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American Journal of Obstetrics and... Jun 2024A cesarean scar pregnancy is an iatrogenic consequence of a previous cesarean delivery. The gestational sac implants into a niche created by the incision of the previous... (Comparative Study)
Comparative Study
BACKGROUND
A cesarean scar pregnancy is an iatrogenic consequence of a previous cesarean delivery. The gestational sac implants into a niche created by the incision of the previous cesarean delivery, and this carries a substantial risk for major maternal complications. The aim of this study was to report, analyze, and compare the effectiveness and safety of different treatments options for cesarean scar pregnancies managed in the first trimester through a registry.
OBJECTIVE
This study aimed to evaluated the ultrasound findings, disease behavior, and management of first-trimester cesarean scar pregnancies.
STUDY DESIGN
We created an international registry of cesarean scar pregnancy cases to study the ultrasound findings, disease behavior, and management of cesarean scar pregnancies. The Cesarean Scar Pregnancy Registry collects anonymized ultrasound and clinical data of individual patients with a cesarean scar pregnancy on a secure, digital information platform. Cases were uploaded by 31 participating centers across 19 countries. In this study, we only included live and failing cesarean scar pregnancies (with or without a positive fetal heart beat) that received active treatment (medical or surgical) before 12+6 weeks' gestation to evaluate the effectiveness and safety of the different management options. Patients managed expectantly were not included in this study and will be reported separately. Treatment was classified as successful if it led to a complete resolution of the pregnancy without the need for any additional medical interventions.
RESULTS
Between August 29, 2018, and February 28, 2023, we recorded 460 patients with cesarean scar pregnancies (281 live, 179 failing cesarean scar pregnancy) who fulfilled the inclusion criteria and were registered. A total of 270 of 460 (58.7%) patients were managed surgically, 123 of 460 (26.7%) patients underwent medical management, 46 of 460 (10%) patients underwent balloon management, and 21 of 460 (4.6%) patients received other, less frequently used treatment options. Suction evacuation was very effective with a success rate of 202 of 221 (91.5%; 95% confidence interval, 87.8-95.2), whereas systemic methotrexate was least effective with only 38 of 64 (59.4%; 95% confidence interval, 48.4-70.4) patients not requiring additional treatment. Overall, surgical treatment of cesarean scar pregnancies was successful in 236 of 258 (91.5%, 95% confidence interval, 88.4-94.5) patients and complications were observed in 24 of 258 patients (9.3%; 95% confidence interval, 6.6-11.9).
CONCLUSION
A cesarean scar pregnancy can be managed effectively in the first trimester of pregnancy in more than 90% of cases with either suction evacuation, balloon treatment, or surgical excision. The effectiveness of all treatment options decreases with advancing gestational age, and cesarean scar pregnancies should be treated as early as possible after confirmation of the diagnosis. Local medical treatment with potassium chloride or methotrexate is less efficient and has higher rates of complications than the other treatment options. Systemic methotrexate has a substantial risk of failing and a higher complication rate and should not be recommended as first-line treatment.
Topics: Humans; Female; Pregnancy; Cicatrix; Cesarean Section; Pregnancy Trimester, First; Pregnancy, Ectopic; Registries; Adult; Abortifacient Agents, Nonsteroidal; Methotrexate; Ultrasonography, Prenatal; Vacuum Curettage; Misoprostol; Uterine Artery Embolization
PubMed: 37865390
DOI: 10.1016/j.ajog.2023.10.028 -
Frontiers in Endocrinology 2023Preterm birth is one of the major causes of neonatal morbidity and mortality across the world. Both term and preterm labour are preceded by inflammatory activation in...
INTRODUCTION
Preterm birth is one of the major causes of neonatal morbidity and mortality across the world. Both term and preterm labour are preceded by inflammatory activation in uterine tissues. This includes increased leukocyte infiltration, and subsequent increase in chemokine and cytokine levels, activation of pro-inflammatory transcription factors as NF-κB and increased prostaglandin synthesis. Prostaglandin F2α (PGF2α) is one of the myometrial activators and stimulators.
METHODS
Here we investigated the role of PGF2α in pro-inflammatory signalling pathways in human myometrial cells isolated from term non-labouring uterine tissue. Primary myometrial cells were treated with G protein inhibitors, calcium chelators and/or PGF2α. Nuclear extracts were analysed by TranSignal cAMP/Calcium Protein/DNA Array. Whole cell protein lysates were analysed by Western blotting. mRNA levels of target genes were analysed by RT-PCR.
RESULTS
The results show that PGF2α increases inflammation in myometrial cells through increased activation of NF-κB and MAP kinases and increased expression of COX-2. PGF2α was found to activate several calcium/cAMP-dependent transcription factors, such as CREB and C/EBP-β. mRNA levels of NF-κB-regulated cytokines and chemokines were also elevated with PGF2α stimulation. We have shown that the increase in PGF2α-mediated COX-2 expression in myometrial cells requires coupling of the FP receptor to both Gαq and Gαi proteins. Additionally, PGF2α-induced calcium response was also mediated through Gαq and Gαi coupling.
DISCUSSION
In summary, our findings suggest that PGF2α-induced inflammation in myometrial cells involves activation of several transcription factors - NF-κB, MAP kinases, CREB and C/EBP-β. Our results indicate that the FP receptor signals via Gαq and Gαi coupling in myometrium. This work provides insight into PGF2α pro-inflammatory signalling in term myometrium prior to the onset of labour and suggests that PGF2α signalling pathways could be a potential target for management of preterm labour.
Topics: Infant, Newborn; Female; Humans; Dinoprost; NF-kappa B; Calcium; Premature Birth; Cyclooxygenase 2; Myometrium; Inflammation; Obstetric Labor, Premature; Cytokines; RNA, Messenger
PubMed: 37547305
DOI: 10.3389/fendo.2023.1150125 -
JAMA Network Open Jul 2023Maternal labor epidural analgesia (LEA) and oxytocin use for labor and delivery have been reported to be associated with child autism spectrum disorders (ASD). However,...
IMPORTANCE
Maternal labor epidural analgesia (LEA) and oxytocin use for labor and delivery have been reported to be associated with child autism spectrum disorders (ASD). However, it remains unclear whether these 2 common medications used during labor and delivery have synergistic associations with ASD risk in children.
OBJECTIVE
To assess the independent associations of LEA and oxytocin during labor and delivery with ASD, as well as outcome modification associated with the concurrent use of both interventions.
DESIGN, SETTING, AND PARTICIPANTS
Data for this cohort study included 205 994 singleton births with vaginal deliveries in a single integrated health care system in Southern California from calendar years 2008 to 2017. Children were followed up to December 31, 2021. Data on use of LEA and oxytocin, covariates, and ASD outcome in children were obtained from electronic medical records. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) adjusting for covariates.
EXPOSURES
Labor epidural analgesia and/or oxytocin use during labor and delivery.
MAIN OUTCOMES AND MEASURES
A child's clinical diagnosis of ASD during follow-up and at age of diagnosis.
RESULTS
Among the cohort, 153 880 children (74.7%) were exposed to maternal LEA and 117 808 children (57.2%) were exposed to oxytocin during labor and delivery. The population of children was approximately half boys and half girls. The median (IQR) age of the mothers was 30.8 (26.8-34.5) years for those not exposed to LEA, 30.0 (25.9-33.8) years for those exposed to LEA, 30.4 (26.5-34.1) years for those unexposed to oxytocin, and 30.0 (25.9-33.9) years for those exposed to oxytocin during labor and delivery. A total of 5146 children (2.5%) had ASD diagnosed during follow-up. Oxytocin exposure was higher among LEA-exposed (67.7%) than -unexposed (26.1%) children. The ASD risk associated with LEA was independent of oxytocin exposure (HR, 1.28; 95% CI, 1.18-1.38); however, the ASD risk associated with oxytocin was not significant after adjusting for LEA exposure (HR, 1.05; 95% CI, 0.99-1.12). A significant interaction of LEA and oxytocin on child ASD risk was found (P = .02 for interaction). Compared with no exposure, HRs were 1.20 (95% CI, 1.09-1.32) for LEA alone, 1.30 (95% CI, 1.20-1.42) for both LEA and oxytocin, and 0.90 (95% CI, 0.78-1.04) for oxytocin alone.
CONCLUSIONS AND RELEVANCE
The findings of this cohort study suggest an association between maternal LEA and ASD risk in children, and the risk appeared to be further increased if oxytocin was also administered. Oxytocin exposure without LEA exposure was not associated with ASD risk in children. These findings must be interpreted with caution. Further studies are needed to replicate or refute the study results and examine biological plausibility.
Topics: Pregnancy; Male; Female; Child; Humans; Adult; Autism Spectrum Disorder; Cohort Studies; Analgesia, Epidural; Oxytocin; Labor, Obstetric; Analgesics
PubMed: 37477919
DOI: 10.1001/jamanetworkopen.2023.24630 -
Proceedings of the National Academy of... Jul 2023To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize...
To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, , re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, , 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, , 88-91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that G-biased signaling, but not G activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-G, EP4-G, and EP4-G in complex with endogenous prostaglandin E (PGE)or two synthetic agonists and comparing with PGE-EP2-G structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the G/G transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their G/G coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for G/G coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.
Topics: Dinoprostone; Signal Transduction; Receptors, Prostaglandin; GTP-Binding Protein alpha Subunits, Gs; Hormones; Receptors, Prostaglandin E, EP4 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP3 Subtype
PubMed: 37478163
DOI: 10.1073/pnas.2216329120 -
International Journal of Molecular... Nov 2023Gintonin, newly extracted from ginseng, is a glycoprotein that acts as an exogenous lysophosphatidic acid (LPA) receptor ligand. This study aimed to demonstrate the in...
Gintonin, newly extracted from ginseng, is a glycoprotein that acts as an exogenous lysophosphatidic acid (LPA) receptor ligand. This study aimed to demonstrate the in vivo preventive effects of gintonin on gastric damage. ICR mice were randomly assigned to five groups: a normal group (received saline, 0.1 mL/10 g, p.o.); a control group (administered 0.3 M HCl/ethanol, 0.1 mL/10 g, p.o.) or indomethacin (30 mg/kg, p.o.); gintonin at two different doses (50 mg/kg or 100 mg/kg, p.o.) with either 0.3 M HCl/ethanol or indomethacin; and a positive control (Ranitidine, 40 mg/kg, p.o.). After gastric ulcer induction, the gastric tissue was examined to calculate the ulcer index. The expression of gastric damage markers, such as tumor necrosis factor (TNF)-α, cyclooxygenase 2 (COX-2), and LPA2 and LPA5 receptors, were measured by Western blotting. Interleukin-6 (IL-6) and prostaglandin E2 (PGE2) levels were measured by enzyme-linked immunosorbent assay. The platelet endothelial cell adhesion molecule (PECAM-1), Evans blue, and occludin levels in gastric tissues were measured using immunofluorescence analysis. Both HCl/ethanol- and indomethacin-induced gastric ulcers showed increased TNF-α, IL-6, Evans blue permeation, and PECAM-1, and decreased COX-2, PGE2, occludin, and LPA5 receptor expression levels. However, oral administration of gintonin alleviated the gastric ulcer index induced by HCl/ethanol and indomethacin in a dose-dependent manner. Gintonin suppressed TNF-α and IL-6 expression, but increased COX-2 expression and PGE2 levels in mouse gastric tissues. Gintonin intake also increased LPA5 receptor expression in mouse gastric tissues. These results indicate that gintonin can play a role in gastric protection against gastric damage induced by HCl/ethanol or indomethacin.
Topics: Mice; Animals; Indomethacin; Stomach Ulcer; Platelet Endothelial Cell Adhesion Molecule-1; Cyclooxygenase 2; Tumor Necrosis Factor-alpha; Ethanol; Interleukin-6; Dinoprostone; Evans Blue; Occludin; Mice, Inbred ICR; Gastric Mucosa
PubMed: 38069044
DOI: 10.3390/ijms242316721 -
American Journal of Respiratory Cell... Nov 2023Prostaglandin E2 imparts diverse physiological effects on multiple airway cells through its actions on four distinct E-type prostanoid (EP) receptor subtypes (EP1-EP4)....
Prostaglandin E2 imparts diverse physiological effects on multiple airway cells through its actions on four distinct E-type prostanoid (EP) receptor subtypes (EP1-EP4). Gs-coupled EP2 and EP4 receptors are expressed on airway smooth muscle (ASM), yet their capacity to regulate the ASM contractile state remains subject to debate. We used EP2 and EP4 subtype-specific agonists (ONO-259 and ONO-329, respectively) in cell- and tissue-based models of human ASM contraction-magnetic twisting cytometry (MTC), and precision-cut lung slices (PCLSs), respectively-to study the EP2 and EP4 regulation of ASM contraction and signaling under conditions of histamine or methacholine (MCh) stimulation. ONO-329 was superior (<0.05) to ONO-259 in relaxing MCh-contracted PCLSs (log half maximal effective concentration [logEC]: 4.9 × 10 vs. 2.2 × 10; maximal bronchodilation ± SE, 35 ± 2% vs. 15 ± 2%). However, ONO-259 and ONO-329 were similarly efficacious in relaxing histamine-contracted PCLSs. Similar differential effects were observed in MTC studies. Signaling analyses revealed only modest differences in ONO-329- and ONO-259-induced phosphorylation of the protein kinase A substrates VASP and HSP20, with concomitant stimulation with MCh or histamine. Conversely, ONO-259 failed to inhibit MCh-induced phosphorylation of the regulatory myosin light chain (pMLC20) and the F-actin/G-actin ratio (F/G-actin ratio) while effectively inhibiting their induction by histamine. ONO-329 was effective in reversing induced pMLC20 and the F/G-actin ratio with both MCh and histamine. Thus, the contractile-agonist-dependent differential effects are not explained by changes in the global levels of phosphorylated protein kinase A substrates but are reflected in the regulation of pMLC20 (cross-bridge cycling) and F/G-actin ratio (actin cytoskeleton integrity, force transmission), implicating a role for compartmentalized signaling involving muscarinic, histamine, and EP receptor subtypes.
Topics: Humans; Receptors, Prostaglandin E, EP2 Subtype; Actins; Histamine; Receptors, Prostaglandin E, EP4 Subtype; Dinoprostone; Muscle, Smooth; Lung; Cyclic AMP-Dependent Protein Kinases
PubMed: 37523713
DOI: 10.1165/rcmb.2022-0445OC -
Frontiers in Immunology 2023For many years, surgery, adjuvant and combination chemotherapy have been the cornerstone of pancreatic cancer treatment. Although these approaches have improved patient...
INTRODUCTION
For many years, surgery, adjuvant and combination chemotherapy have been the cornerstone of pancreatic cancer treatment. Although these approaches have improved patient survival, relapse remains a common occurrence, necessitating the exploration of novel therapeutic strategies. CAR T cell therapies are now showing tremendous success in hematological cancers. However, the clinical efficacy of CAR T cells in solid tumors remained low, notably due to presence of an immunosuppressive tumor microenvironment (TME). Prostaglandin E2, a bioactive lipid metabolite found within the TME, plays a significant role in promoting cancer progression by increasing tumor proliferation, improving angiogenesis, and impairing immune cell's function. Despite the well-established impact of PGE2 signaling on cancer, its specific effects on CAR T cell therapy remain under investigation.
METHODS
To address this gap in knowledge the role of PGE2-related genes in cancer tissue and T cells of pancreatic cancer patients were evaluated . Through our study, we manufactured fully human functional mesoCAR T cells specific for pancreatic cancer and investigated the influence of PGE2-EP2/EP4 signaling on proliferation, cytotoxicity, and cytokine production of mesoCAR T cells against pancreatic cancer cells.
RESULTS
investigations uncovered a significant negative correlation between PGE2 expression and gene signature of memory T cells. Furthermore, experiments demonstrated that the activation of PGE2 signaling through EP2 and EP4 receptors suppressed the proliferation and major antitumor functions of mesoCAR T cells. Interestingly, the dual blockade of EP2 and EP4 receptors effectively reversed PGE2-mediated suppression of mesoCAR T cells, while individual receptor antagonists failed to mitigate the PGE2-induced suppression.
DISCUSSION
In summary, our findings suggest that mitigating PGE2-EP2/EP4 signaling may be a viable strategy for enhancing CAR T cell activity within the challenging TME, thereby improving the efficacy of CAR T cell therapy in clinical settings.
Topics: Humans; Dinoprostone; Receptors, Prostaglandin E, EP2 Subtype; Neoplasm Recurrence, Local; Receptors, Prostaglandin E, EP4 Subtype; Pancreatic Neoplasms; Immunosuppression Therapy; Tumor Microenvironment
PubMed: 37457723
DOI: 10.3389/fimmu.2023.1209572 -
Mediators of Inflammation 2023Inflammation is a major cause of hepatic tissue damage and accelerates the progression of nonalcoholic fatty liver disease (NAFLD). Amphiregulin (AREG), an epidermal...
BACKGROUND
Inflammation is a major cause of hepatic tissue damage and accelerates the progression of nonalcoholic fatty liver disease (NAFLD). Amphiregulin (AREG), an epidermal growth factor receptor ligand, is associated with human liver cirrhosis and hepatocellular carcinoma. We aimed to investigate the effects of AREG on hepatic inflammation during NAFLD progression, and .
METHODS
AREG gene expression was measured in the liver of mice fed a methionine choline-deficient (MCD) diet for 2 weeks. We evaluated inflammatory mediators and signaling pathways in HepG2 cells after stimulation with AREG. Nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were analyzed using an enzyme-linked immunosorbent assay and western blotting. Nuclear transcription factor kappa-B (NF-B) and mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase, were analyzed using western blotting.
RESULTS
Proinflammatory cytokines (interleukin (IL)-6, IL-1, and IL-8) and immune cell recruitment (as indicated by L3T4, F4/80, and ly6G mRNA expression) increased, and expression of AREG increased in the liver of mice fed the MCD diet. AREG significantly increased the expression of IL-6 and IL-1 and the production of NO, PGE2, and IL-8 in HepG2 cells. It also activated the protein expression of iNOS and COX-2. AREG-activated NF-B and MAPKs signaling, and together with NF-B and MAPKs inhibitors, AREG significantly reduced the protein expression of iNOS and COX-2.
CONCLUSION
AREG plays a role in hepatic inflammation by increasing iNOS and COX-2 expression via NF-B and MAPKs signaling.
Topics: Mice; Humans; Animals; NF-kappa B; Cyclooxygenase 2; Amphiregulin; Nitric Oxide Synthase Type II; Non-alcoholic Fatty Liver Disease; Dinoprostone; Interleukin-8; Inflammation; Extracellular Signal-Regulated MAP Kinases; Interleukin-6; Lipopolysaccharides; Nitric Oxide
PubMed: 37868614
DOI: 10.1155/2023/2364121 -
Stem Cell Research & Therapy Aug 2023Mesenchymal stem cells (MSCs) are a class of adult stem cells with self-renewal and multidirectional differentiation potential that may be a treatment for aplastic...
BACKGROUND
Mesenchymal stem cells (MSCs) are a class of adult stem cells with self-renewal and multidirectional differentiation potential that may be a treatment for aplastic anemia (AA).
METHOD
Umbilical cord-derived MSCs were cultured in three media (Mesencult-XF, MCL, and StemPro MSC SFM CTS). HGF, PGE2, ANG-1, TGF-β1, IFN-γ, and TNF-α were detected using ELISA. The AA mouse model was built via post-irradiation lymphocyte infusion. After different treatments, routine blood, VEGF, and Tregs were detected every week. On day 28, all mice were killed, and their femurs were stained with HE.
RESULTS
Umbilical cord-derived MSCs cultured in the three media all conformed to the general characteristics of MSCs. HGF secreted by MSCs in the Mesencult-XF, and MCL was greater than that in the StemPro MSC SFM CTS; ANG-1 and TGF-β1 in the MCL were more than that in Mesencult-XF and StemPro MSC SFM CTS; PGE2 in the MCL and StemPro MSC SFM CTS was more than that in the Mesencult-XF. MSCs in the MCL and StemPro MSC SFM CTS inhibited IFN-γ and TNF-α more than those in the Mesencult-XF. The peripheral blood cell in the AA groups was at a low level while that in the MSC group recovered rapidly. The Treg ratio and VEGF level in the MSC group were higher than those in the AA group. The bone marrow (BM) recovered significantly after MSC infusion.
CONCLUSION
MSCs in the MCL were advantageous in supporting hematopoiesis and modulating immunity and had the potential for effective treatment of AA.
Topics: Animals; Mice; Anemia, Aplastic; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A; Dinoprostone; Tumor Necrosis Factor-alpha; Mesenchymal Stem Cells; Umbilical Cord
PubMed: 37649079
DOI: 10.1186/s13287-023-03417-1 -
PloS One 2023Shiso (Perilla frutescens var crispa f. purprea) is a traditional medicinal herb that exerts anti-inflammatory effects and alleviates lower urinary tract symptoms. In...
Shiso (Perilla frutescens var crispa f. purprea) is a traditional medicinal herb that exerts anti-inflammatory effects and alleviates lower urinary tract symptoms. In this study, we examined the effects of rosmarinic acid, a major polyphenol in shiso, on urinary function and the bladder in a rat hydrochloric acid-induced cystitis model. Sprague-Dawley rats were administered intravesically with hydrochloric acid or saline solution (control) to induce cystitis. Afterwards, the rats were administered orally with distilled water or rosmarinic acid for three days and then the intravesical pressure was measured, a stretch stimulation test was performed using the harvested bladder, and histological and biochemical analyses were performed. In addition, we investigated the effects of rosmarinic acid on the expression of inflammation-related molecules in normal human bladder epithelial cells. Rosmarinic acid ameliorated hydrochloric acid-induced shortening of micturition interval by 49%. In hydrochloric acid-treated bladders, significantly more prostaglandin E2 was released after stretching; however, rosmarinic acid suppressed its release to control levels. Rosmarinic acid also reduced hydrochloric acid-induced epithelial thickening and the levels of inflammatory molecules in the bladder. Furthermore, rosmarinic acid suppressed interleukin 1β-induced increases in Cox2 and Il6 expression in bladder epithelial cells. These findings indicate that rosmarinic acid can ameliorate hydrochloric acid-induced cystitis in rats and that these effects are due, at least in part, to its anti-inflammatory effects on the bladder and inhibition of stretch-induced prostaglandin E2 release.
Topics: Humans; Rats; Animals; Rats, Sprague-Dawley; Hydrochloric Acid; Dinoprostone; Cystitis; Anti-Inflammatory Agents; Rosmarinic Acid
PubMed: 37463180
DOI: 10.1371/journal.pone.0288813