Enhanced drug delivery to the reproductive tract using nanomedicine reveals therapeutic options for prevention of preterm birth.
Ontology highlight
ABSTRACT:
SUBMITTER: Zierden HC
PROVIDER: S-EPMC8713427 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Twin pregnancies are associated with a three-fold greater perinatal mortality than singleton pregnancies. Prematurity is a main contributor, with 50% of twin pregnancies delivering before 37 weeks and 10% delivering before 32 weeks of gestation.The aetiology of preterm delivery in twin pregnancies is likely multifactorial and different from that of singletons.Cervical cerclage reduces preterm birth rates in singletons but has mixed results in twins with some studies showing harm.The use of progesterone to prevent preterm birth in singletons has conflicting results and has not been proven to prevent preterm birth in twins. Studies continue to determine whether the cervical pessary is effective in preventing preterm birth in multiple pregnancies.There is a paucity of data available on the prevention of preterm birth in triplets/higher order multiples but similar principles to twin pregnancy apply.To review the burden of preterm birth in multiple pregnancy.To understand the methods available for preventing preterm birth in multiple pregnancies and the evidence surrounding the use of each one.To be aware of the use of the Arabin pessary.
| S-EPMC6034359 | biostudies-other
Project description:Preterm birth (PTB) is a syndrome with many origins. Among them, infection or inflammation are major risk factors for PTB; however, local defense mechanisms to mount anti-inflammatory responses against inflammation-induced PTB are poorly understood. Here, we show that endothelial TLR4 in the decidual bed is critical for sensing inflammation during pregnancy because mice with endothelial Tlr4 deletion are resistant to lipopolysaccharide (LPS)-induced PTB. Under inflammatory conditions, IL-6 is readily expressed in decidual endothelial cells with signal transducer and activator of transcription 3 (Stat3) phosphorylation in perivascular stromal cells, which then regulates expression of anti-inflammatory IL-10. Our observation that administration of an IL-10 neutralizing antibody predisposing mice to PTB shows IL-10's anti-inflammatory role to prevent PTB. We show that the integration of endothelial and perivascular stromal signaling can determine pregnancy outcomes. These findings highlight a role for endothelial TLR4 in inflammation-induced PTB and may offer a potential therapeutic target to prevent PTB.
| S-EPMC6554729 | biostudies-literature
Project description:Preterm birth (PTB) remains a major obstetric healthcare problem and a significant contributor to perinatal morbidity, mortality, and long-term disability. Over the past few decades, the perinatal outcomes of preterm neonates have improved markedly through research and advances in neonatal care, whereas rates of spontaneous PTB have essentially remained static. However, research into causal pathways and new diagnostic and treatment modalities is now bearing fruit and translational initiatives are beginning to impact upon PTB rates. Successful PTB prevention requires a multifaceted approach, combining public health and educational programs, lifestyle modification, access to/optimisation of obstetric healthcare, effective prediction and diagnostic modalities, and the application of effective, targeted interventions. Progress has been made in some of these areas, although there remain areas of controversy and uncertainty. Attention is now being directed to areas where greater gains can be achieved. In this mini-review, we will briefly and selectively review a range of PTB prevention strategies and initiatives where progress has been made and where exciting opportunities await exploitation, evaluation, and implementation.
| S-EPMC5516782 | biostudies-other
Project description:UnlabelledPharmacogenomics and personalised medicine incorporate genetic factors, historical data, and environmental exposures to predict individual variation in response to medications. The study of pharmacology and pharmacogenomics is challenging in obstetrics, and our knowledge in this area lags behind other disciplines of medicine. Some preliminary data, however, suggest that some of the interindividual variation seen in response to medications given for the prevention (progesterone) and the treatment (nifedipine, terbutaline, and others) of preterm labour may be caused by pharmacogenomic effects. A comprehensive approach, integrating clinical data, environmental factors, including concomitant medications and genotype, to optimise the prevention and treatment strategies for preterm birth, is urgently needed.Tweetable abstractSome of the variation to meds for prematurity prevention/treatment may arise from pharmacogenomic effects.
| S-EPMC4729635 | biostudies-literature
Project description:Zwitterionic surface modification is a promising strategy for nanomedicines to achieve prolonged circulation time and thus effective tumor accumulation. However, zwitterion modified nanoparticles suffer from reduced cellular internalization efficiency. Methods: A polyprodrug-based nanomedicine with zwitterionic-to-cationic charge conversion ability (denoted as ZTC-NMs) was developed for enhanced chemotherapeutic drug delivery. The polyprodrug consists of pH-responsive poly(carboxybetaine)-like zwitterionic segment and glutathione-responsive camptothecin prodrug segment. Results: The ZTC-NMs combine the advantages of zwitterionic surface and polyprodrug. Compared with conventional zwitterionic surface, the ZTC-NMs can respond to tumor microenvironment and realize ZTC surface charge conversion, thus improve cellular internalization efficiency of the nanomedicines. Conclusions: This ZTC method offers a strategy to promote the drug delivery efficiency and therapeutic efficacy, which is promising for the development of cancer nanomedicines.
| S-EPMC7295052 | biostudies-literature
Project description:Preterm birth is one of the major global health problems and part of the Millennium Development goals because of the associated high number of perinatal or neonatal mortality and long-term risks of neurodevelopmental and metabolic diseases. Transvaginal sonography has meanwhile been established as a screening tool for spontaneous preterm birth despite its relatively low sensitivity when considering only the cervical length. Vaginal progesterone has been shown to reduce prematurity rates below 34 weeks in a screening population of singleton pregnancies. Up to now, no positive long-term effect could be demonstrated after 2 years. It seems to have no benefit to prolong pregnancies after a period of preterm contractions and in risk patients without cervical shortening. Meta-analyses still demonstrate conflicting results dependent on quality criteria used for selection. A cerclage is only indicated in singleton pregnancies with previous spontaneous preterm birth and a combined cervical shortening in the current pregnancy. Nevertheless, the short- and long-term outcome has never been evaluated, whereas maternal complications may be increased. There is no evidence for a prophylactic cervical cerclage in twin pregnancies even in cases with cervical shortening. Emergency cerclage remains an indication after individual counseling. The effect of a cervical pessary in singleton pregnancy seems to be more pronounced in studies where a few investigators with increasing experience have treated and followed the patients at risk for preterm birth. Mainly in twin pregnancies, pessary treatment seems to be promising compared to other treatment options of secondary prevention when the therapy is started at early stages of precocious cervical ripening. At present, several international trials with the goal to reduce global rates of prematurity are in progress which will hopefully allow to specify the indications and methods of intervention for certain subgroups. When trials are summarized, prospective meta-analyses carry a lower risk of bias than the meanwhile uncontrolled magnitude of retrospective meta-analyses with conflicting results.
| S-EPMC6018068 | biostudies-literature
Project description:ObjectiveTo investigate the risk of preterm birth among liveborn singletons to primiparas who conceived with assisted reproductive technology (ART) using four mutually exclusive categories of infertility (female infertility only, male infertility only, female and male infertility, and unexplained infertility) and to examine preterm birth risk along the gestational age continuum.DesignRetrospective cohort study.SettingNot applicable.Patient(s)Singletons born to primiparas who conceived with or without ART.Intervention(s)None.Main outcome measure(s)Preterm (<37 weeks' gestation) and preterm/early term birth <39 weeks' gestation).Result(s)For the male infertility only, female infertility only, combined male and female infertility, and unexplained infertility groups, ART-conceived singletons were significantly more likely than non-ART singletons to be born preterm: adjusted odds ratio (aOR) 1.24 (95% CI, 1.13, 1.37), aOR 1.60 (95% CI, 1.50, 1.70), aOR 1.49 (95% CI, 1.35, 1.64), and aOR 1.26 (1.12, 1.43) respectively. Among infants whose mothers were diagnosed with infertility, the odds of preterm birth were highest between 28-30 weeks [female infertility only, aOR 1.95 (95% CI, 1.59, 2.39); male and female infertility: 2.21 (95% CI, 1.62, 3.00)] compared with infants in the general population. Within the ART population, singletons of couples with female infertility only were more likely to be born preterm than singletons born to couples with other infertility diagnoses.Conclusion(s)Among singleton births to primiparas, those conceived with ART had an increased risk for preterm birth, even when only the male partner had been diagnosed with infertility. The risk of preterm birth for ART-conceived infants whose mothers were diagnosed with infertility included the earliest deliveries.
| S-EPMC4515958 | biostudies-literature
Project description:Few therapeutic methods exist for preventing preterm birth (PTB), or delivery before completing 37 weeks of gestation. In the US, progesterone (P4) supplementation is the only FDA-approved drug for use in preventing recurrent spontaneous PTB. However, P4 has limited effectiveness, working in only approximately one-third of cases. Computational drug repositioning leverages data on existing drugs to discover novel therapeutic uses. We used a rank-based pattern-matching strategy to compare the differential gene expression signature for PTB to differential gene expression drug profiles in the Connectivity Map database and assigned a reversal score to each PTB-drug pair. Eighty-three drugs, including P4, had significantly reversed differential gene expression compared with that found for PTB. Many of these compounds have been evaluated in the context of pregnancy, with 13 belonging to pregnancy category A or B - indicating no known risk in human pregnancy. We focused our validation efforts on lansoprazole, a proton-pump inhibitor, which has a strong reversal score and a good safety profile. We tested lansoprazole in an animal inflammation model using LPS, which showed a significant increase in fetal viability compared with LPS treatment alone. These promising results demonstrate the effectiveness of the computational drug repositioning pipeline to identify compounds that could be effective in preventing PTB.
| S-EPMC7098786 | biostudies-literature
Project description:Precise and efficient delivery of nanomedicine to the target site has remained as a major roadblock in advanced cancer treatment. Here, a novel photoacoustic force (PAF)-guided nanotherapeutic system is reported based on a near-infrared (NIR)-absorbing semiconducting polymer (SP), showing significantly improved tumor accumulation and deep tissue penetration for enhanced phototherapeutic efficacy. The accumulation of nanoparticles in 4T1 tumor-bearing mice induced by the PAF strategy displays a fivefold enhancement in comparison with that of the traditional passive targeting pathway, in a significantly shortened time (45 min vs 24 h) with an enhanced penetration depth in tumors. Additionally, a tumor-bearing mouse model is rationally designed to unveil the mechanism, indicating that the nanoparticles enter solid tumors through enhanced transportation across blood vessel barriers via both inter-endothelial gaps and active trans-endothelial pathways. This process is specifically driven by PAF generated from the nanoparticles under NIR laser irradiation. The study thus demonstrates a new nanotherapeutic strategy with low dose, enhanced delivery efficiency in tumor, and boosted therapeutic efficacy, opening new doors for designing novel nanocarriers.
| S-EPMC8373104 | biostudies-literature
Project description:We hypothesized that genetic variation affects responsiveness to 17-alpha hydroxyprogesterone caproate (17P) for recurrent preterm birth prevention.Women of European ancestry with ?1 spontaneous singleton preterm birth at <34 weeks' gestation who received 17P were recruited prospectively and classified as a 17P responder or nonresponder by the difference in delivery gestational age between 17P-treated and -untreated pregnancies. Samples underwent whole exome sequencing. Coding variants were compared between responders and nonresponders with the use of the Variant Annotation, Analysis, and Search Tool (VAAST), which is a probabilistic search tool for the identification of disease-causing variants, and were compared with a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway candidate gene list. Genes with the highest VAAST scores were then classified by the online Protein ANalysis THrough Evolutionary Relationships (PANTHER) system into known gene ontology molecular functions and biologic processes. Gene distributions within these classifications were compared with an online reference population to identify over- and under- represented gene sets.Fifty women (9 nonresponders) were included. Responders delivered 9.2 weeks longer with 17P vs 1.3 weeks' gestation for nonresponders (P < .001). A genome-wide search for genetic differences implicated the NOS1 gene to be the most likely associated gene from among genes on the KEGG candidate gene list (P < .00095). PANTHER analysis revealed several over-represented gene ontology categories that included cell adhesion, cell communication, signal transduction, nitric oxide signal transduction, and receptor activity (all with significant Bonferroni-corrected probability values).We identified sets of over-represented genes in key processes among responders to 17P, which is the first step in the application of pharmacogenomics to preterm birth prevention.
| S-EPMC4266558 | biostudies-literature