An-Shine Chao

Functional Network Analysis of the Transcriptomes of Mesenchymal Stem Cells Derived from Amniotic Fluid, Amniotic Membrane, Cord Blood, and Bone Marrow

Using high‐density oligonucleotide microarrays and functional network analyses, we examined whether MSCs derived from four different origins exhibited unique gene expression profiles individually and then compared the gene expression profiles of all MSCs with those of fetal organs. Our results indicated that within each group of MSCs from the same origin, the variability of the gene expression levels was smaller than that between groups of different origins. Functional genomic studies revealed the specific roles of MSCs from different origins. Our results suggest that amniotic fluid MSCs may initiate interactions with the uterus by upregulating oxytocin and thrombin receptors. Amniotic membrane MSCs may play a role in maintaining homeostasis of fluid and electrolytes by regulating the networks of endothelin, neprilysin, bradykinin receptors, and atrial natriuretic peptide. Cord blood MSCs may be involved in innate immune systems as the neonatal defense system against the earliest encountered pathogens. Adult bone marrow MSCs may be an important source not only of all blood lineages but also of bone formation. However, in spite of the different gene expression profiles seen in MSCs derived from different origins, a set of core gene expression profiles was preserved in these four kinds of MSCs. The core signature transcriptomes of all MSCs, when contrasted against those of fetal organs, included genes involved in the regulation of extracellular matrix and adhesion, transforming growth factor‐β receptor signaling, and the Wnt signaling pathways.

Pain relief by applying transcutaneous electrical nerve stimulation (TENS) on acupuncture points during the first stage of labor: a randomized double-blind placebo-controlled trial.

Abstract Transcutaneous electrical nerve stimulation (TENS) is one of the non‐pharmacological means of pain relief for labor and delivery. We aimed to investigate the efficacy and safety of TENS on specific acupuncture points for reducing pain in the first stage of labor. In this double‐blind, placebo‐controlled trial, we randomly assigned healthy full‐term parturients in active phase of first‐stage labor to either TENS on four acupuncture points (Hegu [Li 4] and Sanyinjiao [Sp 6]) (n = 52) or the TENS placebo (n = 53). Visual analogue scale (VAS) was used to assess pain before and 30 and 60 min after treatment. The primary outcome was the rate of VAS score decrease ⩾3 in each group. A questionnaire was given at 24 h post‐partum to evaluate the satisfaction of pain relieving method and the willingness to have the same treatment again. Mode of delivery and neonatal effect were measured as secondary outcome. One hundred women were eligible for analysis. TENS group experienced VAS score reduction ⩾3 significantly more common than the TENS placebo group (31/50 [62%] vs 7/50 [14%], P < 0.001). Willingness of using the same analgesic method for a future childbirth was also significantly different (TENS: 48/50 [96%] vs TENS placebo: 33/50 [66%], P < 0.001). Operative delivery was increased in the TENS group (12/50 [24%] vs 4/50 [8%], P = 0.05), but the neonatal outcomes were not different. The application of TENS on specific acupuncture points could be a non‐invasive adjunct for pain relief in the first stage of labor.

Regulation of ovarian cancer progression by microRNA-187 through targeting Disabled homolog-2

MicroRNAs (miRNAs) play important roles in tumorigenesis by regulating oncogenes and tumor-suppressor genes. In this study, miR-187 and miR-200a were found to be expressed at higher levels in ovarian cancers than in benign tumors. In patients with ovarian cancer, however, higher levels of miR-187 and miR-200a expression were paradoxically associated with better OS and recurrence-free survival. Further, multivariate analysis showed that miR-187 served as an independent prognostic factor for patients with ovarian cancer (n=176). Computational prediction and microarray results indicated that miR-187 directly targeted Disabled homolog-2 (Dab2), and luciferase reporter assays confirmed that the target site of miR-187 was located at the 3′-UTR of the Dab2 gene. Generally considered as a tumor-suppressor gene, Dab2 may actually promote tumor progression in advanced cancers through epithelial-to-mesenchymal transition (EMT). Ectopic expression of miR-187 in cancer cells promoted cell proliferation, but continued overexpression of miR-187 suppressed Dab2 and inhibited migration. Suppression of miR-187 upregulated Dab2, which, by inhibiting E-cadherin levels while stimulating vimentin and phospho-FAK levels, promoted EMT. Reduced ovarian cancer Dab2 histoscores correlated with high miR-187 levels and improved outcomes of patients. Collectively, these results demonstrate distinct dual roles of Dab2 in cell proliferation and tumor progression. In the initial steps of tumorigenesis, upregulated miR-187 suppresses Dab2, promoting cell proliferation. During the later stages, however, continued increased levels of miR-187 inhibits the Dab2-dependent EMT that is associated with tumor invasiveness, which is presumed to be the reason why cancers with high miR-187 levels were associated with better survivals.

Outcome of antenatally diagnosed cardiac rhabdomyoma: case series and a meta‐analysis

Rhabdomyoma, the most common primary fetal cardiac tumor, is often associated with tuberous sclerosis (TS). We aimed to evaluate outcome in cases diagnosed with fetal cardiac rhabdomyoma.

Molecular characterization of adenocarcinoma and squamous carcinoma of the uterine cervix using microarray analysis of gene expression

In an attempt to understand the molecular mechanisms for the different clinical features between adenocarcinoma/adenosquamous carcinoma (AC/ASC) and squamous carcinoma (SC) of the uterine cervix, we analyzed gene expression profiles of different histological subtypes of cervical cancer. Cancer specimens and the surrounding normal tissue counterparts were separately collected from cervical cancer patients undergoing type III radical hysterectomy. Paired total RNA (cancer and normal tissues) was isolated and analyzed with cDNA microarrays containing duplicate spots of 7 334 sequence‐verified human cDNA clones. Selected differentially expressed genes specific for AC or SC were further verified using real‐time quantitative polymerase chain reaction (RTQ‐PCR) and immunohistochemistry. Genes, including CEACAM5, TACSTD1, S100P and MSLN were upregulated in AC. Contrarily, genes involved in epidermal differentiation complex such as S100A9 and ANXA8 were upregulated in SC. Cross‐validation of the results using an independent but comparable group of patients with known long‐term outcomes (n = 63, median follow‐up 70.3 months; range, 4–208 months) showed that the correlation between the selected 6 differentially expressed genes and histology was highly significant. CEACAM5 (p < 0.0001) and TACSTD1 (p = 0.009) were significant prognostic factors by multivariate Cox proportional hazards regression analysis. The combination of cDNA microarray, RTQ‐PCR and immunohistochemical results of this study showed that it is possible to define different gene profiles for AC and SC. Moreover, TACSTD1 expression may be a novel poor prognostic factor.

Stress-induced Phosphoprotein 1 as a Secreted Biomarker for Human Ovarian Cancer Promotes Cancer Cell Proliferation

Ovarian cancers are frequently not diagnosed until advanced stages, resulting in a high case fatality rate. Because of this, more tumor markers, in addition to CA125, for detecting and monitoring ovarian cancer are needed. During a systematic search for potential biomarkers of ovarian cancer, we compared the protein profiles between tumor interstitial fluid and normal interstitial fluid of ovaries, rationalizing that abnormal levels of proteins in tumor interstitial fluid may be detected in peripheral blood and thus serve as easily accessible tumor markers. Here, we show that stress-induced phosphoprotein 1 (STIP1) was secreted by ovarian cancer tissues into the peripheral blood of patients, resulting in a significant increase of serum levels of STIP1 in cancer patients compared with those in age-matched normal controls. Our results further indicated that combined use of CA125 and STIP1 may increase early detection of ovarian cancer. Functionally, recombinant STIP1 significantly induced ERK phosphorylation, promoted DNA synthesis, and increased Ki-67 immunoreactivity in ovarian cancer cells, suggesting that STIP1 in vitro promotes cell proliferation. Colocalization of STIP1 and phospho-ERK in human ovarian cancer tissues also supports an in vivo activation of ERK by STIP1. Further understanding of molecular roles of STIP1 in human ovarian cancer may shed light on its pathophysiology and development of novel therapeutic strategies.

Clinical outcome and placental territory ratio of monochorionic twin pregnancies and selective intrauterine growth restriction with different types of umbilical artery Doppler

To evaluate the clinical outcome and placental territory ratio in monochorionic diamniotic (MCDA) twin pregnancies and selective intrauterine growth restrictions (sIUGR) with different types of umbilical artery (UA) Doppler.

Change in amniotic fluid levels of multiple anti-angiogenic proteins before development of preeclampsia and intrauterine growth restriction.

CONTEXT The cause of preeclampsia remains unknown. Excessive antiangiogenic proteins have been proposed to play a pathogenic role in preeclampsia. OBJECTIVE Our objective was to determine the differences in soluble endoglin (sEndoglin), soluble fms-like tyrosine kinase receptor-1 (sFLT1), leptin, adiponectin, and endothelin 1 concentrations between normal and preeclampsia amniotic fluid (AF). Such results may help us understand the pathophysiology of preeclampsia. METHODS We performed a nested case-control study. Seventy-one women with preeclampsia were matched to 71 normotensive controls. The preeclamptic women were broken into two subgroups according to the association with fetal intrauterine growth restriction (IUGR). AF concentrations of sEndoglin, sFLT1, leptin, adiponectin, and endothelin 1 were measured by ELISA. Receiver-operating characteristics curve analysis was used to compare the discriminative values of these potential biomarkers. Functional network analysis was performed using MetaCore to reveal the common functions of the interacting proteins. RESULTS Increased AF concentrations of sFLT1, sEndoglin, endothelin 1, and leptin were found in women who later developed preeclampsia. sFLT1, sEndoglin, leptin, and adiponectin were significantly higher in the preeclampsia with IUGR than those without IUGR. Leptin has the largest area under the curve (0.753). Network analysis revealed that elevated amniotic proteins are involved in the inflammatory process of the human placenta. CONCLUSIONS Significant elevation of leptin can be detected in AF 2 months earlier than the appearance of symptoms; thus, it may be used as a predictive marker for preeclampsia. The increase of these antiangiogenic proteins supports the roles of inflammation and oxidative stress in pathogenesis of preeclampsia.

Network analyses of differentially expressed proteins in amniotic fluid supernatant associated with abnormal human karyotypes

OBJECTIVE To investigate the functional roles of differentially expressed proteins in the amniotic fluid supernatant (AFS) with abnormal karyotypes. DESIGN Basic and clinical research. SETTING University hospital. PATIENT(S) Samples of AFS from 34 fetuses with normal-karyotype, 17 with trisomy 18, and 19 with trisomy 21. INTERVENTION(S) Two-dimensional chromatography followed by mass spectrometry to identify the proteins differentially expressed in AFS of trisomy-18 or trisomy-21 fetuses. MAIN OUTCOME MEASURE(S) Differentially expressed proteins were confirmed with Western blot analysis and ELISA. The roles of biologic networks in the pathophysiology of aneuploidies were analyzed using MetaCore mapping tools. RESULT(S) Levels of apolipoprotein A1, AP-3mu, and antitrypsin were significantly decreased in trisomy-18 AFS, whereas placental protein-14 was increased. On the other hand, apolipoprotein A1 was decreased in trisomy-21 AFS, but antitrypsin, prealbumin, and transferrin were increased in trisomy 21. Biologic network analyses revealed that the proteins of the trisomy-18 AFS network were involved in immune processes, dysfunction of skin pigmentation, and platelet disorders, whereas those of trisomy 21 were associated with dysfunctional lipid and cholesterol metabolism, processes of metal ion transport, adenosine triphosphate metabolism, and energy-coupled protein transport. CONCLUSION(S) The combined use of quantitative proteomics and functional network analyses may integrally analyze the pathophysiology of abnormal karyotypes.

Association of Staphylococcus aureus colonization in parturient mothers and their babies.

We recruited a total of 499 mothers and their 501 newborn babies to investigate whether infants acquire Staphylococcus aureus from their mothers. Of the 22 mother-baby paired S. aureus isolates, 11 (50%) paired isolates were unrelated, 1 pair related, and 10 pairs (45%) indistinguishable. Newborn babies acquire S. aureus colonization soon after birth either from the environment or their mothers.