Rapid intrapartum test for maternal group B streptococcal colonisation and its effect on antibiotic use in labouring women with risk factors for early-onset neonatal infection (GBS2): cluster randomised trial with nested test accuracy study.

BACKGROUND: Mother-to-baby transmission of group B Streptococcus (GBS) is the main cause of early-onset infection. We evaluated whether, in women with clinical risk factors for early neonatal infection, the use of point-of-care rapid intrapartum test to detect maternal GBS colonisation reduces maternal antibiotic exposure compared with usual care, where antibiotics are administered due to those risk factors. We assessed the accuracy of the rapid test in diagnosing maternal GBS colonisation, against the reference standard of selective enrichment culture. METHODS: We undertook a parallel-group cluster randomised trial, with nested test accuracy study and microbiological sub-study. UK maternity units were randomised to a strategy of rapid test (GeneXpert GBS system, Cepheid) or usual care. Within units assigned to rapid testing, vaginal-rectal swabs were taken from women with risk factors for vertical GBS transmission in established term labour. The trial primary outcome was the proportion of women receiving intrapartum antibiotics to prevent neonatal early-onset GBS infection. The accuracy of the rapid test was compared against the standard of selective enrichment culture in diagnosing maternal GBS colonisation. Antibiotic resistance profiles were determined in paired maternal and infant samples. RESULTS: Twenty-two maternity units were randomised and 20 were recruited. A total of 722 mothers (749 babies) participated in rapid test units; 906 mothers (951 babies) were in usual care units. There was no evidence of a difference in the rates of intrapartum antibiotic prophylaxis (relative risk 1.16, 95% CI 0.83 to 1.64) between the rapid test (41%, 297/716) and usual care (36%, 328/906) units. No serious adverse events were reported. The sensitivity and specificity measures of the rapid test were 86% (95% CI 81 to 91%) and 89% (95% CI 85 to 92%), respectively. Babies born to mothers who carried antibiotic-resistant Escherichia coli were more likely to be colonised with antibiotic-resistant strains than those born to mothers with antibiotic-susceptible E. coli. CONCLUSION: The use of intrapartum rapid test to diagnose maternal GBS colonisation did not reduce the rates of antibiotics administered for preventing neonatal early-onset GBS infection than usual care, although with considerable uncertainty. The accuracy of the rapid test is within acceptable limits. TRIAL REGISTRATION: ISRCTN74746075 . Prospectively registered on 16 April 2015.

Immediate birth for women between 34 and 37 weeks of gestation with prolonged preterm prelabour rupture of membranes and detection of vaginal or urine group B streptococcus: an economic evaluation.

OBJECTIVE: What are the costs, benefits and harms of immediate birth compared with expectant management in women with prolonged preterm prelabour rupture of membranes (PPROM) at 34+0 -36+6  weeks of gestation and detection of vaginal or urine group B streptococcus (GBS)? DESIGN: Mathematical decision model comprising three independent decision trees. SETTING: UK National Health Service (NHS) and personal social services perspective. POPULATION: Women testing positive for GBS with PPROM at 34+0 -36+6  weeks of gestation. METHODS: The model estimates lifetime costs and quality-adjusted life years (QALYs) using evidence from randomised trials, UK NHS data sources and further observational studies. Simulated events include neonatal infections, morbidity associated with preterm birth and consequences of caesarean birth. Deterministic and probabilistic sensitivity analyses (PSAs) were performed. MAIN OUTCOME MEASURES: QALYs, costs and incremental cost-effectiveness ratio (ICER). RESULTS: In this population, immediate birth dominates expectant management: it is more effective (average lifetime QALYs, 24.705 versus 24.371) and it is cheaper (average lifetime costs, £14,372 versus £19,311). In one-way sensitivity analysis, results are robust to all but the odds ratio estimating the relative effect on incidence of infections. Threshold analysis shows that the odds of infection only need to be >1.5% with expectant management for the benefit of avoiding infections to outweigh the disadvantages of immediate birth. In PSA, immediate birth is the preferred option in >80% of simulations. CONCLUSIONS: Neonatal GBS infections are expensive to treat and may result in substantial adverse health consequences. Therefore, immediate birth, which is associated with a reduced risk of neonatal infection compared with expectant management, is expected to generate better health outcomes and decreased lifetime costs. TWEETABLE ABSTRACT: For women with preterm prelabour rupture of membranes and group B streptococcus in vaginal or urine samples, immediate birth is associated with improved health in their babies and reduced costs, compared with expectant management.

Uncertainties in Screening and Prevention of Group B Streptococcus Disease.

In autumn 2016, the UK Department of Health (now Department of Health and Social Care) convened 2 meetings to discuss how to address research evidence gaps in order to minimize the impact of infant group B streptococcus (GBS) disease in the United Kingdom. At that meeting, a number of research priorities were highlighted, including improving the screening for GBS colonization in pregnant women, offering intrapartum antibiotic prophylaxis and point-of-care testing, and understanding the effect of widespread intrapartum antibiotic use on long-term infant health. Further discussions involved investigating the feasibility of a large prospective study of pregnant women and their infants in order to understand the role of antibodies in the protection against GBS disease in infancy following maternal exposure to GBS colonization. Here, we summarize the research uncertainties identified at that meeting.

Group B streptococcus infection: risk and prevention.

Group B Streptococcus (group B Strep or GBS) is the UK's commonest cause of severe early-onset (up to six days) infection in babies. GBS is a normal body commensal, colonising the gut and vagina. GBS may pass to babies around childbirth; although most are unaffected, some develop severe infection. GBS is also a recognised cause of stillbirth and puerperal sepsis. Most GBS infection in babies is of early onset and most of these infections are highly preventable with the targeted use of intrapartum antibiotic prophylaxis. This article reviews current UK guidelines and prevention strategies.

A rapid intrapartum test for group B Streptococcus to reduce antibiotic usage in mothers with risk factors: the GBS2 cluster RCT.

BACKGROUND: Mother-to-baby transmission of group B Streptococcus (Streptococcus agalactiae) is the main cause of early-onset infection. OBJECTIVES: We investigated if intrapartum antibiotic prophylaxis directed by a rapid intrapartum test reduces maternal and neonatal antibiotic use, compared with usual care (i.e. risk factor-directed antibiotics), among women with risk factors for vertical group B Streptococcus transmission, and examined the accuracy and cost-effectiveness of the rapid test. DESIGN: An unblinded cluster randomised controlled trial with a nested test accuracy study, an economic evaluation and a microbiology substudy. SETTING: UK maternity units were randomised to either a strategy of rapid test or usual care. PARTICIPANTS: Vaginal and rectal swabs were taken from women with risk factors for vertical group B Streptococcus transmission in established term labour. The accuracy of the GeneXpert® Dx IV GBS rapid testing system (Cepheid, Maurens-Scopont, France) was compared with the standard of selective enrichment culture in diagnosing maternal group B Streptococcus colonisation. MAIN OUTCOME MEASURES: Primary outcomes were rates of intrapartum antibiotic prophylaxis administered to prevent early-onset group B Streptococcus infection and accuracy estimates of the rapid test. Secondary outcomes were maternal antibiotics for any indication, neonatal antibiotic exposure, maternal antibiotic duration, neonatal group B Streptococcus colonisation, maternal and neonatal antibiotic resistance, neonatal morbidity and mortality, and cost-effectiveness of the strategies. RESULTS: Twenty-two maternity units were randomised and 20 were recruited. A total of 722 mothers (749 babies) participated in rapid test units and 906 mothers (951 babies) participated in usual-care units. There were no differences in the rates of intrapartum antibiotic prophylaxis for preventing early-onset group B Streptococcus infection in the rapid test units (41%, 297/716) compared with the usual-care units (36%, 328/906) (risk ratio 1.16, 95% confidence interval 0.83 to 1.64). There were no differences between the groups in intrapartum antibiotic administration for any indication (risk ratio 0.99, 95% confidence interval 0.81 to 1.21). Babies born in the rapid test units were 29% less likely to receive antibiotics (risk ratio 0.71, 95% confidence interval 0.54 to 0.95) than those born in usual-care units. The sensitivity and specificity of the rapid test were 86% (95% confidence interval 81% to 91%) and 89% (95% confidence interval 85% to 92%), respectively. In 14% of women (99/710), the rapid test was invalid or the machine failed to provide a result. In the economic analysis, the rapid test was shown to be both less effective and more costly and, therefore, dominated by usual care. Sensitivity analysis indicated potential lower costs for the rapid test strategy when neonatal costs were included. No serious adverse events were reported. CONCLUSIONS: The Group B Streptococcus 2 (GBS2) trial found no evidence that the rapid test reduces the rates of intrapartum antibiotic prophylaxis administered to prevent early-onset group B Streptococcus infection. The rapid test has the potential to reduce neonatal exposure to antibiotics, but economically is dominated by usual care. The accuracy of the test is within acceptable limits. FUTURE WORK: The role of routine testing for prevention of neonatal infection requires evaluation in a randomised controlled trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN74746075. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 12. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Group B Streptococcus is a common bacterium found in the vagina and intestines of approximately one in four women. Group B Streptococcus may be passed to the baby around birth and cause severe infection. In the UK, women are offered antibiotics in labour to protect their baby from group B Streptococcus infection when specific risk factors are present. Most women with risk factors do not carry group B Streptococcus and their babies are unnecessarily exposed to antibiotics. Most women carrying group B Streptococcus do not have risk factors and so will not be offered antibiotics to protect their babies. WHAT DID WE PLAN TO DO?: We planned to find out if, for women with risk factors, a 'rapid test' in labour resulted in fewer women receiving antibiotics compared with 'usual care'. We also wanted to establish if the test correctly identified if mothers were carrying group B Streptococcus, helped reduce infections in babies and represented value for money. WHAT DID WE FIND?: We involved 1627 women (1700 babies) from 20 hospitals randomly allocated to rapid test or usual care. Using the 'rapid test' did not reduce antibiotics provided to mothers (41% in rapid test units and 36% in usual-care units). The test correctly identified 86% of women carrying group B Streptococcus, 89% of those who did not and failed to provide a result in 14% of women. A rapid test policy resulted in 13% fewer babies receiving antibiotics. The rapid test generated no cost savings when only the mothers' care was considered, but there was potential for reduced costs when including the newborns' hospital stay. WHAT DOES THIS MEAN?: The rapid test is accurate; however, using it for women with risk factors for their baby developing group B Streptococcus infection does not reduce antibiotic usage in mothers, although it does in babies. Value for money is uncertain and depends on what costs are included.

Impact of late-onset group B streptococcus infection on families: An observational study.

OBJECTIVES: Understand the parental impact of having a baby affected by late-onset group B Strep (LOGBS) infection. Understand the social, mental and financial impact on parents/carers or family members of those affected by LOGBS infection. Investigate family information needs and experiences of information provided. STUDY DESIGN: We devised a 57-item online survey, composing of binary and matrix questions and free text answers. The survey was distributed internationally to families with a baby(ies) affected by LOGBS infection. The questionnaire was designed as a collaborative effort by Group B Strep Support, its medical advisory panel members, midwives, neonatologists, parents and volunteer analysts. Data were collected from June to September in 2018. RESULTS: 531 participants responded. 252 babies (55 %) made a full recovery from their LOGBS infection, 145 (32 %) recovered with long term sequelae and 61 (13 %) died. 126 respondents (32 %) felt there was a minor to substantial impact on their child's day to day life as a consequence of LOGBS infection. 343 respondents (69 %) had not heard about GBS before their child developed LOGBS infection. 338 respondents (77 %) did not receive an information leaflet on GBS. As a result of their child's LOGBS infection, 177 respondents (39 %) experienced either minor or substantial financial difficulty and 314 respondents (70 %) felt that their own or a family member's mental health was affected. 300 respondents (66 %) experienced problems with planning or reduced enjoyment of subsequent pregnancies. 102 respondents (29 %) reported their other children experienced difficulty due to their sibling's LOGBS infection. CONCLUSIONS: The results of our study provide a novel insight into families' experiences following a baby affected by LOGBS infection. Study findings suggests that families suffer significant financial and psychological difficulties as a result of LOGBS infection. Furthermore, information needs are frequently being left unmet.

Gold nanoparticles for the improved anticancer drug delivery of the active component of oxaliplatin.

The platinum-based anticancer drugs cisplatin, carboplatin, and oxaliplatin are an important component of chemotherapy but are limited by severe dose-limiting side effects and the ability of tumors to develop resistance rapidly. These drugs can be improved through the use of drug-delivery vehicles that are able to target cancers passively or actively. In this study, we have tethered the active component of the anticancer drug oxaliplatin to a gold nanoparticle for improved drug delivery. Naked gold nanoparticles were functionalized with a thiolated poly(ethylene glycol) (PEG) monolayer capped with a carboxylate group. [Pt(1R,2R-diaminocyclohexane)(H(2)O)(2)]2NO(3) was added to the PEG surface to yield a supramolecular complex with 280 (+/-20) drug molecules per nanoparticle. The platinum-tethered nanoparticles were examined for cytotoxicity, drug uptake, and localization in the A549 lung epithelial cancer cell line and the colon cancer cell lines HCT116, HCT15, HT29, and RKO. The platinum-tethered nanoparticles demonstrated as good as, or significantly better, cytotoxicity than oxaliplatin alone in all of the cell lines and an unusual ability to penetrate the nucleus in the lung cancer cells.

Group B streptococcal disease in the mother and newborn-A review.

Group B Streptococcus, a common commensal in the gut of humans and in the lower genital tract in women, remains an important cause of neonatal mortality and morbidity. The incidence of early onset disease has fallen markedly in countries that test women for carriage at 35-37 weeks of pregnancy and then offer intrapartum prophylaxis with penicillin during labour. Countries that do not test, but instead employ a risk factor approach, have not seen a similar fall. There are concerns about the effect on the neonatal microbiome of widespread use of antibiotic prophylaxis during labour, but so far the effects seem minor and temporary. Vaccination against GBS would be acceptable to most women and GBS vaccines are in the early stages of development. Tweetable abstract: Group B Strep is a key cause of infection, death and disability in young babies. Antibiotics given in labour remain the mainstay of prevention, until a vaccine is available.

A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors.

PURPOSE: To determine the safety, dose-limiting toxicity, maximum tolerated dose, and pharmacokinetic and pharmacodynamic profiles of the novel hydroxamate histone deacetylase inhibitor belinostat (previously named PXD101) in patients with advanced refractory solid tumors. EXPERIMENTAL DESIGN: Sequential dose-escalating cohorts of three to six patients received belinostat administered as a 30-min i.v. infusion on days 1 to 5 of a 21-day cycle. Pharmacokinetic variables were evaluated at all dose levels. Pharmacodynamic measurements included acetylation of histones extracted from peripheral blood mononuclear cells, caspase-dependent cleavage of cytokeratin-18, and interleukin-6 levels. RESULTS: Forty-six patients received belinostat at one of six dose levels (150-1,200 mg/m(2)/d). Dose-limiting toxicities were grade 3 fatigue (one patient at 600 mg/m(2); one patient at 1,200 mg/m(2)), grade 3 diarrhea combined with fatigue (one patient at 1,200 mg/m(2)), grade 3 atrial fibrillation (one patient at 1,200 mg/m(2); one patient at 1,000 mg/m(2)), and grade 2 nausea/vomiting leading to inability to complete a full 5-day cycle (two patients at 1,000 mg/m(2)). The maximum tolerated dose was 1,000 mg/m(2)/d. I.v. belinostat displayed linear pharmacokinetics with respect to C(max) and AUC. The intermediate elimination half-life was 0.3 to 1.3 h and was independent of dose. Histone H4 hyperacetylation was observed after each infusion and was sustained for 4 to 24 h in a dose-dependent manner. Increases in interleukin-6 levels were detected following belinostat treatment. Stable disease was observed in a total of 18 (39%) patients, including 15 treated for > or =4 cycles, and this was associated with caspase-dependent cleavage of cytokeratin-18. Of the 24 patients treated at the maximum tolerated dose (1,000 mg/m(2)/d), 50% achieved stable disease. CONCLUSIONS: I.v. belinostat is well tolerated, exhibits dose-dependent pharmacodynamic effects, and has promising antitumor activity.

Developing a serocorrelate of protection against invasive group B streptococcus disease in pregnant women: a feasibility study.

BACKGROUND: Group B streptococcus is the leading cause of infection in infants. Currently, intrapartum antibiotic prophylaxis is the major strategy to prevent invasive group B streptococcus disease. However, intrapartum antibiotic prophylaxis does not prevent maternal sepsis, premature births, stillbirths or late-onset disease. Maternal vaccination may offer an alternative strategy. Multivalent polysaccharide protein conjugate vaccine development is under way and a serocorrelate of protection is needed to expedite vaccine licensure. OBJECTIVES: The ultimate aim of this work is to determine the correlate of protection against the major group B streptococcus disease-causing serotypes in infants in the UK. The aim of this feasibility study is to test key operational aspects of the study design. DESIGN: Prospective cohort study of pregnant women and their infants in a 6-month period (1 July to 31 December 2018). SETTING: Five secondary and tertiary hospitals from London and South England. National iGBS disease surveillance was conducted in all trusts in England and Wales. PARTICIPANTS: Pregnant women aged ≥ 18 years who were delivering at one of the selected hospitals and who provided consent during the study period. There were no exclusion criteria. INTERVENTIONS: No interventions were performed. MAIN OUTCOME MEASURES: (1) To test the feasibility of collecting serum at delivery from a large cohort of pregnant women. (2) To test the key operational aspects for a proposed large serocorrelates study. (3) To test the feasibility of collecting samples from those with invasive group B streptococcus. RESULTS: A total of 1823 women were recruited during the study period. Overall, 85% of serum samples were collected at three sites collecting only cord blood. At the two sites collecting maternal, cord and infant blood samples, the collection rate was 60%. A total of 614 women were screened for group B streptococcus with a colonisation rate of 22% (serotype distribution: 30% III, 25% Ia, 16% II, 14% Ib, 14% V and 1% IV). A blood sample was collected from 34 infants who were born to colonised women. Maternal and infant blood and the bacterial isolates for 15 newborns who developed invasive group B streptococcal disease during the study period were collected (serotype distribution: 29% III, 29% II, 21% Ia, 7% Ib, 7% IV and 7% V). LIMITATIONS: Recruitment and sample collection were dependent on the presence of research midwives rather than the whole clinical team. In addition, individualised consent limited the number of women who could be approached each day, and site set-up for the national surveillance study and the limited time period of this feasibility study limited recruitment of all eligible participants. CONCLUSIONS: We have verified the feasibility of collecting and processing rectovaginal swabs and blood samples in pregnant women, as well as samples from those with invasive group B streptococcal disease. We have made recommendations for the recruitment of cases within the proposed GBS3 study and for controls both within GBS3 and as an extension of this feasibility study. FUTURE WORK: A large case-control study comparing specific immunoglobulin G levels in mothers whose infants develop invasive group B streptococcal disease with those in colonised mothers whose infants do not develop invasive group B streptococcal disease is recommended. TRIAL REGISTRATION: Current Controlled Trials ISRCTN49326091; IRAS project identification number 246149/REC reference number 18/WM/0147. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 67. See the NIHR Journals Library website for further project information.

Group B streptococcus is often carried by healthy women and usually causes no problems. Group B streptococcus may be passed from mother to child, primarily through the birth canal, and, in rare cases, can cause serious disease (i.e. pneumonia, sepsis or meningitis) and even death in babies. It may be possible to prevent group B streptococcus disease in babies by giving a vaccine to pregnant women. The reason for vaccinating the mother is so that she can pass on protection (antibodies) during the pregnancy to her baby. A vaccine is currently being developed against group B streptococcus that aims to boost this protection. To help vaccine development progress faster, we need to find out how much antibody is actually needed to protect babies from group B streptococcus disease. A large study is needed to address this question; therefore, we have performed a feasibility study to assess the practicalities of performing this large study. Specifically, we will assess (1) women's willingness to participate in a swabbing and cord blood study, (2) the ability to collect swabs and cord blood once recruited, (3) the ability to identify group B streptococcus disease in this population and (4) the laboratory processing of samples. We recruited 1823 pregnant women from five maternity units in England in a 6-month period: 22% of all women delivering at all sites and 74% of those women who were approached. In three hospitals, cord blood samples from 85% of 1201 women were collected. In two hospitals, we collected 60% of maternal blood samples, 53% of cord blood samples and 99% of swabs from the vagina and rectum from 622 women. A total of 22% of these women carried group B streptococcus in their vagina or gut and we collected blood samples from 34 healthy babies born to these women. During the study, we collected samples from 15 babies who had developed severe group B streptococcus disease; four babies were born to women participating in the study and the rest were identified through national surveillance. In conclusion, we have verified the feasibility of collecting and processing swabs from the vagina and rectum and blood samples in pregnant women, as well as samples from babies who developed group B streptococcus disease. In addition, we have identified a number of strategies that could be adopted in a future study in order to increase recruitment and sample collection.

Hypoxia-inducible factor 1 alpha is required for the tumourigenic and aggressive phenotype associated with Rab25 expression in ovarian cancer.

The small GTPase Rab25 has been functionally linked to tumour progression and aggressiveness in ovarian cancer and promotes invasion in three-dimensional environments. This type of migration has been shown to require the expression of the hypoxia-inducible factor 1 alpha (HIF-1α). In this report we demonstrate that Rab25 regulates HIF-1α protein expression in an oxygen independent manner in a panel of cancer cell lines. Regulation of HIF-1α protein expression by Rab25 did not require transcriptional upregulation, but was dependent on de novo protein synthesis through the Erbb2/ERK1/2 and p70S6K/mTOR pathways. Rab25 expression induced HIF-1 transcriptional activity, increased cisplatin resistance, and conferred intraperitoneal growth to the A2780 cell line in immunocompromised mice. Targeting HIF1 activity by silencing HIF-1ß re-sensitised cells to cisplatin in vitro and reduced tumour formation of A2780-Rab25 expressing cells in vivo in a mouse ovarian peritoneal carcinomatosis model. Similar effects on cisplatin resistance in vitro and intraperitoneal tumourigenesis in vivo were obtained after HIF1b knockdown in the ovarian cancer cell line SKOV3, which expresses endogenous Rab25 and HIF-1α at atmospheric oxygen concentrations. Our results suggest that Rab25 tumourigenic potential and chemoresistance relies on HIF1 activity in aggressive and metastatic ovarian cancer. Targeting HIF-1 activity may potentially be effective either alone or in combination with standard chemotherapy for aggressive metastatic ovarian cancer.

Attitudes towards antenatal vaccination, Group B streptococcus and participation in clinical trials: Insights from focus groups and interviews of parents and healthcare professionals.

INTRODUCTION: Antenatal vaccination has become a part of routine care during pregnancy in the UK and worldwide, leading to improvements in health for both pregnant women and their infants. However, uptake remains sub-optimal. Other antenatal vaccines targeting major neonatal pathogens, such as Group B streptococcus (GBS), the commonest cause of sepsis and meningitis in the neonatal period, are undergoing clinical trials but more information is needed on how to improve acceptance of such vaccines. METHODS: Qualitative study using focus groups and interviews; involving 14 pregnant women, 8 mothers with experience of GBS, and 28 maternity healthcare professionals. Questions were asked regarding antenatal vaccines, knowledge of GBS, attitudes to a potential future GBS vaccine and participation in antenatal vaccine trials. RESULTS: All participants were very cautious about vaccination during pregnancy, with harm to the baby being a major concern. Despite this, the pregnant women and parents with experience of GBS were open to the idea of an antenatal GBS vaccine and participating in research, while the maternity professionals were less positive. Major barriers identified included lack of knowledge about GBS and the reluctance of maternity professionals to be involved. INTERPRETATION: In order for a future GBS vaccine to be acceptable to both pregnant women and the healthcare professionals advising them, a major awareness campaign would be required with significant focus on convincing and training maternity professionals.

Factors influencing women's attitudes towards antenatal vaccines, group B Streptococcus and clinical trial participation in pregnancy: an online survey.

OBJECTIVES: To explore factors influencing the likelihood of antenatal vaccine acceptance of both routine UK antenatal vaccines (influenza and pertussis) and a hypothetical group B Streptococcus (GBS) vaccine in order to improve understanding of how to optimise antenatal immunisation acceptance, both in routine use and clinical trials. SETTING: An online survey distributed to women of childbearing age in the UK. PARTICIPANTS: 1013 women aged 18-44 years in England, Scotland and Wales. METHODS: Data from an online survey conducted to gauge the attitudes of 1013 women of childbearing age in England, Scotland and Wales to antenatal vaccination against GBS were further analysed to determine the influence of socioeconomic status, parity and age on attitudes to GBS immunisation, using attitudes to influenza and pertussis vaccines as reference immunisations. Factors influencing likelihood of participation in a hypothetical GBS vaccine trial were also assessed. RESULTS: Women with children were more likely to know about each of the 3 conditions surveyed (GBS: 45% vs 26%, pertussis: 79% vs 63%, influenza: 66% vs 54%), to accept vaccination (GBS: 77% vs 65%, pertussis: 79% vs 70%, influenza: 78% vs 68%) and to consider taking part in vaccine trials (37% vs 27% for a hypothetical GBS vaccine tested in 500 pregnant women). For GBS, giving information about the condition significantly increased the number of respondents who reported that they would be likely to receive the vaccine. Health professionals were the most important reported source of information. CONCLUSIONS: Increasing awareness about GBS, along with other key strategies, would be required to optimise the uptake of a routine vaccine, with a specific focus on informing women without previous children. More research specifically focusing on acceptability in pregnant women is required and, given the value attached to input from healthcare professionals, this group should be included in future studies.

Selective ablation of human cancer cells by telomerase-specific adenoviral suicide gene therapy vectors expressing bacterial nitroreductase.

Reactivation of telomerase maintains telomere function and is considered critical to immortalization in most human cancer cells. Elevation of telomerase expression in cancer cells is highly specific: transcription of both RNA (hTR) and protein (hTERT) components is strongly upregulated in cancer cells relative to normal cells. Therefore, telomerase promoters may be useful in cancer gene therapy by selectively expressing suicide genes in cancer cells and not normal cells. One example of suicide gene therapy is the bacterial nitroreductase (NTR) gene, which bioactivates the prodrug CB1954 into an active cytotoxic alkylating agent. We describe construction of adenovirus vectors harbouring the bacterial NTR gene under control of the hTR or hTERT promoters. Western blot analysis of NTR expression in normal and cancer cells infected with adenoviral vectors showed cancer cell-specific nitroreductase expression. Infection with adenoviral telomerase-NTR constructs in a panel of seven cancer cell lines resulted in up to 18-fold sensitization to the prodrug CB1954, an effect that was retained in two drug-resistant ovarian lines. Importantly, no sensitization was observed with either promoter in any of the four normal cell strains. Finally, an efficacious effect was observed in cervical and ovarian xenograft models following single intratumoural injection with low doses of vector, followed by injection with CB1954.

Development of nonsymmetrical 1,4-disubstituted anthraquinones that are potently active against cisplatin-resistant ovarian cancer cells.

A novel series of 1,4-disubstituted aminoanthraquinones were prepared by ipso-displacement of 1,4-difluoro-5,8-dihydroxyanthraquinones by hydroxylated piperidinyl- or pyrrolidinylalkylamino side chains. One aminoanthraquinone (13) was further derivatized to a chloropropylamino analogue by treatment with triphenylphosphine-carbon tetrachloride. The compounds were evaluated in the A2780 ovarian cancer cell line and its cisplatin-resistant variants (A2780/cp70 and A2780/MCP1). The novel anthraquinones were shown to possess up to 5-fold increased potency against the cisplatin-resistant cells compared to the wild-type cells. Growth curve analysis of the hydroxyethylaminoanthraquinone 8 in the osteosarcoma cell line U-2 OS showed that the cell cycle is not frozen, rather there is a late cell cycle arrest consistent with the action of a DNA-damaging topoisomerase II inhibitor. Accumulative apoptotic events, using time lapse photography, indicate that 8 is capable of fully engaging cell cycle arrest pathways in G2 in the absence of early apoptotic commitment. 8 and its chloropropyl analogue 13 retained significant activity against human A2780/cp70 xenografted tumors in mice.

Highly stable phenanthridinium frameworks as a new class of tunable DNA binding agents with cytotoxic properties.

A new class of cytotoxic heteroaromatic cations is presented, based on the dihydro-imidazo-phenanthridinium framework (DIP), that have affinity for DNA and cytotoxicity toward cancerous cells. The DIP framework is particularly tunable due to the flexible synthetic methodology. Furthermore, the central moiety has proved to be very stable to hydrolysis and reduction compared to other phenanthridinium-based agents.

Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101.

Histone acetylation has a central role in the control of gene expression, influencing transcriptional control of many genes, including tumor suppressor genes. PXD101 is a novel hydroxamate-type inhibitor of histone deacetylase activity that inhibits histone deacetylase activity in HeLa cell extracts with an IC(50) of 27 nM and induces a concentration-dependent (0.2-5 micro M) increase in acetylation of histone H4 in tumor cell lines. PXD101 is cytotoxic in vitro in a number of tumor cell lines with IC(50)s in the range 0.2-3.4 micro M as determined by a clonogenic assay and induces apoptosis. Treatment of nude mice bearing human ovarian and colon tumor xenografts with PXD101 (10-40 mg/kg/day i.p.) daily for 7 days causes a significant dose-dependent growth delay with no obvious signs of toxicity to the mice. Growth delay is also observed for xenografts of cisplatin-resistant ovarian tumor cells. A marked increase in acetylation of H4 is detected in blood and tumor of mice 3 h after treatment with PXD101. The inhibition of growth of human tumor xenografts in mice, with no apparent toxicity, suggests that PXD101 has potential as a novel antitumor agent. Furthermore, the ability to measure histone acetylation in blood samples could provide a suitable pharmacodynamic end point to monitor drug activity.