The association between induction of labour in nulliparous women at term and subsequent spontaneous preterm birth: a retrospective cohort study.

OBJECTIVES: To evaluate the rate of subsequent spontaneous preterm birth in patients with previous induction of labour at term compared to women with previous spontaneous labour at term. METHODS: This was a retrospective cohort study of all women with consecutive births at the Royal Brisbane and Women's Hospital between 2014 and 2018. All nulliparous women with a singleton pregnancy and induction of labour at term or in spontaneous labour at term in the index pregnancy were included. Data was extracted from electronic medical records. The outcome of spontaneous preterm birth in the subsequent pregnancy was compared between patients with previous term induction of labour and in previous term spontaneous labour. RESULTS: A total of 907 patients with consecutive births met the inclusion criteria; of which 269 (29.7%) had a term induction of labour and 638 (70.3%) had a term spontaneous labour in the index pregnancy. The overall subsequent spontaneous preterm birth rate was 2.3%. Nulliparous women who underwent term induction of labour were less likely to have a subsequent preterm birth compared to nulliparous women in term spontaneous labour (0.74 vs. 2.98%; odds ratio [OR], 0.25; 95% confidence interval, 0.06-1.07; p=0.0496) in the index pregnancy. This however was not significant once adjusted for confounders (adjusted OR, 0.29; p=0.10). Spontaneous preterm birth was associated with a previous spontaneous labour compared to induction of labour between 37 to 37+6 and 38 to 38+6 weeks (adjusted OR 0.18 and 0.21; p=0.02 and 0.004 respectively). CONCLUSIONS: Term induction of labour does not increase the risk of subsequent spontaneous preterm birth compared to spontaneous labour at term in nulliparous women. Further research is needed to validate these findings in a larger cohort of women and to evaluate the effect of elective IOL among low-risk nulliparous women.

Inflammation Regulates Haematopoietic Stem Cells and Their Niche.

Haematopoietic stem cells (HSCs) reside in the bone marrow and are supported by the specialised microenvironment, a niche to maintain HSC quiescence. To deal with haematopoietic equilibrium disrupted during inflammation, HSCs are activated from quiescence directly and indirectly to generate more mature immune cells, especially the myeloid lineage cells. In the process of proliferation and differentiation, HSCs gradually lose their self-renewal potential. The extensive inflammation might cause HSC exhaustion/senescence and malignant transformation. Here, we summarise the current understanding of how HSC functions are maintained, damaged, or exhausted during acute, prolonged, and pathological inflammatory conditions. We also highlight the inflammation-altered HSC niche and its impact on escalating the insults on HSCs.

CD271+CD51+PALLADIN- Human Mesenchymal Stromal Cells Possess Enhanced Ossicle-Forming Potential.

Human mesenchymal stem/stromal cells (hMSCs), when engrafted into immunodeficient mice, can form ectopic bone organs with hematopoietic stem cell (HSC) supportive functions. However, the ability to do so, through a cartilage intermediate, appears limited to 30% of donor bone marrow samples. In this study, we characterize the heterogeneous nature of hMSCs and their ability to efficiently form humanized ossicles observed in "good donors" to correlate with the frequency and functionality of chondrocyte progenitors. Flow cytometry of putative hMSC markers was enriched in the CD271+CD51+ stromal cell subset, which also possessed enhanced hMSC activity as assessed by single-cell colony-forming unit fibroblast (CFU-F) and undifferentiated mesensphere formation. Transcriptome analysis of CD271+ cells presented upregulation of chondrogenesis-/osteogenesis-related genes and HSC/niche maintenance factors such as C-X-C motif chemokine 12 (CXCL12) and ANGIOPOIETIN 1. Among the candidate genes selected to enrich for subsets with greater chondrogenic ability, cells negative for the actin cross-linker PALLADIN displayed the greatest CFU-F potential. Our study contributes to a better characterization of ossicle-forming hMSCs and their efficient isolation for the optimized engineering of human bone organs.

The interplay of UBE2T and Mule in regulating Wnt/ß-catenin activation to promote hepatocellular carcinoma progression.

Emerging evidence indicates the role of cancer stem cells (CSCs) in tumor relapse and therapeutic resistance in patients with hepatocellular carcinoma (HCC). To identify novel targets against liver CSCs, an integrative analysis of publicly available datasets involving HCC clinical and stemness-related data was employed to select genes that play crucial roles in HCC via regulation of liver CSCs. We revealed an enrichment of an interstrand cross-link repair pathway, in which ubiquitin-conjugating enzyme E2 T (UBE2T) was the most significantly upregulated. Consistently, our data showed that UBE2T was upregulated in enriched liver CSC populations. Clinically, UBE2T overexpression in HCC was further confirmed at mRNA and protein levels and was correlated with advanced tumor stage and poor patient survival. UBE2T was found to be critically involved in the regulation of liver CSCs, as evidenced by increases in self-renewal, drug resistance, tumorigenicity, and metastasis abilities. Mule, an E3 ubiquitin ligase, was identified to be the direct protein binding partner of UBE2T. Rather than the canonical role of acting as a mediator to transfer ubiquitin to E3 ligases, UBE2T is surprisingly able to physically bind and regulate the protein expression of Mule via ubiquitination. Mule was found to directly degrade ß-catenin protein, and UBE2T was found to mediate liver CSC functions through direct regulation of Mule-mediated ß-catenin degradation; this effect was abolished when the E2 activity of UBE2T was impaired. In conclusion, we revealed a novel UBE2T/Mule/ß-catenin signaling cascade that is involved in the regulation of liver CSCs, which provides an attractive potential therapeutic target for HCC.

Prediction of time of delivery using cervical length measurement in women with threatened preterm labor.

OBJECTIVE: To evaluate the use of transvaginal (TV) sonographic cervical length (CL) measurement alone in predicting time of delivery in women who present in threatened preterm labor. METHODS: A retrospective cohort study at Royal Brisbane and Women's Hospital of all women who presented between 22 weeks and 0 days and 35 weeks and six-day gestation in threatened preterm labor and were admitted for ongoing management including a TV sonographic CL measure. The accuracy of CL for predicting time of delivery was compared between women with a short cervix (CL < 25 mm) and those with a normal cervix (CL ≥25 mm). The predictive accuracy of CL for spontaneous preterm delivery was analyzed with different outcome-specific thresholds. RESULTS: One hundred and forty-six women with threatened preterm labor met the inclusion criteria; of which 74 (50.7%) had a short cervix and 72 (49.3%) had a normal cervix. The group with short cervix were more likely to deliver prematurely before 37-week gestation, as well as a shorter time interval between initial presentation and delivery and delivery within 14 days from presentation (p = .0002, p = .0001, and p = .0001, respectively). Similarly, with respect to the area under the receiver operator characteristic curves, CL measurement was found to be significant for time of delivery before or after 37 weeks (p < .0001), preterm delivery before 34 (p = .0003) and 31 (p < .0001) weeks; and preterm delivery within 14 days from presentation (p < .0001). Cervical length measurement has a high negative predictive value ranging from 94.9 to 97.1% depending on the different CL threshold used. CONCLUSIONS: Cervical length measurement at the time of presentation was significantly associated with the risk of preterm delivery in women presenting with threatened preterm labor and a short cervix. Cervical length measurement was also helpful in predicting time of delivery within 14 days from presentation. The negative predictive value and predictive accuracy of CL as a single measure were of significance.

The risk of preterm delivery and pregnancy outcomes in women with asymptomatic short cervix: a retrospective cohort study.

OBJECTIVE: Routine cervical length measurement in asymptomatic pregnant women to prevent preterm birth has not been universally adopted due to poor predictive accuracy. The purpose of our study was to evaluate the risk of preterm delivery and pregnancy outcomes in women with asymptomatic short cervix and examine the implications of gestational age at presentation on these outcomes. STUDY DESIGN: This was a retrospective cohort study of women with singleton pregnancies who presented prior to or at 32 + 0 weeks with an asymptomatic short cervix (≤25 mm) between April 2014 to March 2018 at a single tertiary maternity center. Women with cervical length ≤25 mm were grouped into four cohorts according to gestational age at presentation: Obstetric outcomes were compared between the cohorts and the general cohort of women delivering during the same period. Outcomes were compared using Mann-Whitney U, chi-square tests, and logistic regression. Survival analysis was carried out to compare the probability of delivery for each subgroup. RESULTS: The rate of spontaneous preterm birth <37 weeks was highest in the cohort presenting at 25 + 0-27 + 6 weeks, and lowest in the first cohort presenting at <22 + 0 (60.0 versus 22.2%, p < .05). When compared with the general cohort, the rate of spontaneous preterm birth at <37-week gestation was significantly higher in the asymptomatic short cervix cohort (40.4 versus 8.7%, p < .001), with a 7.1-fold increase in the relative risk of spontaneous PTB. CONCLUSIONS: In asymptomatic women, cervical shortening showed significant increase in the risk of preterm birth. Our study findings suggest that routine cervical screening may be helpful in predicting risk of preterm birth even in women who are considered low-risk for preterm birth.

Does the length of second stage of labour or second stage caesarean section in nulliparous women increase the risk of preterm birth in subsequent pregnancies?

OBJECTIVES: This study aimed to investigate the role of prolonged second stage of labour and second stage caesarean section on the risk of spontaneous preterm birth (sPTB) in a subsequent pregnancy. METHODS: This was a retrospective cohort study of nulliparous women with two consecutive singleton deliveries between 2014 and 2017 at a tertiary centre. In the vaginal delivery cohort, subsequent pregnancy outcomes for women with a prolonged second stage (>2 h) were compared with those with a normal second stage (≤2 h). In the caesarean delivery cohort, women with a first stage or a second stage were compared with the vaginal delivery cohort. The primary outcome was subsequent sPTB. RESULTS: A total of 821 women met inclusion criteria, of which 74.8% (614/821) delivered vaginally and 25.2% (207/821) delivered by caesarean section. There was no association between a prolonged second stage in the index pregnancy and subsequent sPTB (aOR 0.70, 95% CI 0.13-3.83, p=0.7). The risk of subsequent sPTB was threefold for those with a second stage caesarean section; however this did not reach statistical significance. CONCLUSIONS: A prolonged second stage of labour in the index pregnancy is not associated with an increased risk of subsequent sPTB. A second stage caesarean section in the index pregnancy may be associated with an increased risk of subsequent sPTB, however there was no statistically significant difference. These findings are important for counseling and suggest that the effects of these factors are not clinically significant to justify additional interventions in the subsequent pregnancy.

IRAK1 Augments Cancer Stemness and Drug Resistance via the AP-1/AKR1B10 Signaling Cascade in Hepatocellular Carcinoma.

Frequent relapse and drug resistance in patients with hepatocellular carcinoma (HCC) can be attributed to the existence of tumor-initiating cells (TIC) within the tumor bulk. Therefore, targeting liver TICs may improve the prognosis of these patients. From transcriptome sequencing of 16 pairs of clinical HCC samples, we report that interleukin-1 receptor-associated kinase 1 (IRAK1) in the TLR/IRAK pathway is significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at the mRNA and protein levels and correlated with advanced tumor stages and poor patient survival. Interestingly, IRAK4, an upstream regulator of IRAK1, was also consistently upregulated. IRAK1 regulated liver TIC properties, including self-renewal, tumorigenicity, and liver TIC marker expression. IRAK1 inhibition sensitized HCC cells to doxorubicin and sorafenib treatment in vitro via suppression of the apoptotic cascade. Pharmacological inhibition of IRAK1 with a specific IRAK1/4 kinase inhibitor consistently suppressed liver TIC populations. We identified aldo-keto reductase family 1 member 10 (AKR1B10) as a novel downstream target of IRAK1, which was found to be overexpressed in HCC and significantly correlated with IRAK1 expression. Knockdown of AKR1B10 negated IRAK1-induced TIC functions via modulation of the AP-1 complex. Inhibition of IRAK1/4 inhibitor in combination with sorafenib synergistically suppressed tumor growth in an HCC xenograft model. In conclusion, targeting the IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway may be a potential therapeutic strategy against HCC.Significance: IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway regulates cancer stemness and drug resistance and may be a novel therapeutic target in HCC. Cancer Res; 78(9); 2332-42. ©2018 AACR.

A test for clinal variation in Artemisia californica and associated arthropod responses to nitrogen addition.

The response of plant traits to global change is of fundamental importance to understanding anthropogenic impacts on natural systems. Nevertheless, little is known about plant genetic variation in such responses or the indirect effect of environmental change on higher trophic levels. In a three-year common garden experiment, we grew the shrub Artemisia californica from five populations sourced along a 700 km latitudinal gradient under ambient and nitrogen (N) addition (20 kg N ha-1) and measured plant traits and associated arthropods. N addition increased plant biomass to a similar extent among all populations. In contrast, N addition effects on most other plant traits varied among plant populations; N addition reduced specific leaf area and leaf percent N and increased carbon to nitrogen ratios in the two northern populations, but had the opposite or no effect on the three southern populations. N addition increased arthropod abundance to a similar extent among all populations in parallel with an increase in plant biomass, suggesting that N addition did not alter plant resistance to herbivores. N addition had no effect on arthropod diversity, richness, or evenness. In summary, genetic variation among A. californica populations mediated leaf-trait responses to N addition, but positive direct effects of N addition on plant biomass and indirect effects on arthropod abundance were consistent among all populations.

The CCCTC-binding factor (CTCF)-forkhead box protein M1 axis regulates tumour growth and metastasis in hepatocellular carcinoma.

CCCTC-binding factor (CTCF) is a DNA-binding protein that interacts with a large number of highly divergent target sequences throughout the genome. It is implicated in a variety of functions, including chromatin organization and transcriptional control. The functional role of CTCF in tumour pathogenesis remains elusive. We showed that CTCF is frequently upregulated in a subset of primary hepatocellular carcinomas (HCCs) as compared with non-tumoural liver. Overexpression of CTCF was associated with shorter disease-free survival of patients. Short hairpin RNA (shRNA)-mediated suppression of CTCF inhibited cell proliferation, motility and invasiveness in HCC cell lines; these effects were correlated with prominent reductions in the expression of telomerase reverse transcriptase (TERT), the shelterin complex member telomerase repeat-binding factor 1, and forkhead box protein M1 (FOXM1). In contrast, upregulation of CTCF was positively correlated with FOXM1 and TERT expression in clinical HCC biopsies. Depletion of CTCF resulted in reduced motility and invasiveness in HCC cells that could be reversed by ectopic expression of FOXM1, suggesting that FOXM1 is one of the important downstream effectors of CTCF in HCC. Reporter gene analysis suggested that depletion of CTCF is associated with reduced FOXM1 and TERT promoter activity. Chromatin immunoprecipitation (ChIP)-polymerase chain reaction (PCR) analysis further revealed occupancy of the FOXM1 promoter by CTCF in vivo. Importantly, depletion of CTCF by shRNA significantly inhibited tumour progression and metastasis in HCC mouse models. Our work uncovered a novel functional role of CTCF in HCC pathogenesis, which suggests that targeting CTCF could be further explored as a potential therapeutic strategy for HCC. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Stearoyl-CoA desaturase regulates sorafenib resistance via modulation of ER stress-induced differentiation.

BACKGROUND & AIMS: We investigated the functional role and clinical significance of stearoyl-CoA desaturase-1 (SCD1) mediated endoplasmic reticulum (ER) stress in regulating liver tumor-initiating cells (T-ICs) and sorafenib resistance, with the aim of developing a novel therapeutic strategy against hepatocellular carcinomas (HCCs). METHODS: We evaluated the clinic-pathological relevance of SCD1 and its correlation with sorafenib resistance in large cohorts of HCC clinical samples by qPCR and immunohistochemical analyses. Lentiviral-based overexpression and knockdown approaches were performed to characterize the functional roles of SCD1 in regulating liver T-ICs and sorafenib resistance. Molecular pathways mediating the phenotypic alterations were identified through RNA sequencing analysis and functional rescue experiments. The combinatorial effect of SCD1 inhibition and sorafenib was tested using a patient-derived tumor xenograft (PDTX) model. RESULTS: SCD1 overexpression was found in HCC, which was associated with shorter disease-free survival (p = 0.008, log rank test). SCD1 was found to regulate the populations of liver T-ICs; while its suppression by a SCD1 inhibitor suppressed liver T-ICs and sorafenib resistance. Interestingly, SCD1 was markedly upregulated in our established sorafenib-resistant PDTX model, and its overexpression predicts the clinical response of HCC patients to sorafenib treatment. Suppression of SCD1 forces liver T-ICs to differentiate via ER stress-induced unfolded protein response, resulting in an enhanced sensitivity to sorafenib. The PDTX#1 model, combined with sorafenib treatment and a novel SCD1 inhibitor (SSI-4), showed a maximal growth suppressive effect. CONCLUSIONS: SCD1-mediated ER stress regulates liver T-ICs and sorafenib sensitivity. Targeting SCD1 alone or in combination with sorafenib might be a novel personalized medicine against HCC. Lay summary: In this study, SCD1 was found to play a critical role in regulating liver tumor-initiating cells and sorafenib resistance through the regulation of ER stress-mediated differentiation. Targeting SCD1 in combination with sorafenib may be a novel therapeutic strategy against liver cancer.

Cancer Stem Cells and Their Microenvironment: Biology and Therapeutic Implications.

Tumor consists of heterogeneous cancer cells including cancer stem cells (CSCs) that can terminally differentiate into tumor bulk. Normal stem cells in normal organs regulate self-renewal within a stem cell niche. Likewise, accumulating evidence has also suggested that CSCs are maintained extrinsically within the tumor microenvironment, which includes both cellular and physical factors. Here, we review the significance of stromal cells, immune cells, extracellular matrix, tumor stiffness, and hypoxia in regulation of CSC plasticity and therapeutic resistance. With a better understanding of how CSC interacts with its niche, we are able to identify potential therapeutic targets for the development of more effective treatments against cancer.