Human astrocytic brain tumors select for mutations in the p53 tumor suppressor gene early in malignant progression. p53 is activated upon various kinds of cellular stress leading to apoptosis or cell ...cycle arrest, but is also implicated in complex biological processes such as inhibition of angiogenesis and metastasis. In an effort to shed light on consequences mediated by p53 inactivation in gliomas, we established the Tet-On system for p53 in the LN-Z308 glioblastoma cell line. The macrophage inhibitory cytokine-1 (MIC-1) gene was identified as a most prominent p53 target gene upon gene expression profiling. Oxygen deprivation, an important cellular stress, revealed MIC-1 as an anoxia responsive gene in glioblastoma cell lines. MIC-1 up-regulation by anoxia is mediated through an alternative, p53 and hypoxia inducible factor 1 (HIF-1) independent pathway. Furthermore, ectopic expression of MIC-1 in LN-Z308 cell line completely abolished its inherent tumorigenicity in nude mice, while proliferation in vitro was not affected. In the present experimental model MIC-1 may exert its anti-tumorigenic properties via a paracrine mechanism mediated by host cells in vivo. Taken together, these data suggest that MIC-1 is an important downstream mediator of p53 function, while acting itself as an intercessor of cellular stress signaling and exerting anti-tumorigenic activities.
Obstetric and neonatal outcomes of women who had a history of recurrent miscarriage were compared with a control population from 1 January 1992 to 30 June 1998. Amongst a total of 162 pregnancies ...which progressed beyond 24 weeks gestation in women with a history of recurrent miscarriage, there were four perinatal deaths and 16 babies were admitted to the special care baby unit. The rates of preterm delivery (13%), small-for-gestational-age (13%), perinatal loss (2.5%) and Caesarean section (36%) were significantly (P < 0.05) higher than those of the control group (3.9, 2.1, 1 and 16.7% respectively). The ratio of male to female babies was equal. There was no significant difference in the incidence of hypertension or diabetes between the two groups. Patients with recurrent miscarriage represent a population at high risk of obstetric problems and close surveillance in the antenatal period is therefore required.
Objective(
s): The primary objective was to examine the effect of formal education and training on instrumental delivery with respect to its success rate and associated neonatal and maternal ...morbidity. The secondary objective was to determine factors that could influence the success rate of instrumental delivery.
Study design: Prospective case-control study with historical controls set in a teaching hospital in Sheffield. The prospective group included all women who had instrumental deliveries between 1 November 1999 and 29 February 2000. The control group included all women who delivered between 1 February 1997 and 1 February 1998. An educational package involving formal postgraduate training and self-directed learning were introduced in the time period between the prospective and the control groups. Medical notes were reviewed in the historical controls. For both the control and prospective groups, the following patient characteristics were recorded: maternal age, parity, whether or not onset of labour was induced, use of oxytocin in the second stage of labour, delay in the second stage, operator grade, vaginal findings at delivery and the use of epidural analgesia.
Results: The overall failure rate was not different in the prospective group (16%) compared with the control group (18.5%). However, the introduction of an educational package was associated with significant decrease in maternal morbidity associated with cervical, severe labial and high vaginal tears (Odds Ratio (OR) 0.29, CI 0.09–0.97) and neonatal morbidity associated with admission to SCBU (OR 0.72, CI 0.02–0.60), severe neonatal scalp injury (OR 0.14, CI 0.02–0.98) and facial injuries (OR 0.02, CI 0.01–0.04). The factors identified to affect the success of instrumental deliveries were: OP and OT positions of the baby at delivery (OR 0.28, CI 0.17–0.44) and inexperienced operators (OR 0.11, CI 0.02–0.58).
Conclusion: In this study, formal education and training of medical staff did not influence the success rate of instrumental delivery but was associated with improved safety for both mother and baby.
Objective
To compare the pain relief and side effects of intramuscular pethidine with intramuscular diamorphine in labour.
Design
Double‐blind randomised controlled trial.
Setting
The labour ward in ...a UK teaching hospital.
Participants
Sixty‐nine nulliparous women and 64 multiparous women in labour who requested narcotic analgesia and remained undelivered one hour after trial entry.
Methods
Nulliparous women were randomised to receive either 150 mg intramuscular pethidine or 7–5 mg intramuscular diamorphine. Multiparous women were randomised to receive either 100 mg intramuscular pethidine or 5 mg intramuscular diamorphine. All participants received the anti‐emetic prochloroperazine at the same time as the trial drugs.
Main outcome measures
Maternal analgesia assessed by a visual analogue score and verbal scales of pain intensity and pain relief, maternal sedation and vomiting, neonatal outcome assessed by Apgar scores and the need for resuscitation.
Results
More women allocated to receiving pethidine than to diamorphine reported slight or no pain relief at 60 minutes after administration of these drugs (P= 0.03). This trend was repeated in most of the other measures for maternal analgesia. There was no difference in maternal sedation, but the incidence of vomiting within 60 minutes was lower for women who received diamorphine (P= 0.02). Pethidine was associated with lower Apgar scores at 1 minute (P < 0.05).
Conclusion
Intramuscular diamorphine in labour appears to have some benefits, compared with intramuscular pethidine, but the trial was small and further research, particularly into alternative opioids and long term effects on the infants is still needed.
In stressed cells, apoptosis ensues when Bcl-2 family members Bax or Bak oligomerize and permeabilize the mitochondrial outer membrane. Certain BH3-only relatives can directly activate them to ...mediate this pivotal, poorly understood step. To clarify the conformational changes that induce Bax oligomerization, we determined crystal structures of BaxΔC21 treated with detergents and BH3 peptides. The peptides bound the Bax canonical surface groove but, unlike their complexes with prosurvival relatives, dissociated Bax into two domains. The structures define the sequence signature of activator BH3 domains and reveal how they can activate Bax via its groove by favoring release of its BH3 domain. Furthermore, Bax helices α2–α5 alone adopted a symmetric homodimer structure, supporting the proposal that two Bax molecules insert their BH3 domain into each other’s surface groove to nucleate oligomerization. A planar lipophilic surface on this homodimer may engage the membrane. Our results thus define critical Bax transitions toward apoptosis.
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► Activator BH3 domains bind the Bax canonical groove and help free the Bax BH3 ► Bax:BH3 peptide complexes reveal sequence characteristics of activator BH3 domains ► Bax activation separates its “core” domain (helices α1–α5) and “latch” (α6–α8) ► The freed core forms a symmetric BH3-in-groove dimer with a lipophilic surface
The structural transitions that set proapoptotic Bax on the pathway to forming a pore in the outer mitochondrial membrane are revealed in crystal structures of Bax bound to activator BH3 peptides.
Safe and potent antiretroviral medications in child-friendly formulations are needed to treat young children living with HIV-1. We aimed to select dosing for a dispersible tablet formulation of ...dolutegravir that achieved pharmacokinetic exposures similar to those in adults, and was safe and well tolerated in young children.
International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) P1093 is a phase 1–2 ongoing multicentre, open-label, non-comparative study of dolutegravir. A 5 mg dispersible tablet formulation of dolutegravir was studied in children aged 4 weeks to less than 6 years old, weighing at least 3 kg, with HIV RNA of greater than 1000 copies per mL and no previous treatment with integrase strand transfer inhibitor recruited from IMPAACT clinical research sites in Africa, the Americas, and Asia. Doses were selected on the basis of intensive pharmacokinetic evaluation on days 5–10, with safety and tolerability assessed up to 48 weeks. The primary objectives of this study are to evaluate the pharmacokinetics of dolutegravir in combination with optimised background therapy and to establish the dose of dolutegravir that achieves the targeted 24-h trough concentration and 24-h area under the curve for infants, children, and adolescents with HIV-1, to establish the safety and tolerability of dolutegravir at 24 and 48 weeks, and to select a dose that achieves similar exposure to the dolutegravir 50 mg once daily dose in adults. This analysis included participants treated with the proposed dose of dolutegravir dispersible tablets in two stages for each of three age cohorts. This trial is registered at ClinicalTrials.gov (NCT01302847) and is ongoing.
We recruited 181 participants from April 20, 2011, to Feb 19, 2020; of these, 96 received dolutegravir dispersible tablets. This analysis included 73 (35, 48% female) participants who received the final proposed dose with median (range) age of 1 year (0·1 to 6·0), weight (minimum–maximum) of 8·5 kg (3·7 to 18·5), plasma HIV-1 RNA concentration of 4·2 log10 copies per mL (2·1 to 7·0), and CD4% of 24·0% (0·3 to 49·0); 64 (87·7%) were treatment-experienced. The selected dose within each age cohort (≥2 years to <6 years, ≥6 months to <2 years of age and ≥4 weeks to <6 months) achieved geometric mean trough (ng/mL) of 688, 1179, and 1446, and 24 h area-under-the-curve (h·mg/L) of 53, 74, and 65, respectively. No grade 3 or worse adverse events were attributed to dolutegravir.
In this study, the proposed once daily dosing of dolutegravir dispersible tablets provided drug exposures similar to those for adults, and was safe and well tolerated. These data support the use of dolutegravir dispersible tablets as first-line or second-line treatment for infants and children aged less than 6 years living with HIV-1.
National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, and ViiV Healthcare–GlaxoSmithKline.
Malignant melanoma is one of the most difficult cancers to treat due to its resistance to chemotherapy. Despite recent successes with BRAF inhibitors and immune checkpoint inhibitors, many patients ...do not respond or become resistant to these drugs. Hence, alternative treatments are still required. Due to the importance of the BCL-2-regulated apoptosis pathway in cancer development and drug resistance, it is of interest to establish which proteins are most important for melanoma cell survival, though the outcomes of previous studies have been conflicting. To conclusively address this question, we tested a panel of established and early passage patient-derived cell lines against several BH3-mimetic drugs designed to target individual or subsets of pro-survival BCL-2 proteins, alone and in combination, in both 2D and 3D cell cultures. None of the drugs demonstrated significant activity as single agents, though combinations targeting MCL-1 plus BCL-XL, and to a lesser extent BCL-2, showed considerable synergistic killing activity that was elicited via both BAX and BAK. Genetic deletion of BFL-1 in cell lines that express it at relatively high levels only had minor impact on BH3-mimetic drug sensitivity, suggesting it is not a critical pro-survival protein in melanoma. Combinations of MCL-1 inhibitors with BRAF inhibitors also caused only minimal additional melanoma cell killing over each drug alone, whilst combinations with the proteasome inhibitor bortezomib was more effective in multiple cell lines. Our data show for the first time that therapies targeting specific combinations of BCL-2 pro-survival proteins, namely MCL-1 plus BCL-XL and MCL-1 plus BCL-2, could have significant benefit for the treatment of melanoma.
Gitelman's syndrome is a rare genetic disease associated with chronic hypokalaemia, hypomagnesaemia and hypocalciuria. It requires lifelong supplementation with potassium and magnesium. Pregnancy ...management can be difficult and there are few published reports. Our case adds to the literature and illustrates some of the potential problems.
Although delivery is widely used for preterm babies failing to thrive in utero, the effect of altering delivery timing has never been assessed in a randomised controlled trial. We aimed to compare ...the effect of delivering early with delaying birth for as long as possible.
548 pregnant women were recruited by 69 hospitals in 13 European countries. Participants had fetal compromise between 24 and 36 weeks, an umbilical-artery doppler waveform recorded, and clinical uncertainty about whether immediate delivery was indicated. Before birth, 588 babies were randomly assigned to immediate delivery (n=296) or delayed delivery until the obstetrician was no longer uncertain (n=292). The main outcome was death or disability at or beyond 2 years of age. Disability was defined as a Griffiths developmental quotient of 70 or less or the presence of motor or perceptual severe disability. Analysis was by intention-to-treat. This trial has been assigned the International Standard Randomised Controlled Trial Number ISRCTN41358726.
Primary outcomes were available on 290 (98%) immediate and 283 (97%) deferred deliveries. Overall rate of death or severe disability at 2 years was 55 (19%) of 290 immediate births, and 44 (16%) of 283 delayed births. With adjustment for gestational age and umbilical-artery doppler category, the odds ratio (95% CrI) was 1·1 (0·7–1·8). Most of the observed difference was in disability in babies younger than 31 weeks of gestation at randomisation: 14 (13%) immediate versus five (5%) delayed deliveries. No important differences in the median Griffiths developmental quotient in survivors was seen.
The lack of difference in mortality suggests that obstetricians are delivering sick preterm babies at about the correct moment to minimise mortality. However, they could be delivering too early to minimise brain damage. These results do not lend support to the idea that obstetricians can deliver before terminal hypoxaemia to improve brain development.
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