Antibody-mediated delivery of viral epitopes to redirect EBV-specific CD8+ T-cell immunity towards cancer cells

Antibody-mediated delivery of immunogenic epitopes to redirect virus-specific CD8+ T-cells towards cancer cells is an emerging and promising new therapeutic strategy. These so-called antibody-epitope conjugates (AECs) rely on the proteolytic release of the epitopes close to the tumor surface for presentation by HLA class I molecules to eventually redirect and activate virus-specific CD8+ T-cells towards tumor cells. We fused the immunogenic EBV-BRLF1 epitope preceded by a protease cleavage site to the C-terminus of the heavy and/or light chains of cetuximab and trastuzumab. We evaluated these AECs and found that, even though all AECs were able to redirect the EBV-specific T-cells, AECs with an epitope fused to the C-terminus of the heavy chain resulted in higher levels of T-cell activation compared to AECs with the same epitope fused to the light chain of an antibody. We observed that all AECs were depending on the presence of the antibody target, that the level of T-cell activation correlated with expression levels of the antibody target, and that our AECs could efficiently deliver the BRLF1 epitope to cancer cell lines from different origins (breast, ovarian, lung, and cervical cancer and a multiple myeloma). Moreover, in vivo, the AECs efficiently reduced tumor burden and increased the overall survival, which was prolonged even further in combination with immune checkpoint blockade. We demonstrate the potential of these genetically fused AECs to redirect the potent EBV-specific T-cells towards cancer in vitro and in vivo. Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Comparison of methods generating antibody-epitope conjugates for targeting cancer with virus-specific T cells

Therapeutic antibody-epitope conjugates (AECs) are promising new modalities to deliver immunogenic epitopes and redirect virus-specific T-cell activity to cancer cells. Nevertheless, many aspects of these antibody conjugates require optimization to increase their efficacy. Here we evaluated different strategies to conjugate an EBV epitope (YVL/A2) preceded by a protease cleavage site to the antibodies cetuximab and trastuzumab. Three approaches were taken: chemical conjugation (i.e. a thiol-maleimide reaction) to reduced cysteine side chains, heavy chain C-terminal enzymatic conjugation using sortase A, and genetic fusions, to the heavy chain (HC) C-terminus. All three conjugates were capable of T-cell activation and target-cell killing via proteolytic release of the EBV epitope and expression of the antibody target was a requirement for T-cell activation. Moreover, AECs generated with a second immunogenic epitope derived from CMV (NLV/A2) were able to deliver and redirect CMV specific T-cells, in which the amino sequence of the attached peptide appeared to influence the efficiency of epitope delivery. Therefore, screening of multiple protease cleavage sites and epitopes attached to the antibody is necessary. Taken together, our data demonstrated that multiple AECs could sensitize cancer cells to virus-specific T cells.Bio-organic Synthesi

Fermentative production of isobutene

Isobutene (2-methylpropene) is one of those chemicals for which bio-based production might replace the petrochemical production in the future. Currently, more than 10 million metric tons of isobutene are produced on a yearly basis. Even though bio-based production might also be achieved through chemocatalytic or thermochemical methods, this review focuses on fermentative routes from sugars. Although biological isobutene formation is known since the 1970s, extensive metabolic engineering is required to achieve economically viable yields and productivities. Two recent metabolic engineering developments may enable anaerobic production close to the theoretical stoichiometry of 1isobutene + 2CO2 + 2H2O per mol of glucose. One relies on the conversion of 3-hydroxyisovalerate to isobutene as a side activity of mevalonate diphosphate decarboxylase and the other on isobutanol dehydration as a side activity of engineered oleate hydratase. The latter resembles the fermentative production of isobutanol followed by isobutanol recovery and chemocatalytic dehydration. The advantage of a completely biological route is that not isobutanol, but instead gaseous isobutene is recovered from the fermenter together with CO2. The low aqueous solubility of isobutene might also minimize product toxicity to the microorganisms. Although developments are at their infancy, the potential of a large scale fermentative isobutene production process is assessed. The production costs estimate is 0.9 € kg−1, which is reasonably competitive. About 70% of the production costs will be due to the costs of lignocellulose hydrolysate, which seems to be a preferred feedstock

Urban coral reefs: Degradation and resilience of hard coral assemblages in coastal cities of East and Southeast Asia

© 2018 The Author(s) Given predicted increases in urbanization in tropical and subtropical regions, understanding the processes shaping urban coral reefs may be essential for anticipating future conservation challenges. We used a case study approach to identify unifying patterns of urban coral reefs and clarify the effects of urbanization on hard coral assemblages. Data were compiled from 11 cities throughout East and Southeast Asia, with particular focus on Singapore, Jakarta, Hong Kong, and Naha (Okinawa). Our review highlights several key characteristics of urban coral reefs, including “reef compression” (a decline in bathymetric range with increasing turbidity and decreasing water clarity over time and relative to shore), dominance by domed coral growth forms and low reef complexity, variable city-specific inshore-offshore gradients, early declines in coral cover with recent fluctuating periods of acute impacts and rapid recovery, and colonization of urban infrastructure by hard corals. We present hypotheses for urban reef community dynamics and discuss potential of ecological engineering for corals in urban areas

Development and testing of a composite index to monitor the continuum of maternal health service delivery at provincial and district level in South Africa

The continuum of care is a recommended framework for comprehensive health service delivery for maternal health, and it integrates health system and social determinants of health. There is a current lack of knowledge on a measurement approach to monitor performance on the framework. In this study we aim to develop and test a composite index for assessing the maternal health continuum in a province in South Africa with the possibility of nationwide use

Reducing Alcohol Use During Pregnancy Via Health Counseling by Midwives and Internet-Based Computer-Tailored Feedback: A Cluster Randomized Trial

BACKGROUND: Effective interventions are needed to reduce neurobehavioral impairments in children due to maternal alcohol use during pregnancy. Currently, health-counseling interventions have shown inconsistent results to reduce prenatal alcohol use. Thus, more research using health counseling is needed to gain more knowledge about the effectiveness of this type of intervention on reducing alcohol use during pregnancy. An alternative and promising strategy is computer tailoring. However, to date, no study has shown the effectiveness of this intervention mode. OBJECTIVE: The aim was to test the effectiveness of health counseling and computer tailoring on stopping and reducing maternal alcohol use during pregnancy in a Dutch sample of pregnant women using alcohol. METHODS: A total of 60 Dutch midwifery practices, randomly assigned to 1 of 3 conditions, recruited 135 health counseling, 116 computer tailoring, and 142 usual care respondents from February to September 2011. Health-counseling respondents received counseling from their midwife according to a health-counseling protocol, which consisted of 7 steps addressed in 3 feedback sessions. Computer-tailoring respondents received usual care from their midwife and 3 computer-tailored feedback letters via the Internet. Usual care respondents received routine alcohol care from their midwife. After 3 and 6 months, we assessed the effect of the interventions on alcohol use. RESULTS: Multilevel multiple logistic regression analyses showed that computer-tailoring respondents stopped using alcohol more often compared to usual care respondents 6 months after baseline (53/68, 78% vs 51/93, 55%; P=.04). Multilevel multiple linear regression analyses showed that computer-tailoring respondents (mean 0.35, SD 0.31 units per week) with average (P=.007) or lower (P<.001) alcohol use before pregnancy or with average (P=.03) or lower (P=.002) social support more strongly reduced their alcohol use 6 months after baseline compared to usual care respondents (mean 0.48, SD 0.54 units per week). Six months after baseline, 72% (62/86) of the health-counseling respondents had stopped using alcohol. This 17% difference with the usual care group was not significant. CONCLUSIONS: This is the first study showing that computer tailoring can be effective to reduce alcohol use during pregnancy; health counseling did not effectively reduce alcohol use. Future researchers developing a health-counseling intervention to reduce alcohol use during pregnancy are recommended to invest more in recruitment of pregnant women and implementation by health care providers. Because pregnant women are reluctant to disclose their alcohol use to health professionals and computer tailoring preserves a person’s anonymity, this effective computer-tailoring intervention is recommended as an attractive intervention for pregnant women using alcohol. TRIAL REGISTRATION: Dutch Trial Register NTR 2058; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2058 (Archived by WebCite at http://www.webcitation.org/6NpT1oHol