Primary cancer prevention for cancers with no known infectious etiology: Time for a new paradigm.

Vaccines developed for hepatitis B and human papilloma virus infections have been very successful in reducing the burden of cancer due to these infections. In the past decade, our understanding of the immunology of cancer has greatly improved and important progress has been made in the use of immunotherapy for several cancers. However, for the majority of cancers, an infectious etiology is either unknown or does not exist. Prostate cancer, for which no infectious etiology is known, is the most common cancer in men in the United States. Here we discuss the rationale for developing a preventive vaccine for prostate cancer, discuss a possible approach for further work in this area and a means of testing the effectiveness of a prostate cancer prevention vaccine in a clinical trial.

Polychlorinated Biphenyls and Pulmonary Hypertension.

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that were banned because of their potential carcinogenicity. Population studies have shown that PCBs are associated with lung toxicity and hypertension. The objective of this study was to evaluate whether higher exposure to PCB congeners is associated with the risk of pulmonary hypertension. Serum levels of PCBs in 284 subjects with combined risk factors for pulmonary arterial hypertension (PAH) were compared to 4210 subjects with no risk for PAH using the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004. The major findings from this study include significantly higher PCB levels in PAH subjects compared to non-PAH subjects; for example, the geometric mean (GM) of PCB74 was 15.91 (ng/g) (14.45-17.53) vs. 11.48 (ng/g) (10.84-12.16), respectively. Serum levels of PCB congeners showed an increasing trend in the age group 20-59 years as PCB180 GM was 19.45 (ng/g) in PAH vs. 12.75 (ng/g) in the control. A higher body burden of PCB153 followed by PCB138, PCB180, and PCB118 was observed. Estimated age, race, BMI, and gender-adjusted ORs for PCB congener levels in subjects with the combined risk factors for PAH compared to controls was significant; for example, PCB99 (OR: 1.5 (CI: 1.49-1.50). In summary, these findings indicate that exposure, as well as body burden estimated based on lipid adjustment of PCBs, were higher in people with risk factors for PAH, and PCB congeners accumulated with age. These findings should be interpreted with caution because of the use of cross-sectional self-reported data and a small sample size of subjects with combined risk factors for pulmonary arterial hypertension. Nonetheless, our finding emphasizes a need for a comprehensive environmental molecular epidemiologic study to determine the potential role of environmental exposures to PCBs in the development of pulmonary arterial hypertension.

Just How Attractive is the ATTRACT Trial?

Venous thromboembolism (VTE) is a major public health issue; deep vein thrombosis (DVT) affects about 1/1000 patients. Each year, VTE kills more patients in Western Europe than breast cancer, prostate cancer, acquired immune deficiency syndrome (AIDS) and road traffic accidents combined and is responsible for the deaths of approximately 370,000 European citizens (Cohen et al. in Thromb Haemost 98:756-764, 2007; Belohlávek et al. in Exp Clin Cardiol 18(2):129-138, 2013). The recently published ATTRACT trial (Acute Venous Thrombosis Thrombus Removal with Adjunctive Catheter-directed Thrombolysis) (Vedantham et al. in N Engl J Med 377:2240-2252, 2017) concluded that the addition of catheter-directed thrombolysis to standard therapy with anticoagulation and compression stockings offers no significant clinical benefit over standard therapy in terms of reduction in the rate of post-thrombotic syndrome (PTS) at 2 years. It is the largest, prospective, multi-centre, randomised controlled trial (RCT) and represents the culmination over a decade of planning, execution and analysis. In this opinion article, we analyse why it was needed, what it demonstrated, some limitations, and the directions in which this important publication will take us.

The Safety of PsA-TT in Pregnancy: An Assessment Performed Within the Navrongo Health and Demographic Surveillance Site in Ghana.

BACKGROUND: Group A meningococcal disease occurs in large epidemics within the meningitis belt of Africa that includes northern Ghana. Major epidemics in the meningitis belt have infection rates ranging from 100 to 800 per 100 000 population. In 2012, a group A meningococcal conjugate vaccine, PsA-TT (MenAfriVac), was introduced into the region in large campaigns. METHODS: We report here on the safety of this vaccine when used in pregnant women in the Navrongo region of Ghana. RESULTS: Rates of events in 1730 immunized pregnant women and their infants were compared to the rates of the same events in pregnant women who did not receive the vaccine during the campaign and also to women who were pregnant in the prior year. CONCLUSIONS: We found no evidence of any safety concerns when this vaccine was administered during pregnancy.

Developing vaccines for an aging population.

The demographics of the world's population are changing, with many adults now surviving into their 80s. With this change comes the need to protect the aging and other underserved populations not only against infectious diseases but also against cancer and other chronic conditions. New technologies derived from recent advances in the fields of immunology, structural biology, synthetic biology, and genomics have brought a revolution in the vaccine field. Among them, vaccine adjuvants have the potential to harness the immune system to provide protection against new types of diseases, improve protection in young children, and expand this protection to adults and the elderly. However, in order to do so we need also to overcome the nontechnical challenges that could limit the implementation of innovative vaccines, including controversies regarding the safety of adjuvants, increasing regulatory complexity, the inadequate methods used to assess the value of novel vaccines, and the resulting industry alienation from future investment. This Perspective summarizes the outcome of a recent multidisciplinary symposium entitled "Enhancing Vaccine Immunity and Value," held in Siena, Italy, in July 2014, that addressed two related questions: how to improve vaccine efficacy by using breakthrough technologies and how to capture the full potential of novel vaccines.

Clinical outcomes of single versus staged hybrid repair for thoracoabdominal aortic aneurysm.

OBJECTIVE: We investigated the outcomes of hybrid repair of thoracoabdominal aortic aneurysms and performed meta-analyses and meta-regressions to assess whether the number of stages during hybrid repair is associated with mortality. METHODS: Review methods were according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The primary outcome was 30-day mortality. Secondary outcomes of procedural and clinical success were reported descriptively. Meta-analyses, meta-regressions, and logistic regressions were performed to estimate the odds ratio (OR) describing the association between the staging of the operation and in-hospital death. RESULTS: We included 19 studies of 660 patients. Procedures were single-staged in 288 patients and staged in 372. Perioperative mortality ranged from 0% to 44.4%, and spinal cord ischemia ranged from 0% to 15.3%. After a mean follow-up of 26 months (range, 6-88.5 months), the overall mortality was 20.8%. The meta-regression of all studies' summary data (OR, 0.64; 95% confidence interval [CI], 0.19-2.16; P = .45; I(2) = 0.42) and a meta-regression where mortality rates in four studies were stratified by operative staging (OR, 0.57; 95% CI, 0.24-1.36; P = .19; I(2) = 0.38) supported a two-stage procedure but failed to reach statistical significance. Logistic regressions of individual patient data from a single center demonstrated evidence that a staged procedure was safer (adjusted OR, 0.04; 95% CI, 0.00-0.96; P < .05). CONCLUSIONS: Hybrid repair of thoracoabdominal aortic aneurysms may reduce early morbidity and mortality even in a group considered high risk for open surgery but still carries risks of perioperative complications. This study suggested advantages to a staged procedure, but statistically significant evidence is lacking. Prospective data are still needed to optimize hybrid repair and best define its role.

Use of MenACWY-CRM in adolescents in the United States.

Adolescents constitute a high-risk group for invasive meningococcal disease. MenACWY-CRM (Menveo, Novartis Vaccines, Cambridge, MA) is a quadrivalent meningococcal conjugate vaccine indicated to prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, W-135, and Y. It has been approved for use in persons age 2-55 years. The tolerability and immunogenicity of MenACWY-CRM in adolescents have been ascertained in phase 2 and 3 trials against MPSV4 (Menomune, sanofi pasteur, Swiftwater, PA), an unconjugated quadrivalent meningococcal vaccine, and MenACWY-D (Menactra, sanofi pasteur), another conjugated quadrivalent meningococcal vaccine. Clinical trials also have demonstrated that MenACWY-CRM is well tolerated and immunogenic when administered to adolescents concomitantly with the combined tetanus, diphtheria, and acellular pertussis vaccine (Boostrix, GlaxoSmithKline Biologicals, Rixensart, Belgium) and the quadrivalent human papillomavirus vaccine (Gardasil, Merck & Co., Inc., Whitehouse Station, NJ).

Toward a meningitis-free world.

Meningococcal meningitis is a devastating disease that is often fatal. Vaccines against the five major meningococcal serogroups causing disease are about to become available, a conjugate vaccine against meningococcus A is in use for mass vaccination in Africa, and a protein-based vaccine against meningococcal B is ready for licensure. With the availability of these new vaccines, the world can finally be rid of meningococcal meningitis, thus rewriting a new chapter in medical history.

Vaccine discovery and translation of new vaccine technology.

An unprecedented increase in new vaccine development has occurred over the past three decades. This activity has resulted in vaccines that protect against an increased range of vaccine-preventable diseases, vaccines that reduce the number of required injections, and vaccines with improved safety and purity. New methods of discovery, such as reverse vaccinology, structural biology, and systems biology, promise new vaccines for different diseases and efficient development pathways for these vaccines. We expect development of vaccines not only for infectious diseases in children but also for healthy adults, pregnant women, and elderly people, and for new indications such as autoimmune disease and cancer. We have witnessed a concomitant development of new technology for assessment of vaccine safety to rapidly identify potential safety issues. Success of these new approaches will depend on effective implementation of vaccination programmes, creative thinking on the part of manufacturers and regulators as to how best to ensure that safe and effective vaccines are available in a timely manner, and improvement of public awareness about the benefits and risks of new vaccines in a way that encourages confidence in vaccines.

The A2B adenosine receptor promotes Th17 differentiation via stimulation of dendritic cell IL-6.

Adenosine is an endogenous metabolite produced during hypoxia or inflammation. Previously implicated as an anti-inflammatory mediator in CD4(+) T cell regulation, we report that adenosine acts via dendritic cell (DC) A(2B) adenosine receptor (A(2B)AR) to promote the development of Th17 cells. Mouse naive CD4(+) T cells cocultured with DCs in the presence of adenosine or the stable adenosine mimetic 5'-(N-ethylcarboximado) adenosine resulted in the differentiation of IL-17- and IL-22-secreting cells and elevation of mRNA that encode signature Th17-associated molecules, such as IL-23R and RORγt. The observed response was similar when DCs were generated from bone marrow or isolated from small intestine lamina propria. Experiments using adenosine receptor antagonists and cells from A(2B)AR(-/-) or A(2A)AR(-/-)/A(2B)AR(-/-) mice indicated that the DC A(2B)AR promoted the effect. IL-6, stimulated in a cAMP-independent manner, is an important mediator in this pathway. Hence, in addition to previously noted direct effects of adenosine receptors on regulatory T cell development and function, these data indicated that adenosine also acts indirectly to modulate CD4(+) T cell differentiation and suggested a mechanism for putative proinflammatory effects of A(2B)AR.

Brain angiogenesis inhibitor 1 (BAI1) is a pattern recognition receptor that mediates macrophage binding and engulfment of Gram-negative bacteria.

Bacterial recognition by host cells is essential for initiation of infection and the host response. Bacteria interact with host cells via multiple pattern recognition receptors that recognize microbial products or pathogen-associated molecular patterns. In response to this interaction, host cell signaling cascades are activated that lead to inflammatory responses and/or phagocytic clearance of attached bacteria. Brain angiogenesis inhibitor 1 (BAI1) is a receptor that recognizes apoptotic cells through its conserved type I thrombospondin repeats and triggers their engulfment through an ELMO1/Dock/Rac1 signaling module. Because thrombospondin repeats in other proteins have been shown to bind bacterial surface components, we hypothesized that BAI1 may also mediate the recognition and clearance of pathogenic bacteria. We found that preincubation of bacteria with recombinant soluble BAI1 ectodomain or knockdown of endogenous BAI1 in primary macrophages significantly reduced binding and internalization of the Gram-negative pathogen Salmonella typhimurium. Conversely, overexpression of BAI1 enhanced attachment and engulfment of Salmonella in macrophages and in heterologous nonphagocytic cells. Bacterial uptake is triggered by the BAI1-mediated activation of Rac through an ELMO/Dock-dependent mechanism, and inhibition of the BAI1/ELMO1 interaction prevents both Rac activation and bacterial uptake. Moreover, inhibition of ELMO1 or Rac function significantly impairs the proinflammatory response to infection. Finally, we show that BAI1 interacts with a variety of Gram-negative, but not Gram-positive, bacteria through recognition of their surface lipopolysaccharide. Together these findings identify BAI1 as a pattern recognition receptor that mediates nonopsonic phagocytosis of Gram-negative bacteria by macrophages and directly affects the host response to infection.

Beta-actin association with endothelial nitric-oxide synthase modulates nitric oxide and superoxide generation from the enzyme.

Protein-protein interactions represent an important post-translational mechanism for endothelial nitric-oxide synthase (eNOS) regulation. We have previously reported that beta-actin is associated with eNOS oxygenase domain and that association of eNOS with beta-actin increases eNOS activity and nitric oxide (NO) production. In the present study, we found that beta-actin-induced increase in NO production was accompanied by decrease in superoxide formation. A synthetic actin-binding sequence (ABS) peptide 326 with amino acid sequence corresponding to residues 326-333 of human eNOS, one of the putative ABSs, specifically bound to beta-actin and prevented eNOS association with beta-actin in vitro. Peptide 326 also prevented beta-actin-induced decrease in superoxide formation and increase in NO and L-citrulline production. A modified peptide 326 replacing hydrophobic amino acids leucine and tryptophan with neutral alanine was unable to interfere with eNOS-beta-actin binding and to prevent beta-actin-induced changes in NO and superoxide formation. Site-directed mutagenesis of the actin-binding domain of eNOS replacing leucine and tryptophan with alanine yielded an eNOS mutant that exhibited reduced eNOS-beta-actin association, decreased NO production, and increased superoxide formation in COS-7 cells. Disruption of eNOS-beta-actin interaction in endothelial cells using ABS peptide 326 resulted in decreased NO production, increased superoxide formation, and decreased endothelial monolayer wound repair, which was prevented by PEG-SOD and NO donor NOC-18. Taken together, this novel finding indicates that beta-actin binding to eNOS through residues 326-333 in the eNOS protein results in shifting the enzymatic activity from superoxide formation toward NO production. Modulation of NO and superoxide formation from eNOS by beta-actin plays an important role in endothelial function.

The blind nasotracheal aspiration method is not a useful tool for pathogen detection of pneumonia in children.

BACKGROUND: Acute lower respiratory infection (ALRI) is a major cause of hospitalization for children in China, while the etiological diagnosis of ALRI remains a challenge. This study was performed to evaluate the utility of the blind Nasotracheal aspiration (NTA) in the pathogen detection in ALRI through an evaluation of the test's specificity. METHODOLOGY/PRINCIPAL FINDINGS: A hospital-based study of children ≤3 years was carried out from March 2006 through March 2007 in Suzhou University Affiliated Children's Hospital, including 379 cases with ALRI from the respiratory wards, and 394 controls receiving elective surgery. Nasopharyngeal swabs (NPS) and NTA specimens were taken on admission. S. pneumoniae was isolated from 10.3% of NTA samples from ALRI children, H. influenzae from 15.3%, and M. catarrhalis from 4.7%. The false positive rate--the strains from NTA in control group children--was 8.4% (95% CI: 5.8%-11.4%) for S. pneumoniae, 27.2% (95% CI: 22.7-31.5%) for H. influenzae, and 22.1% (95% CI: 18.0%-26.2%) for M. catarrhalis. The agreement between NPS and NTA in the control group was over 70%. CONCLUSION/SIGNIFICANCE: The blind NTA test is not a useful test for etiologic diagnosis of ALRI.

Preterm infants' T cell responses to inactivated poliovirus vaccine.

BACKGROUND: The antigen-specific T cell responses of preterm infants to immunization are not well understood. The aim of the present study was to compare the T cell responses of preterm infants after inactivated poliovirus vaccination with those of term infants. METHODS: We prospectively enrolled 2-month-old preterm (gestational age, 33 weeks) and term (gestational age, 37 weeks) infants to receive 3 doses of diphtheria-tetanus toxoids-acellular pertussis-hepatitis B virus-inactivated poliovirus vaccine. Whole blood and peripheral blood mononuclear cells (PBMCs) were stimulated with poliovirus vaccine, and memory T cell activation was analyzed by flow cytometry and lymphoproliferation, respectively. Levels of poliovirus neutralizing antibodies were measured in serum. RESULTS: We enrolled 33 preterm and 50 term infants. Preterm infants had fewer circulating CD4(+)CD45RO(+) memory (P = .005) and CD4(+)CD69(+)IFN-gamma(+) cells activated by staphylococcus enterotoxin B at 2 (P = .015) and 7 (P = .05) months of age. After immunization, preterm and term infants had comparable frequencies of poliovirus-specific CD4(+)CD45RO(+)CD69(+)IFN-gamma(+) memory T cells (P = .79). PBMCs from preterm infants had diminished poliovirus-specific lymphoproliferation (P<.001). Although all infants developed seroprotective poliovirus antibody titers, serotype 1 titers were lower among preterm infants (P = .03). CONCLUSIONS: Preterm infants develop poliovirus-specific T cell responses that are comparable to those of term infants. However, they demonstrate nonspecific and poliovirus-specific functional T cell limitations, suggesting that investigations into whether T cell differences remain as preterm infants mature are warranted.

Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines.

Because of the advent of a new influenza A H1N1 strain, many countries have begun mass immunisation programmes. Awareness of the background rates of possible adverse events will be a crucial part of assessment of possible vaccine safety concerns and will help to separate legitimate safety concerns from events that are temporally associated with but not caused by vaccination. We identified background rates of selected medical events for several countries. Rates of disease events varied by age, sex, method of ascertainment, and geography. Highly visible health conditions, such as Guillain-Barré syndrome, spontaneous abortion, or even death, will occur in coincident temporal association with novel influenza vaccination. On the basis of the reviewed data, if a cohort of 10 million individuals was vaccinated in the UK, 21.5 cases of Guillain-Barré syndrome and 5.75 cases of sudden death would be expected to occur within 6 weeks of vaccination as coincident background cases. In female vaccinees in the USA, 86.3 cases of optic neuritis per 10 million population would be expected within 6 weeks of vaccination. 397 per 1 million vaccinated pregnant women would be predicted to have a spontaneous abortion within 1 day of vaccination.

Human papilloma virus immunization in adolescent and young adults: a cohort study to illustrate what events might be mistaken for adverse reactions.

BACKGROUND: The large-scale implementation of human papilloma virus (HPV) immunization will be followed by cases of autoimmune diseases occurring in temporal association with immunizations. To anticipate events that might be mistakenly assumed to be caused by immunization, their prevalence was monitored before vaccine introduction. METHOD: Cohort study carried out within a database of female adolescents (n = 214,896) and young adults (n = 221,472) followed in the pre-HPV vaccine era (2005), computing rates of emergency consultations, hospitalizations and outpatient consultations, and estimation of risks of coincident associations. RESULTS: Immune-mediated conditions were a frequent cause (10.3%) of emergency room consultation by adolescent girls. Nonallergic immune-mediated conditions affected 86 per 100,000, diabetes ranking first. In 2005, 53 per 100,000 adolescents and 389 per 100,000 women were hospitalized for diseases of presumed autoimmune origin, thyroiditis being the most frequent diagnosis. If HPV immunization had been used with 80% coverage, 3 per 100,000 adolescents would have required emergency care for asthma/allergy within 24 hours and 2 per 100,000 for diabetes within 1 week of an injection. The risks of hospitalization in temporal association with immunization are 4 times higher for thyroiditis than for multiple sclerosis or Guillain-Barré's syndrome, and more than 20 times higher in young women than in adolescents. CONCLUSION: The distinction between HPV vaccine-caused adverse reactions and events only observed by chance in temporal association is difficult. The prior use of population-based data allows for identification of issues of potential concern, for monitoring the impact of large-scale interventions and for addressing rapidly vaccine-safety issues that may compromise vaccine programs.

Adenophostin A and analogues modified at the adenine moiety: synthesis, conformational analysis and biological activity.

The synthesis of adenophostin A (2) and two analogues [etheno adenophostin (4) and 8-bromo adenophostin (5)] modified at the adenine moiety, is reported. A combination of NMR analysis and molecular modelling was used to compare their structures in solution and determined that they all adopt very similar conformations. The analogues were tested for their ability to mobilise Ca(2+) from DT40 cells expressing recombinant Type 1 rat Ins(1,4,5)P(3)R which reveals etheno adenophostin as a high affinity fluorescent probe of the Ins(1,4,5)P(3)R. 8-Bromo adenophostin was only slightly less potent. The biological results support our current hypothesis regarding the binding mode of adenophostin A at the Ins(1,4,5)P(3)R, i. e. that a cation-pi interaction between the base moiety and Arg 504 of the receptor in combination with H-bonding may be responsible for the high potency of adenophostin A relative to Ins(1,4,5)P(3).

First enzymatic synthesis of an N1-cyclised cADPR (cyclic-ADP ribose) analogue with a hypoxanthine partial structure: discovery of a membrane permeant cADPR agonist.

Nicotinamide 8-Br-hypoxanthine dinucleotide (8-Br-NHD+) was cyclised at the N1 position by the ADP-ribosyl cyclase from Aplysia californica to give cyclic 8-Br-inosine diphosphoribose (8-Br-N1-cIDPR), a novel membrane-permeant agonist of Ca2+ release in human T cells.