Toshiyuki Yoshizato

Amphiregulin regulates the activation of ERK and Akt through epidermal growth factor receptor and HER3 signals involved in the progression of pancreatic cancer

Pancreatic cancer is one of the most lethal malignancies. Epidermal growth factor receptor (EGFR), HER3, Akt, and amphiregulin have been recognized as targets for pancreatic cancer therapy. Although gemcitabine + erlotinib has been the recommended chemotherapy for pancreatic cancer, the prognosis is extremely poor. The development of molecularly targeted therapies has been required for patients with pancreatic cancer. To assess the validation of amphiregulin as a target for pancreatic cancer therapy, we examined its expression in pancreatic cancer using real‐time PCR analyses and ELISA. We also measured the apoptotic cell rate using TUNEL assays. In addition, alterations in signaling pathways were detected by immunoblotting analyses. Treatment with gemcitabine, which reduced the cell viability and augmented the cell apoptotic rate, activated and subsequently attenuated ERK and EGFR signals. However, gemcitabine, paclitaxel, or cisplatin treatment enhanced the Akt activation, heterodimer formation of EGFR with HER3, and secretion of amphiregulin, indicating that the presence of gemcitabine promoted the activity of targeted molecules including amphiregulin, Akt, and HER3 for pancreatic cancer therapy. Combined treatment with an inhibitor for amphiregulin and gemcitabine, paclitaxel, or cisplatin induced synergistic antitumor effects, accompanied by the suppression of Akt and ERK activation. Blockade of amphiregulin suppressed the activities of EGFR, HER3, and Akt and the expression of amphiregulin itself. According to this evidence, combination chemotherapy of conventional anticancer drugs plus an inhibitor for amphiregulin would allow us to provide more favorable clinical outcomes for patients with pancreatic cancer. (Cancer Sci 2010; 101: 2351–2360)

Fetal cell-free DNA fraction in maternal plasma is affected by fetal trisomy.

The purpose of this noninvasive prenatal testing (NIPT) study was to compare the fetal fraction of singleton gestations by gestational age, maternal characteristics and chromosome-specific aneuploidies as indicated by z-scores. This study was a multicenter prospective cohort study. Test data were collected from women who underwent NIPT by the massively parallel sequencing method. We used sequencing-based fetal fraction calculations in which we estimated fetal DNA fraction by simply counting the number of reads aligned within specific autosomal regions and applying a weighting scheme derived from a multivariate model. Relationships between fetal fractions and gestational age, maternal weight and height, and z-scores for chromosomes 21, 18 and 13 were assessed. A total of 7740 pregnant women enrolled in the study, of which 6993 met the study criteria. As expected, fetal fraction was inversely correlated with maternal weight (P<0.001). The median fetal fraction of samples with euploid result (n=6850) and trisomy 21 (n=70) were 13.7% and 13.6%, respectively. In contrast, the median fetal fraction values for samples with trisomies 18 (n=35) and 13 (n=9) were 11.0% and 8.0%, respectively. The fetal fraction of samples with trisomy 21 NIPT result is comparable to that of samples with euploid result. However, the fetal fractions of samples with trisomies 13 and 18 are significantly lower compared with that of euploid result. We conclude that it may make detecting these two trisomies more challenging.

Investigation of β2‐adrenoceptor subtype selectivity and organ specificity for bedoradrine (KUR‐1246), a novel tocolytic beta‐adrenergic receptor stimulant

Objectives:  The aim of this study was to evaluate the beta‐adrenergic receptor (β‐AR) selectivity, organ specificity and efficacy of delaying the onset of spontaneous delivery of bedoradrine (KUR‐1246), a novel uterine relaxant.

Involvement of anticentromere antibody in interference with oocyte meiosis and embryo cleavage.

The aim of this study was to investigate the clinical significance of anticentromere antibody (ACA) among types of antinuclear antibody (ANA) in the properties of oocytes retrieved from infertile women. The rate of metaphase II oocytes or embryo cleavage was significantly decreased in patients with positive ACA compared with patients with negative ACA, suggesting that ACA is an essential marker for flawed oocytes in infertile women with any type of ANA.

Intermittent ‘Double Bubble’ Sign in a Case of Congenital Pyloric Atresia

We report a case of congenital pyloric atresia in which two cystic masses in the fetal upper abdomen and polyhydramnios were observed from 24 weeks’ gestation to term. The two cystic masses were thought to indicate the ‘double bubble’ sign in utero, leading to a misdiagnosis of congenital duodenal obstruction. At 33 weeks’ gestation, continuous ultrasound observation of the two cystic masses was made for 60 min. During the periods when gastric peristalsis was absent, the ‘double bubble’ sign was observed. However, during the periods when gastric peristalsis was present, the ‘double bubble’ sign disappeared. In retrospect, both cystic masses were stomach and the ‘double bubble’ sign disappeared with peristalsis of the antrum. In order to differentiate from congenital duodenal obstruction, whole stomach configuration should be delineated by continuous observation covering periods when gastric peristalsis is active as well as quiet.

Amphiregulin regulates the production of human chorionic gonadotropin in trophoblasts

AIMS The aim of this study was to investigate the significance of epidermal growth factor receptor (EGFR) ligands produced in syncytiotrophoblasts during normal pregnancy. MAIN METHODS We examined the expression of EGFR ligands in human pregnancy by real-time PCR, and analyzed the relationship between EGFR ligands and human chorionic gonadotropin (hCG) or human placental lactogen in amniotic fluid by ELISA. In addition, we also examined the EGFR ligands in syncytiotrophoblasts and the amount of hCG secretion in JAR, JEG3 and BeWo cells in the presence of each EGFR ligand. KEY FINDINGS In order to identify possible candidates among the EGFR ligands, we examined the predominant expression of an EGFR ligand in the chorionic villi and amniotic fluid during normal pregnancy, and analyzed the relationship between EGFR ligands and hCG in trophoblastic model cells. Amphiregulin was primarily expressed throughout human pregnancy and stimulated the secretion of hCG, indicating that amphiregulin is a key molecule among EGFR ligands. SIGNIFICANCE Amphiregulin may play a pivotal role in the development or maturation of placenta.

Fetal heart rate variation described using a probability distribution matrix.

We devised a new method using a probability distribution matrix to simultaneously describe variation in the characteristics of fetal heart rate (FHR) and beat-to-beat difference (DFHR) between the present and the immediately following FHR. The FHRs were plotted in columns, DFHRs in rows and probabilities in the corresponding elements of the matrix. The age-related changes of FHR data obtained from 743 fetuses at 23-40 weeks gestation were analysed using a pulsed Doppler cardiotocograph with an autocorrelation system. While keeping an almost symmetrical spread around 0 beats/min of DFHR, three particular probability distribution patterns of FHR versus DFHR emerged with advance in gestation: (i) oval with a monomodal peak from 23/24 to 29/30 weeks, (ii) ellipsoid with a monomodal peak and plateau from 31/32 to 33/34 weeks and (iii) elongated ellipsoid with bimodal peaks from 35/36 weeks of gestation onwards. The probability distribution matrix presented enables one to condense any amount of FHR data into one uniform description. This allows analysis of data, en bloc, achieving a quantitative inter-group comparison, on an equivalent scale.

2 Quantification of fetal heart rate variation using a probability distribution matrix

Analysis of FHR variability attempts to be able to distinguish which FHR changes are physiological and which are pathological. From the results of such studies, it is hoped that clinicians will be provided with the means to identify accurately which fetuses are healthy, which are at risk and which are actually in distress at any gestational age. The probability distribution matrix presented has the outstanding advantage of enabling one to condense any amount of FHR data into one uniform description for analysis en bloc. Not even one FHR is sacrificed; each one contributes to the FHR vs. DFHR distribution pattern. Where the probability distribution matrix is made from many FHR samples taken from healthy fetuses under natural day-to-day maternal circumferences, as we have done, this matrix can be considered as a physiologically unbiased reference. The subtraction matrix is characterized by the difference in FHR vs. DFHR distribution patterns between two probability distribution matrices compared, representing the equal residue of net absolute value. The larger the difference in FHR vs. DFHR distribution between two probability distribution matrices, the larger these kinds of residue values, and if two probability distribution matrices are identical, all the elements in the subtraction matrix indicate the residue values of zero. Our probability distribution matrix approach confirms the results of previously reported studies which utilized other analytical strategies. Therefore, we can evaluate quantitatively age-related FHR changes used as variables, such as the subtraction matrix and difference rate. By varying intervals between paired FHRs (e.g. selecting the original FHR--skip--select the following FHR--skip 2 FHR--select the next FHR, etc.), the probability distribution matrix could be adopted as a general tool for analysis of sequential changes in large numbers of FHR for further studies.

Predictive factors related to the efficacy of pelvic arterial embolization for postpartum hemorrhage: A retrospective analysis of 21 cases

OBJECTIVE This retrospective study aimed to determine the predictive factors for the efficacy of pelvic arterial embolization for postpartum hemorrhage. MATERIALS AND METHODS Twenty-one patients who underwent pelvic arterial embolization for postpartum hemorrhage of >1000 mL between September 2006 and September 2011 were enrolled in this study. The patients were divided into two subgroups according to the blood loss and time from the end of pelvic arterial embolization to complete hemostasis: good-response (16 patients) and poor-response groups (5 patients). The following predictive factors were compared between the groups: (1) patient characteristics; (2) blood loss; (3) time between delivery (or onset of bleeding) and pelvic arterial embolization; (4) obstetrical disseminated intravascular coagulation score comprising clinical background, clinical signs, and laboratory data; (5) individual disseminated intravascular coagulation score; (6) shock index; and (7) laboratory data including platelet count, prothrombin time-international normalized ratio, fibrinogen, fibrin degradation products, and antithrombin-III at the time of pelvic arterial embolization. RESULTS In the poor-response group, the obstetrical and individual disseminated intravascular coagulation scores and prothrombin time-international normalized ratio were higher than those in the good-response group (p < 0.05). Platelet count, fibrinogen, and fibrin degradation products were lower than those in the good-response group (p < 0.05). All obstetrical disseminated intravascular coagulation scores in the poor-response group were >9 points. CONCLUSION The efficacy of pelvic arterial embolization is related to the presence or absence of coagulation disorders. When the obstetrical disseminated intravascular coagulation score is high (>9 points), the efficacy may be poor.

Percutaneous cardiopulmonary support for pulmonary thromboembolism caused by large uterine leiomyomata

OBJECTIVE Acute pulmonary thromboembolism (PTE) is a common illness that causes death and disability. Deep vein thrombosis (DVT) is often found in patients with a large myomatous uterus, and can occasionally result in acute PTE. Here, we describe the achievement of a favorable outcome in a case of acute PTE. CASE REPORT The patient presented with acute PTE caused by a large uterine leiomyoma, without DVT of the lower extremities. Percutaneous cardiopulmonary support (PCPS) was used as an adjunct to thrombolytic therapy to treat the right ventricular thrombus with acute PTE. According to emergency practice, PCPS was initiated, and the patient was successfully treated with thrombolytic and anticoagulant therapy associated with total abdominal hysterectomy. CONCLUSIONS This case suggests that PCPS can lead to favorable clinical outcomes in patients with large uterine leiomyomata and severe PTE.