Analysis of Defined Combinations of Monoclonal Antibodies in Anthrax Toxin Neutralization Assays and Their Synergistic Action

Antibodies against the protective antigen (PA) component of anthrax toxin play an important role in protection against disease caused by Bacillus anthracis. In this study, we examined defined combinations of PA-specific monoclonal antibodies for their ability to neutralize anthrax toxin in cell culture assays. We observed additive, synergistic, and antagonistic effects of the antibodies depending on the specific antibody combination examined and the specific assay used. Synergistic toxin-neutralizing antibody interactions were examined in more detail. We found that one mechanism that can lead to antibody synergy is the bridging of PA monomers by one antibody, with resultant bivalent binding of the second antibody. These results may aid in optimal design of new vaccines and antibody therapies against anthrax.     

Haemangiopericytoma of the central nervous system

The records of four patients presenting with a histological diagnosis of haemangiopericytoma of the central nervous system, in Auckland, New Zealand, between 1970 and 1990 were reviewed retrospectively, with the aim of determining the natural history of the disease and response to various treatment modalities. Three out of the four patients reviewed presented with primary cerebral disease and the fourth with a primary spinal cord tumour. All three cerebral primary patients were initially treated with local surgical excision. All three patients received radical radiotherapy following local recurrence. The first two patients remained disease-free locally although one patient developed a solitary liver metastasis 5 years after radiotherapy. The third patient was referred with multiple cerebral metastases and failed to respond to radiotherapy. The patient with the primary lesion in the spinal cord was treated with local excision followed by postoperative radiotherapy and remains disease-free 17 years after treatment. One patient failed to respond to chemotherapy, prescribed to treat a local recurrence adjacent to the previous radiotherapy field. This was successfully excised subsequently. The patient presenting with multiple cerebral metastases was the only patient to die of this disease. Results suggest that local recurrence is avoidable with adequate wide excision of the primary tumour followed by local radical radiotherapy. The role of chemotherapy remains controversial and no conclusion could be drawn regarding the role of palliative radiotherapy from this study. Active treatment and long-term follow-up are necessary because of the relative aggressiveness of this disease and the propensity for late relapses.     

A chronic 1 year assessment of MRI contrast agent-labelled neural stem cell transplants in stroke

Non-invasive identification of transplanted neural stem cells in vivo by pre-labelling with contrast agents may play an important role in the translation of cell therapy to the clinic. Understanding the impact of these labels on the cells' ability to repair is therefore vital. In rats with middle cerebral artery occlusion (MCAo), a model of stroke, the transhemispheric migration of MHP36 cells labelled with the bimodal contrast agent GRID was detected on magnetic resonance images (MRI) up to 4 weeks following transplantation. However, compared to MHP36 cells labelled with the red fluorescent dye PKH26, GRID-labelled transplants did not significantly improve behaviour, and performance was akin to non-treated animals. Likewise, the evolution of anatomical damage as assessed by serial, T(2)-weighted MRI over 1 year indicated that GRID-labelled transplants resulted in a slight increase in lesion size compared to MCAo-only animals, whereas the same, PKH26-labelled cells significantly decreased lesion size by 35%. Although GRID labelling allows the in vivo identification of transplanted cells up to 1 month after transplantation, it is likely that some is gradually degraded inside cells. The translation of cellular imaging therefore does not only require the in vitro assessment of contrast agents on cellular functions, but also requires the chronic, in vivo assessment of the label on the stem cells' ability to repair in preclinical models of neurological disease.     

Ischaemic heart disease mortality risks for smokers and non-smokers.

Although many studies have shown that smoking is associated with an increased risk of death from ischaemic heart disease (IHD), and that the increase appears to vary with age and amount smoked, there has been little formal specification or estimation of the relationship. In this paper two alternative models are tested, using data for different ages and levels of smoking from four major studies in three countries. One model explains 80% of the variation in mortality in terms of a positive linear function of the number of cigerettes smoked, the parameters of which decrease with age. We estimate that every cigerette smoked per day increases the risk of dying from IHD by as much as 35% at ages 35 to 44, reducing to 2% at ages 65 to 74. The risk attributable to smoking may account for more than 80% of IHD deaths of men aged 35 to 44, and 27% of those of men aged 45 to 64. Although the relative risk is highest for younger age groups, the absolute risk of death from IHD that is attributable to smoking increases with age. The evidence suggests that both are increasing with time.     

Allocation of authorship and patient enrollment among global clinical trials in oncology

Background

Oncology randomized controlled trials (RCTs) are increasingly global in scope. Whether authorship is equitably shared between investigators from high-income countries (HIC) and low-middle/upper-middle incomes countries (LMIC/UMIC) is not well described. The authors conducted this study to understand the allocation of authorship and patient enrollment across all oncology RCTs conducted globally.

Methods

A cross-sectional retrospective cohort study of phase 3 RCTs (published 2014–2017) that were led by investigators in HIC and recruited patients in LMIC/UMIC.

Findings

During 2014–2017, 694 oncology RCTs were published; 636 (92%) were led by investigators from HIC. Among these HIC-led trials, 186 (29%) enrolled patients in LMIC/UMIC. One-third (33%, 62 of 186) of RCTs had no authors from LMIC/UMIC. Forty percent (74 of 186) of RCTs reported patient enrollment by country; in 50% (37 of 74) of these trials, LMIC/UMIC contributed <15% of patients. The relationship between enrollment and authorship proportion is very strong and is comparable between LMIC/UMIC and HIC (Spearman’s ρ LMIC/UMIC 0.824, p < .001; HIC 0.823, p < .001). Among the 74 trials that report country enrollment, 34% (25 of 74) have no authors from LMIC/UMIC.

Conclusions

Among trials that enroll patients in HIC and LMIC/UMIC, authorship appears to be proportional to patient enrollment. This finding is limited by the fact that more than half of RCTs do not report enrollment by country. Moreover, there are important outliers as a significant proportion of RCTs had no authors from LMIC/UMIC despite enrolling patients in these countries. The findings in this study reflect a complex global RCT ecosystem that still underserves cancer control outside high-income settings.     

The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells

Recent evidence suggests a role for natural killer (NK) cells in the control of multiple myeloma. We show that expression of the NK cell receptor DNAM-1 (CD226) is reduced on CD56(dim) NK cells from myeloma patients with active disease compared with patients in remission and healthy controls. This suggested that this receptor might play a role in NK-myeloma interactions. The DNAM-1 ligands Nectin-2 (CD112) and the poliovirus receptor (PVR; CD155) were expressed by most patient myeloma samples analyzed. NK killing of patient-derived myelomas expressing PVR and/or Nectin-2 was DNAM-1 dependent, revealing a functional role for DNAM-1 in myeloma cell killing. In myeloma cell lines, cell surface expression of PVR was associated with low levels of NKG2D ligands, whereas cells expressing high levels of NKG2D ligands did not express PVR protein or mRNA. Furthermore, NK cell-mediated killing of myeloma cell lines was dependent on either DNAM-1 or NKG2D but not both molecules. In contrast, the natural cytotoxicity receptor NKp46 was required for the killing of all myeloma cell lines analyzed. Thus, DNAM-1 is important in the NK cell-mediated killing of myeloma cells expressing the cognate ligands. The importance of NKp46, NKG2D, and DNAM-1 in myeloma killing mirrors the differential expression of NK cell ligands by myeloma cells, reflecting immune selection during myeloma disease progression.