Intramuscular versus intravenous oxytocin for the third stage of labor after vaginal delivery to prevent postpartum hemorrhage: a meta-analysis of randomized controlled trials.

INTRODUCTION: To examine the effects and safety of oxytocin administered intramuscularly or intravenously for preventing postpartum hemorrhage (PPH) in the third stage of labor after vaginal deliveries. MATERIAL AND METHODS: Before data extraction, the review was registered with the PROSPERO International Prospective Register of Systematic Reviews (registration No. CRD42019145912). We searched the published electronic databases, including Medline, EMBASE, PubMed, Web of Science, CNKI, VIP, Wanfang, the Cochrane Library, clinicaltrial.gov and PROSPERO database, from their inception until February 2019. We included all randomized controlled trials (RCTs) comparing intramuscular and intravenous oxytocin administered just after the birth of the anterior shoulder or soon after the birth of the baby during a vaginal delivery. The primary outcomes were the incidence of PPH and severe PPH. PPH was defined as a blood loss ≥500 ml within 24 hours after vaginal birth. Severe PPH refers to a clinically estimated blood loss equal to or greater than 1000 mL within 24 hours after vaginal birth. Statistical heterogeneity was assessed by the I2 test, the Cochran Q statistic and the Galbraith plot for heterogeneity. RESULTS: Six RCTs, including 7320 women undergoing vaginal delivery, were identified in the meta-analysis. Women who were randomized to have intravenous oxytocin for the third stage of labor had a significantly lower incidence of PPH (relative risk 1.35, 95% CI 1.11-1.64, p = 0.003), severe PPH (relative risk 1.61, 95% CI 1.05-2.46, p = 0.03) and blood transfusion (relative risk 2.50, 95% CI 1.37-4.59, p = 0.003) compared with those who were randomized to have intramuscular oxytocin during the third stage of labor after vaginal delivery. There was no significant difference with regard to changes in hemoglobin level, third stage of labor duration, mean postpartum blood loss, or the incidences of a need for additional uterotonics and of retained placenta or manual removal of placenta between groups. CONCLUSIONS: For women in the third stage of labor who are undergoing a vaginal delivery, the use of intravenous oxytocin reduces the incidence of PPH, severe PPH and blood transfusion and does not increase the risk of adverse effects compared with intramuscular oxytocin.

TGF-ß1 and TNF-α synergistically induce epithelial to mesenchymal transition of breast cancer cells by enhancing TAK1 activation.

TGF-ß1 is a main inducer of epithelial to mesenchymal transition (EMT). However, many breast cancer cells are not sensitive to the EMT induction by TGF-ß1 alone. So far, the mechanisms underlying the induction of TGF-ß1-insensitive breast cancer cells remains unclear. Here we report that TNF-α can induce EMT and invasiveness of breast cancer cells which are insensitive to TGF-ß1. Intriguingly, TGF-ß1 could cooperate with TNF-α to promote the EMT and invasiveness of breast cancer cells. The prolonged co-stimulation with TGF-ß1 and TNF-α could enhance the sustained activation of Smad2/3, p38 MAPK, ERK, JNK and NF-κB pathways by enhancing the activation of TAK1, which was mediated by the gradually up-regulated TßRs. Except for JNK, all of these pathways were required for the effects of TGF-ß1 and TNF-α. Importantly, the activation of p38 MAPK and ERK pathways resulted in a positive feed-back effect on TAK1 activation by up-regulating the expression of TßRs, favoring the activation of multiple signaling pathways. Moreover, SLUG was up-regulated and required for the TGF-ß1/TNF-α-induced EMT and invasiveness. In addition, SLUG could also enhance the activation of signaling pathways by promoting TßRII expression. These findings suggest that the up-regulation of TßRs contributes to the sustained activation of TAK1 induced by TGF-ß1/TNF-α and the following activation of multiple signaling pathways, resulting in EMT and invasiveness of breast cancer cells.

Antivirals for Respiratory Viral Infections: Problems and Prospects.

In the past two decades, several newly emerging and reemerging viral respiratory pathogens including several influenza viruses (avian influenza and pandemic influenza), severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV), have continued to challenge medical and public health systems. Thereafter, the development of cost-effective, broad-spectrum antiviral agents is the urgent mission of both virologists and pharmacologists. Current antiviral developments have focused targets on viral entry, replication, release, and intercellular pathways essential for viral life cycle. Here, we review the current literature on challenges and prospects in the development of these antivirals.

The cytokine storm of severe influenza and development of immunomodulatory therapy.

Severe influenza remains unusual in its virulence for humans. Complications or ultimately death arising from these infections are often associated with hyperinduction of proinflammatory cytokine production, which is also known as 'cytokine storm'. For this disease, it has been proposed that immunomodulatory therapy may improve the outcome, with or without the combination of antiviral agents. Here, we review the current literature on how various effectors of the immune system initiate the cytokine storm and exacerbate pathological damage in hosts. We also review some of the current immunomodulatory strategies for the treatment of cytokine storms in severe influenza, including corticosteroids, peroxisome proliferator-activated receptor agonists, sphingosine-1-phosphate receptor 1 agonists, cyclooxygenase-2 inhibitors, antioxidants, anti-tumour-necrosis factor therapy, intravenous immunoglobulin therapy, statins, arbidol, herbs, and other potential therapeutic strategies.

TLR4 ligand/H2O2 enhances TGF-ß1 signaling to induce metastatic potential of non-invasive breast cancer cells by activating non-Smad pathways.

TGF-ß1 has the potential to activate multiple signaling pathways required for inducing metastatic potential of tumor cells. However, TGF-ß1 was inefficient in inducing metastatic potential of many non-invasive human tumor cells. Here we report that the enhancement of TGF-ß1 signaling is required for inducing metastatic potential of non-invasive breast cancer cells. TGF-ß1 alone could not efficiently induce the sustained activation of Smad and non-Smad pathways in non-invasive breast cancer cells. TLR4 ligand (LPS) and H2O2 cooperated with TGF-ß1 to enhance the sustained activation of non-Smad pathways, including p38MAPK, ERK, JNK, PI3K, and NF-κB. The activation of MAPK and PI3K pathways resulted in a positive feed-back effect on TGF-ß1 signaling by down-regulating Nm23-H1 expression and up-regulating the expression of TßRI and TßRII, favoring further activation of multiple signaling pathways. Moreover, the enhanced TGF-ß1 signaling induced higher expression of SNAI2, which also promoted TßRII expression. Therefore, the sustained activation levels of both Smad and non-Smad pathways were gradually increased after prolonged stimulation with TGF-ß1/H2O2/LPS. Consistent with the activation pattern of signaling pathways, the invasive capacity and anoikis-resistance of non-invasive breast cancer cells were gradually increased after prolonged stimulation with TGF-ß1/H2O2/LPS. The metastatic potential induced by TGF-ß1/H2O2/LPS was sufficient for tumor cells to extravasate and form metastatic foci in an experimental metastasis model in nude mice. The findings in this study suggested that the enhanced signaling is required for inducing higher metastatic capacity of tumor cells, and that targeting one of stimuli or signaling pathways might be potential approach in comprehensive strategy for tumor therapy.

IL-6 cooperates with G-CSF to induce protumor function of neutrophils in bone marrow by enhancing STAT3 activation.

Neutrophils are known to have antitumor potential. However, in recent years the tumor-promoting effect of neutrophils has been well demonstrated. So far, it remains unclear what causes the conversion of neutrophil function from tumor suppressive to tumor promoting. In this article, we report that the conversion of murine neutrophil function occurs in bone marrow, and that IL-6 cooperation with G-CSF is required for this conversion. IL-6 cooperated with G-CSF to modulate neutrophils in bone marrow, altering the activation potential of signaling pathways in neutrophils, especially that of STAT3. Costimulation with G-CSF and IL-6 induced a higher level of phospho-STAT3 in neutrophils, which was further increased by upregulation of STAT3 expression in neutrophils owing to downregulation of IFN-ß expression in bone marrow macrophages by IL-6. Augmented STAT3 activation was crucial for upregulating the expression of Mmp9 and Bv8 genes and downregulating the expression of Trail and Rab27a genes in neutrophils. Moreover, G-CSF/IL-6-modulated neutrophils could not efficiently release azurophilic granules because of downregulation of Rab27a and inefficient activation of PI3K and p38 MAPK pathways. Because of premodulation by G-CSF and IL-6, neutrophils in response to complex stimuli in tumor released much less myeloperoxidase, neutrophil elastase, and TRAIL, but showed much higher expression of Mmp9 and Bv8 genes. Taken together, these results demonstrate that G-CSF and IL-6, despite their well-known physiological functions, could modulate the activation potential of signaling pathways in neutrophils, resulting in the production or release of the above-mentioned factors in a way that favors tumor angiogenesis and tumor growth.

Targeting nuclear factor-κB suppresses the negative effect of toll-like receptor 4 signaling on antimetastasis therapy based on targeting αvß3.

The targeting of αvß3 is a promising therapeutic strategy for suppressing tumor metastasis. However, it is unclear whether the therapeutic efficacy could be influenced by metastasis-promoting factor(s) in vivo. Here we report that Toll-like receptor 4 (TLR4) ligand released from damaged tumor cells or bacteria had a negative effect on the therapeutic effect of a recombinant CBD-HepII polypeptide of fibronectin (CH50) that suppresses tumor metastasis by targeting αvß3. The TLR4 ligand could antagonize the inhibitory effect of CH50 on tumor cell adhesion and invasion by promoting the expression and activity of αvß3 in tumor cells. The TLR4 ligand also reduced the antimetastasis effect of CH50 by promoting tumor cell survival in circulation. Moreover, TLR4 ligands released by tumor cells in circulation could increase the survival and proliferation capacity of tumor cells after extravasation, resulting in the formation of more metastatic nodules. The effect of TLR4 signaling was mainly mediated by nuclear factor-κB (NF-κB). Inhibiting NF-κB could abrogate the negative effect of TLR4 ligand, and augment the inhibitory effect of CH50 on tumor metastasis. Consistently, the combination of NF-κB inhibitor and CH50 significantly inhibited metastasis of tumor cells in vivo and prolonged the survival of mice. The findings in this study suggest that the combination of NF-κB inhibitor and αvß3 antagonist would be a novel therapeutic option for the prevention of tumor metastasis.

Extracellular HSPA1A promotes the growth of hepatocarcinoma by augmenting tumor cell proliferation and apoptosis-resistance.

Intracellular HSP70 has been implicated as a cytoprotective protein, whereas the effect of extracellular HSP70 on tumor cells has not been fully understood to date. Here we report that extracellular HSPA1A, a stress-inducible member of HSP70 family, could promote tumor growth. HSPA1A promoted the proliferation of H22 hepatocarcinoma cells through TLR2 and TLR4 signaling. The effect of HSPA1A was abolished by inhibiting NF-κB. HSPA1A also augmented the apoptosis-resistance of H22 cells by activating NF-κB, thus to promote the proliferation of H22 cells in presence of mitomycin C. Furthermore, the promoting effect of HSPA1A on tumor cell proliferation was existent after the removal of HSPA1A, which might involve HSPA1A-promoted upregulation of TLR4 expression in tumor cells and release of HMGB1 from tumor cells. These findings suggest that extracellular HSPA1A functions as endogenous ligand for TLR2 and TLR4 to facilitate tumor growth.

Triggering of Toll-like receptor 4 on metastatic breast cancer cells promotes αvß3-mediated adhesion and invasive migration.

Triggering of Toll-like receptor 4 (TLR4) on tumor cells has been found to promote tumor progression by promoting tumor cell proliferation and survival. So far, however, the effect of TLR4 signaling on tumor metastasis has not been well elucidated. Here, we report that triggering of TLR4 on metastatic breast cancer cells could reciprocally regulate the expression of αvß3 and the expressions of TPM1 and maspin, and promote αvß3-mediated adhesion and invasive migration of the cells. In metastatic breast cancer cells, TLR4 signaling increased the expression of integrin αvß3 by activating NF-κB, resulting in the increased adhesion capacity of tumor cells to the ligand for αvß3, and the increased polymerization of actin and production of MMP-9 in tumor cells in response to ECM. HoxD3 was required for the up-regulation of αv and ß3 expressions by NF-κB. Moreover, TLR4 signaling increased the expression of miR-21 in breast cancer cells by activating NF-κB. Accordingly, the expressions of TPM1 and maspin were decreased at protein level, whereas the transcription activity of these genes was not influenced. Consistent with the promoting effect on αvß3-mediated adhesion and invasive migration, TLR4 signaling promoted the arrest of metastatic breast cancer cells in circulation and following invasion. The effect of TLR4 signaling could be abrogated by inhibiting NF-κB. These findings suggest that metastatic breast cancer cells could acquire higher metastatic potential due to triggering of TLR4 and activation of NF-κB in the cells, and that both TLR4 and NF-κB could be therapeutic targets for preventing metastasis of breast cancer cells.