition, M1-specific T cells rapidly undergo cytotoxic degranulation, release granzyme B and proinflammatory cytokines, leading to target cell killing. CONCLUSIONS: MVA-NP+M1 elicits a substantial M1-specific T-cell response, including TRM cells, in nasopharynx-associated lymphoid tissue, demonstrating its strong capacity to expand memory T-cell pool exhibiting effector memory T-cell phenotype, therefore offering great potential for rapid and broad protection against influenza reinfection.

Local and Systemic Immunity against Respiratory Syncytial Virus Induced by a Novel Intranasal Vaccine. A Randomized, Double-Blind, Placebo-controlled Clinical Trial.

Rationale: Needle-free intranasal vaccines offer major potential advantages, especially against pathogens entering via mucosal surfaces. As yet, there is no effective vaccine against respiratory syncytial virus (RSV), a ubiquitous pathogen of global importance that preferentially infects respiratory epithelial cells; new strategies are urgently required.Objectives: Here, we report the safety and immunogenicity of a novel mucosal RSV F protein vaccine linked to an immunostimulatory bacterium-like particle (BLP).Methods: In this phase I, randomized, double-blind, placebo-controlled trial, 48 healthy volunteers, aged 18-49 years, were randomly assigned to receive placebo or SynGEM (low or high dose) intranasally by prime-boost administration. The primary outcome was safety and tolerability, with secondary objectives assessing virus-specific immunogenicity.Measurements and Main Results: There were no significant differences in adverse events between placebo and vaccinated groups. SynGEM induced systemic plasmablast responses and significant, durable increases in RSV-specific serum antibody in healthy, seropositive adults. Volunteers given low-dose SynGEM (140 µg F, 2 mg BLP) required a boost at Day 28 to achieve plateau responses with a maximum fold change of 2.4, whereas high-dose recipients (350 µg F, 5 mg BLP) achieved plateau responses with a fold change of 1.5 after first vaccination that remained elevated up to 180 days after vaccination, irrespective of further boosting. Palivizumab-like antibodies were consistently induced, but F protein site ∅-specific antibodies were not detected, and virus-specific nasal IgA responses were heterogeneous, with the strongest responses in individuals with lower pre-existing antibody levels.Conclusions: SynGEM is thus the first nonreplicating intranasal RSV subunit vaccine to induce persistent antibody responses in human volunteers.Clinical trials registered with www.clinicaltrials.gov (NCT02958540).

Macrophage-Derived Granulin Drives Resistance to Immune Checkpoint Inhibition in Metastatic Pancreatic Cancer.

The ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumor microenvironment that suppresses and excludes cytotoxic CD8+ T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immunoprotective role of the metastatic tumor microenvironment in pancreatic cancer is not completely understood. In this study, we find that macrophage-derived granulin contributes to cytotoxic CD8+ T-cell exclusion in metastatic livers. Granulin expression by macrophages was induced in response to colony-stimulating factor 1. Genetic depletion of granulin reduced the formation of a fibrotic stroma, thereby allowing T-cell entry at the metastatic site. Although metastatic PDAC tumors are largely resistant to anti-PD-1 therapy, blockade of PD-1 in granulin-depleted tumors restored the antitumor immune defense and dramatically decreased metastatic tumor burden. These findings suggest that targeting granulin may serve as a potential therapeutic strategy to restore CD8+ T-cell infiltration in metastatic PDAC, thereby converting PDAC metastatic tumors, which are refractory to immune checkpoint inhibitors, into tumors that respond to immune checkpoint inhibition therapies.Significance: These findings uncover a mechanism by which metastatic PDAC tumors evade the immune response and provide the rationale for targeting granulin in combination with immune checkpoint inhibitors for the treatment of metastatic PDAC.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4253/F1.large.jpg Cancer Res; 78(15); 4253-69. ©2018 AACR.

Plant-expressed Fc-fusion protein tetravalent dengue vaccine with inherent adjuvant properties.

Dengue is a major global disease requiring improved treatment and prevention strategies. The recently licensed Sanofi Pasteur Dengvaxia vaccine does not protect children under the age of nine, and additional vaccine strategies are thus needed to halt this expanding global epidemic. Here, we employed a molecular engineering approach and plant expression to produce a humanized and highly immunogenic poly-immunoglobulin G scaffold (PIGS) fused to the consensus dengue envelope protein III domain (cEDIII). The immunogenicity of this IgG Fc receptor-targeted vaccine candidate was demonstrated in transgenic mice expressing human FcγRI/CD64, by induction of neutralizing antibodies and evidence of cell-mediated immunity. Furthermore, these molecules were able to prime immune cells from human adenoid/tonsillar tissue ex vivo as evidenced by antigen-specific CD4+ and CD8+ T-cell proliferation, IFN-γ and antibody production. The purified polymeric fraction of dengue PIGS (D-PIGS) induced stronger immune activation than the monomeric form, suggesting a more efficient interaction with the low-affinity Fcγ receptors on antigen-presenting cells. These results show that the plant-expressed D-PIGS have the potential for translation towards a safe and easily scalable single antigen-based tetravalent dengue vaccine.

Unilateral renal agenesis with subseptate uterus and sacrococcygeal teratoma: A unique triad.

Unilateral renal agenesis (URA) is a rare condition with a reported incidence of 0.93-1.8 per 1000 autopsies. It is commonly diagnosed as an incidental finding on imaging. URA is frequently associated with other genitourinary anomalies. Different associations have been described in both males and females, however, to our knowledge, it has not been reported with subseptate uterus (SSU) and sacrococcygeal teratoma (SCT) in the same individual. Here, we present a unique case of URA with SSU and SCT.

Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors.

Tumor-associated macrophages (TAM) and myofibroblasts are key drivers in cancer that are associated with drug resistance in many cancers, including pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the molecular mechanisms by which TAM and fibroblasts contribute to chemoresistance is unclear. In this study, we found that TAM and myofibroblasts directly support chemoresistance of pancreatic cancer cells by secreting insulin-like growth factors (IGF) 1 and 2, which activate insulin/IGF receptors on pancreatic cancer cells. Immunohistochemical analysis of biopsies from patients with pancreatic cancer revealed that 72% of the patients expressed activated insulin/IGF receptors on tumor cells, and this positively correlates with increased CD163+ TAM infiltration. In vivo, we found that TAM and myofibroblasts were the main sources of IGF production, and pharmacologic blockade of IGF sensitized pancreatic tumors to gemcitabine. These findings suggest that inhibition of IGF in combination with chemotherapy could benefit patients with PDAC, and that insulin/IGF1R activation may be used as a biomarker to identify patients for such therapeutic intervention. Cancer Res; 76(23); 6851-63. ©2016 AACR.

Cross-reactive immunity against influenza viruses in children and adults following 2009 pandemic H1N1 infection.

UNLABELLED: 2009 H1N1 pandemic influenza (A(H1N1)pdm09) virus infected large numbers of people worldwide. Recent studies suggest infection with A(H1N1)pdm09 virus elicited cross-reactive anti-hemagglutinin (HA) memory B cell response to conserved regions of HA. However, the breadth and magnitude of cross-reactive immunity in children and adults following A(H1N1)pdm09 infection are unknown. METHODS: We investigated serum anti-HA immunity to a number of group-1 and -2 viruses in children and adults using hemagglutination inhibition (HAI), enzyme-linked immunosorbent assay and virus neutralization assay. RESULTS: Applying hemagglutination inhibition (HAI) titers ⩾40 against A(H1N1)pdm09 as threshold of sero-positivity, we observed significantly higher levels of anti-HA antibodies to a number of virus subtypes, including those neutralizing H5N1, in subjects with HAI titer ⩾40 than those with HAI <40. Adults demonstrated broader and stronger cross-reactive anti-HA antibodies than children, including cross-reactive anti-HA1 and -HA2 antibodies. By comparison, individuals with serologic evidence of recent exposure to seasonal H1N1 or H3N2 did not show such broad cross-reactive immunity. CONCLUSION: Our results suggest individuals exposed to A(H1N1)pdm09 virus developed a broad and age-associated cross-reactive anti-HA immunity which may have important implications for future vaccination strategies to enable protection against a broader range of influenza viruses.

Immune responses to pneumococcal pilus RrgA and RrgB antigens and their relationship with pneumococcal carriage in humans.

OBJECTIVES: Pneumococcal pilus antigens are shown to be important in pneumococcal pathogenesis and induce protective immunity in animal studies, but data in humans are limited. We aimed to investigate serum and mucosal immune responses to pilus-1 proteins (RrgA and RrgB) and their relationship with pneumococcal carriage in humans. METHODS: Serum and salivary antibodies to RrgA and RrgB in children and adults were analysed by ELISA and immunoblotting. Induction of B cell antibody responses to RrgA and RrgB in nasopharynx-associated lymphoid tissue was studied by ELISpot assay following stimulation with pneumococcal culture supernatants containing pilus proteins. RESULTS: Significant levels of serum anti-RrgA and -RrgB antibodies were observed, and anti-RrgA antibody appeared to develop earlier in childhood. Importantly, anti-RrgA IgG titres in both serum and saliva were shown to be higher in culture-negative children than in those who were culture-positive for Streptococcus pneumoniae. Stimulation of adenotonsillar cells with pneumococcal culture supernatant induced significant RrgA- and RrgB-specific antibody secreting cells and antibody production. CONCLUSIONS: Pneumococcal pilus antigens, particularly RrgA, seem to induce significant serum and mucosal antibody responses that may contribute to natural immunity against pneumococcal carriage in children.

Should rituximab be the rescue therapy for refractory mixed cryoglobulinemia associated with hepatitis C?

BACKGROUND: Mixed cryoglobulinemia (CG) is a systemic immune complex-mediated disease that involves small-to-medium vessel vasculitis, provoked by the CG containing immune complexes that precipitate in cold. It is associated with hepatitis C virus (HCV) infection in 80% of patients. Mixed CG-mediated vasculitis can affect vital organs such as kidney, liver and heart. Laboratory parameters show presence of cryoglobulin, and in most cases of mixed CG, rheumatoid factor IgM kappa. The current treatment strategy of HCV-associated CG includes targeting the viral trigger HCV with a combination of antiviral medication, interferon-alpha (IFN-alpha) and ribavirin, or the downstream pathogenic events by means of plasmapheresis, steroids or immunosuppression. With multiorgan involvement, the antiviral therapy may be limited due to severity of renal disease, treatment failure, side effects or contraindications. On the other hand, immunosuppressive therapy may be poorly tolerated or ineffective. Therefore, new treatment options such as rituximab (RIT), a chimeric monoclonal anti-CD20 antibody, have been proposed as a rescue therapy. METHODS: We reviewed the literature to evaluate the current evidence in treating HCV-related refractory mixed CG. RESULTS: The use of RIT in treatment of HCV-related CG was first described by Zaja et al. Since then there have been numerous published case series and case reports. So far there has been no randomized controlled trial. In the literature, there have been 60 patients with CG treated with RIT. The male to female ratio was 14:46. Fifty-three patients were HCV-positive. Forty-six patients had mixed type II CG, 7 had type III CG and for 7 the type was not specified. Twenty-five patients had renal involvement ranging from proteinuria, to nephrotic syndrome, to nephritic syndrome to chronic kidney disease. Eight patients had had a renal transplant and were on immunosuppression. Most patients responded to RIT, with only 17 of 60 patients relapsing, and 8 of 17 of those were rechallenged with RIT with a good response. Total follow-up period varied between 3 and 31 months. CONCLUSION: RIT is a suitable rescue therapy in recalcitrant CG associated with HCV. There is evidence supporting the use of RIT as first-line therapy, as opposed to the proposals of others who would strongly recommend antiviral therapy. However, a prospective randomized controlled trial is required to evaluate the efficacy and safety of RIT compared with current standard therapy, which includes antiviral therapy, immunosuppression and plasmapheresis.