GlaxoSmithKline Adjuvant Systems in vaccines: concepts, achievements and perspectives

The need for potentiating immune responses to recombinant or subunit antigens has prompted GlaxoSmithKline (GSK) Biologicals to develop various Adjuvant Systems for the design of prophylactic and therapeutic vaccines. Adjuvant Systems are formulations of classical adjuvants mixed with immunomodulators, specifically adapted to the antigen and the target population. They can activate the appropriate innate immune system and subsequently impact on adaptive immune responses. AS04 is an Adjuvant System that has demonstrated significant achievements in several vaccines against viral diseases. AS02, another Adjuvant System, is being evaluated in various contexts, where a strong T-cell response is needed to afford protection. Likewise, AS01 has been developed for vaccines where the induction of a yet stronger T-cell-mediated immune response is required. Altogether, the promising clinical results strongly support the concept of Adjuvant Systems and allow for further development of new vaccines, best adapted to the target population and the immune mechanisms of protection.     

Geminivirus pathogenicity protein C4 interacts with Arabidopsis thaliana shaggy-related protein kinase AtSKeta, a component of the brassinosteroid signalling pathway

Beet curly top virus (BCTV) C4 interacted with two members of the shaggy-related protein kinase family (AtSKeta and AtSKzeta) and a putative leucine-rich repeat receptor-like kinase (LRR-RLK) in a yeast two-hybrid assay. Tomato golden mosaic virus (TGMV) AC4 also bound with similar efficiency to AtSKeta and AtSKzeta but was unable to interact with the LRR-RLK. BCTV C4 interaction with AtSKeta was confirmed using an in vitro binding assay. The protein kinases were capable of autophosphorylation in vitro and AtSKeta phosphorylated BCTV C4 at threonine and serine residues. AtSKeta phosphorylation of TGMV AC4 was significantly less efficient. The LRR-RLK did not efficiently phosphorylate BCTV C4. BCTV C4 localisation to the cell periphery in Nicotiana benthamiana was dependent on an intact N-terminal myristoylation motif, consistent with plasma membrane targeting. The intact motif was also required to produce the wild-type disease phenotype. Transient expression of BCTV C4 and TGMV AC4 derivatives in N. benthamiana identified additional amino acids within a central domain that contribute to the phenotype. The interaction with AtSKeta indicates that BCTV C4 interacts with the brassinosteroid signalling pathway.     

Detection of human bocavirus in Canadian children in a 1-year study

Human bocavirus was detected by PCR in 65 (5.1%) of 1,265 respiratory specimens collected in 2002 and 2003 from the Stollery Children's Hospital from children <17 years of age. The spectrum of illness included upper respiratory infection, croup, bronchiolitis, and pneumonia with a prominence of cough and fever.     

Cricothyroid muscle electrical activity during respiration and apneas in lambs

Respiratory function of the cricothyroid muscle (CT) is virtually unknown in the neonatal period. This study was aimed at assessing CT electrical activity (EMG) during respiration and central apneas in non-sedated lambs. Seven full-term and four preterm lambs were instrumented for polysomnographic recording, including EMG of the diaphragm, thyroarytenoid (TA, a glottal constrictor), posterior cricoarytenoid (PCA, the primary glottal dilator) and CT. Phasic CT EMG was usually observed during inspiration and late expiration, whereas phasic TA EMG was observed during early expiration. While TA EMG virtually disappeared in REM sleep, both inspiratory and expiratory CT EMG increased. Overall, while CT EMG was not frequently observed during central apneas in either full-term (10% of apneas, but never simultaneously with TA EMG) or preterm lambs (30% of apneas), it was associated with decreased lung volume and subglottal pressure when present alone or with PCA EMG. Our results concur with the assumption that CT behaves as a laryngeal dilator in the neonatal period.     

Growth factors and heme oxygenase-1: perspectives in physiology and pathophysiology

Growth factors are mediators of both normal homeostasis and pathophysiology through their effects on various cellular processes. Similarly, heme oxygenase-1 (HO-1) has a role in maintaining physiologic equilibrium, by which it can either alleviate or exacerbate disease, depending on several considerations, including amount, timing, and location of expression, as well as the disease setting. Thus, the synthesis and activities of growth factors and HO-1 are intricately regulated. Interestingly, several growth factors induce HO-1, and, conversely, HO-1 can regulate the expression of some growth factors. This review focuses on the influence of growth factors and HO-1 and potential physiologic effects of the growth factor(s)-HO-1 interaction.     

Mutually exclusive lymphangiogenesis or perineural infiltration in human skin squamous-cell carcinoma

Although tumor-associated lymphangiogenesis correlates with metastasis and poor prognosis in several cancers, it also supports T cell infiltration into the tumor and predicts favorable outcome to immunotherapy. The role of lymphatic vessels in skin squamous-cell carcinoma (sSCC), the second most common form of skin cancer, remains mostly unknown. Although anti-PD-1 therapy is beneficial for some patients with advanced sSCC, a greater understanding of disease mechanisms is still needed to develop better therapies.Using quantitative multiplex immunohistochemistry, we analyzed sSCC sections from 36 patients. CD8+ T cell infiltration showed great differences between patients, whereby these cells were mainly excluded from the tumor mass. Similar to our data in melanoma, sSCC with high density of lymphatic endothelial cells showed increased CD8+ T cell density in tumor areas. An entirely new observation is that sSCC with perineural infiltration but without metastasis was characterized by low lymphatic endothelial cell density. Since both, metastasis and perineural infiltration are known to affect tumor progression and patients’ prognosis, it is important to identify the molecular drivers, opening future options for therapeutic targeting. Our data suggest that the mechanisms underlying perineural infiltration may be linked with the biology of lymphatic vessels and thus stroma.     

Intervention rates for placental removal following induction abortion with misoprostol

BACKGROUND: Second-trimester terminations can be performed via surgical or medical methods. It is essential to have the ability to safely and effectively perform induction terminations to offer a full range of services. Many studies of induction abortions report routine operative removal of the placenta after a set time period resulting in high rates of operative procedures. STUDY DESIGN: A retrospective chart review was performed for 233 women who underwent second-trimester induction abortions between November 2003 and November 2006. All women received intraamniotic injection of digoxin for feticide 1 day prior to induction. All inductions were performed using a schedule of 400 mcg of misoprostol initially followed by 200 mcg every 6 h for a maximum of 48 h. There were three methods of administering misoprostol: (1) vaginal administration for all doses, (2) vaginal and buccal used in combination and (3) buccal for all doses. Spontaneous expulsion of the placenta was expected. Operative intervention was performed for excessive bleeding or to expedite hospital discharge after a minimum of 4 h. No manual removal of placenta was done. RESULTS: The rate of operative intervention for retained placentas was 6% (14/233). Most (11/14) of the patients who underwent operative extraction for retained placentas did so to expedite discharge from the hospital. Overall, expectant management to allow spontaneous expulsion of the placenta for at least 4 h was not associated with serious morbidity. CONCLUSIONS: Our regimen of digoxin and misoprostol with a policy of expectant management of placental passage is associated with a very low rate of instrumented removal of the placenta. In the absence of bleeding, patients may be afforded intervals to at least 4 h for spontaneous expulsion of the placenta after fetal expulsion.     

Mifepristone versus laminaria: a randomized controlled trial of cervical ripening in midtrimester termination

BACKGROUND: Mifepristone was compared with laminaria for cervical ripening in second-trimester induction of labor (IOL). STUDY DESIGN: We performed a randomized, controlled, open-label study of women undergoing second-trimester IOL for fetal demise, aneuploidy or anomalies at a single tertiary care center from January 2004 to May 2006. Main outcome measures were induction-to-delivery time and pain with cervical ripening. RESULTS: Of 50 eligible women, 37 were enrolled in the study, of whom 33 completed the study: 16 were randomized to laminaria and 17 to mifepristone. Induction-to-delivery time was significantly shorter in the mifepristone arm (mean=10 h vs. 16 h, p=.01; median=7.5 h vs. 13.4 h, p=.01). Pain with cervical ripening was also significantly less in the mifepristone group than in the laminaria group (median=1 vs. 6 on an 11-point visual analogue scale, p<.001). Maternal age, parity, gestational age, fetal demise prior to induction, need for postpartum curettage, blood loss, pain during induction, delivery and at the time of discharge were not significantly different between the two groups. CONCLUSION: Mifepristone shortens the induction-to-delivery time and decreases pain with cervical ripening when compared with laminaria for second-trimester induction.