REG Iα is a biomarker for predicting response to chemotherapy with S-1 plus cisplatin in patients with unresectable stage IV gastric cancer.

BACKGROUND: The regenerating gene Iα (REG Iα) is involved in gastric carcinogenesis as an antiapoptotic factor. Therefore, we investigated whether REG Iα confers resistance to chemotherapeutic drugs in gastric cancer (GC) cells and whether REG Iα expression is useful for predicting the response to chemotherapy and outcome in patients with GC. METHODS: A total of 70 patients with unresectable stage IV GC received first-line chemotherapy with S-1 and cisplatin (S-1/CDDP). The expression of REG Iα was evaluated immunohistochemically using biopsy samples obtained before chemotherapy, and its relationship to clinicopathological parameters was analysed statistically. The effects of REG Iα gene induction on resistance to 5-FU or CDDP treatment were examined by cell survival assay and flow cytometry. RESULTS: Of the 70 patients with unresectable stage IV GC, 19 (27%) were positive for REG Iα expression. The expression of REG Iα was independently predictive of poorer progression-free and overall survival in such patients (hazard ratio (HR) 2.46; P=0.002 and HR 1.89; P=0.037, respectively). The gene induction of REG Iα conferred resistance to cell death induced by 5-FU or CDDP in GC cells. CONCLUSION: In patients with stage IV GC, REG Iα, which confers resistance to chemotherapeutic drugs in GC cells, is a potential biomarker for predicting resistance to S-1/CDDP treatment.

Oral administration of milk fermented with Lactococcus lactis subsp. cremoris FC protects mice against influenza virus infection.

AIMS: To evaluate the protective effects of oral administration of milk fermented with a Lactococcus strain against influenza virus (IFV) infection in a mouse model. METHODS AND RESULTS: Milk fermented with exopolysaccharide-producing Lactococcus lactis subsp. cremoris (L. cremoris) FC was orally administered to BALB/c mice for 12 days. Mice were intranasally infected with IFV A/New Caledonia/20/99 (H1N1) on day 8, and survival was determined for 14 days after IFV infection. Survival rate and body weight loss after IFV infection in the L. cremoris FC fermented milk-administered group were significantly improved compared with those in the control group. In the unfermented milk-administered group, survival rate was not improved, whereas body weight loss was slightly improved compared with that in the control group. The mean virus titre in the lung of the L. cremoris FC fermented milk-administered group 3 days after infection was significantly decreased compared with that in the control group. CONCLUSIONS: These results suggest that oral administration of milk fermented with L. cremoris FC protects mice against IFV infection. SIGNIFICANCE AND IMPACT OF THE STUDY: These results demonstrate that oral administration of milk fermented with exopolysaccharide-producing Lactococcus strains might protect host animals against IFV infection.

Identification of cancer stem cells derived from a canine lung adenocarcinoma cell line.

Accumulating evidence supporting the cancer stem cell (CSC) hypothesis is based on the finding that tumors contain a small population of self-renewing cells that generate differentiated progeny and thereby contribute to tumor heterogeneity. CSCs are reported to exist in several human cancers, yet only a few reports demonstrate the existence of CSCs in primary lung cancer in dogs. In this study, the authors established a cancer cell line derived from a canine primary lung adenocarcinoma and identified a side population (SP) of cells that displayed drug-resistant features. To confirm the characteristics of these SP cells, the authors investigated the tumorigenicity of the cells in vivo by using a nude mouse xenograft model. Only 100 SP cells were able to give rise to new tumors, giving a 10-fold enrichment over the main population (MP) of cells, suggesting that these cells have the cancer-initiating ability of CSCs. Further studies characterizing CSCs in canine lung adenocarcinoma might contribute to the elucidation of the mechanisms of tumorigenesis and to the establishment of novel therapeutic strategies.

Feasibility of virtual surgical simulation in the head and neck region for soft tissue reconstruction using free flap: a comparison of preoperative and postoperative volume measurement.

In the head and neck region, preoperative evaluation of the free flap volume is challenging. The current study validated preoperative three-dimensional (3D) virtual surgical simulation for soft tissue reconstruction by assessing flap volume and evaluated fat and muscle volume changes at follow-up in 13 head and neck cancer patients undergoing anterolateral craniofacial resection. Patients received 3D virtual surgical simulation, and the volume of the planned defects was estimated by surgical simulation. Following en bloc resection of the tumor, the defect in the skull base was covered using a rectus abdominis myocutaneous flap. Following surgery, computed tomography scans were acquired at day 1 and at 6 and 12 months. Virtual planned defect was on average 227 ml (range, 154-315) and was 10% smaller than the actual flap volume in patients without skin involvement of the tumor. Between day 1 and 12 months post-surgery, the volume of fat and muscle tissue in the free flap dropped by 9% and 58%, respectively. Our results indicate that 3D virtual surgical simulation provides essential information in determining the accurate volume of the required free flap for surgical defect repair and may thus help improve surgical planning and functional and esthetic outcome.

The development of placenta increta following pelvic transcatheter artery embolization for postpartum hemorrhage.

OBJECTIVE: Pelvic transcatheter artery embolization (TAE) has been widely used for the management of postpartum hemorrhage (PPH). However, the adverse effects of TAE on the subsequent pregnancy remain poorly understood. CASE: A 30-year-old woman, gravida 2, para 1, developed PPH due to atonic bleeding and underwent TAE. Thereafter, her menstrual cycle became irregular with less blood volume. Three years later, she became pregnant despite a thin endometrial thickness of 6 mm during the ovulatory period. She delivered a healthy baby at 39 weeks of gestation. No signs of placental separation were obtained, and an attempt at manual extraction of the placenta failed, followed by massive PPH. She underwent emergent TAE. The placenta was not spontaneously delivered even on day 8 postpartum. A supracervical hysterectomy was performed due to a worsening intrauterine infection. Pathological examination revealed findings compatible with placenta increta. CONCLUSION: A TAE-associated thin endometrium may be attributable to the development of placenta increta. Pregnant women undergoing TAE should be managed carefully because the information about pregnancy outcomes after TAE remains scanty.

Large granular lymphocytic leukaemia complicated with histiocytic sarcoma in a dog.

A 10-year-old castrated male Golden retriever, weighing 36.3 kg was referred for evaluation owing to a decline in general condition. Findings from the complete blood count revealed a marked lymphocytosis (113000/ml). Examination of Wright-Giemsa-stained films of peripheral blood revealed the presence of large granular lymphocytes (LGL). Seventy-two per cent (81360/ml) of the lymphocytes were found to be 12-17 microm in diameter, containing nuclei with mature clumped chromatin and abundant lightly basophilic cytoplasm with a variable number of fine azurophilic granules. Based on these findings this case was diagnosed as LGL leukaemia. As a result of multiple-agent chemotherapy, the markedly elevated levels of lymphocytes gradually decreased to 7500/ml on day 122 and the patient maintained a good quality of life for the following 3 months. However, on around day 237, a soft, raised, bosselated mass on the labial region was noted. The dog was diagnosed as having histiocytic sarcoma based on cytological and histological examination of the mass. Shortly after diagnosis, the dog developed sudden onset of central nervous system signs and died on day 270. A common outcome of canine LGL is the development of acute blast crisis or lymphoma. However, this case was notable for complication with histiocytic sarcoma from another origin.

Association study of vascular endothelial growth factor gene polymorphisms in endometrial carcinomas in a Japanese population.

OBJECTIVE: Vascular endothelial growth factor (VEGF) is one of the most potent endothelial cell mitogens and plays a critical role in angiogenesis of endometrial carcinomas. Several studies have demonstrated positive associations between VEGF gene polymorphisms and several carcinomas. In this study we investigated whether VEGF gene polymorphisms are associated with endometrial carcinomas in a Japanese population. METHODS: The allele frequencies and genotype distributions of VEGF -460 C/T, +405 G/C, and +936 C/T polymorphisms were examined in 105 endometrial carcinomas and 179 controls using PCR-RFLP analysis. An association of these polymorphisms with three-year disease-free survival was evaluated using the Kaplan-Meier method. RESULTS: No significant differences in the allele frequencies and genotype distributions of VEGF -460 C/T (p = 0.54, 0.90), +405 G/C (p = 0.31, 0.17), and +936 C/T polymorphisms (p = 0.46, 0.24) were observed between endometrial carcinoma patients and controls. There were no significant differences in the frequencies of haplotype -460 T/+405 C between patients and controls. Futhermore, VEGF -460 C/T, +405 G/C, and +936 C/T polymorphisms were not associated with three-year disease-free survival of endometrial carcinoma patients. CONCLUSIONS: Although limited by sample size, our study did not demonstrated any evidence that VEGF -460 C/T, +405 G/C, and +936 C/T polymorphisms are associated with an increased risk of endometrial carcinomas in Japanese women.

Association study between catechol-O-methyltransferase polymorphisms and uterine leiomyomas in a Japanese population.

PURPOSE: To investigate a possible association between uterine leiomyomas and catechol-O-methyltransferase (COMT) polymorphisms in a Japanese population. METHODS: We compared the allele frequencies and genotype distributions of the exon 4 NlaIII restriction site polymorphism (RSP), the P2 promoter HindIII RSP at -1217, and the exon 6 BglI RSP in the COMT gene in 250 leiomyoma cases and 182 controls using polymerase chain reaction-restriction fragment-length polymorphism analysis. RESULTS: No significant differences in allele frequencies and genotype distributions of the exon 4 NlaIII RSP, the P2 promoter HindIII RSP at -1217, and the exon 6 BglI RSP were found between uterine leiomyoma cases and controls. Moreover, no associations were noted between these three polymorphisms in COMT genes and leiomyoma size or a family history of uterine leiomyomas. CONCLUSION: COMT gene polymorphisms are unlikely to be associated with an increased risk of uterine leiomyomas in a Japanese population.

Uterine bizarre epithelioid lipoleiomyoma with a myxoid stroma.

The first case of uterine bizarre epithelioid lipoleiomyoma with a myxoid component occurring in an 86-year-old woman is described. An intramural 22 cm mass in the anterior wall of the uterine body had a lipoma-like appearance with strands of fibrous tissue. Histologically, the tumor consisted of adipocytes which varied in size and shape, and epithelioid smooth muscle cells with nuclear atypia within a myxoid stroma. No mitotic features were noted despite an extensive search. The patient was well without disease 24 months after hysterectomy. Patients with this type of tumor need close and long-term follow-up because of the paucity of clinical information.

Radioresistance of cancer stem-like cell derived from canine tumours.

Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are a small subpopulation of cancer cells that are responsible for the initiation, recurrence and metastasis of cancer. We previously demonstrated that, using the Hoechst 33342 dye-based side population technique, CSCs/CICs in canine lung adenocarcinoma cell line exist. In this study, as CSCs/CICs are known to form spheres in anchorage-independent environment in vitro, we evaluated the stemness of spheroid cells derived from canine lung adenocarcinoma and osteosarcoma cells by expression of stemness markers, and investigated radioresistance. Spheroid cells showed greater expression of stemness markers Oct-4 and CD133 gene than those of adherent-cultured cells. In nude mouse xenograft models, spheroid cells showed higher tumourigenic ability than adherent-cultured cells. In addition, spheroid cells showed significantly resistant against radioactivity as compared with adherent-cultured cells. These results suggest that spheroid cells could possess stemness and provide a CSCs/CICs research tool to investigate CSCs/CICs of canine tumour cells.

Adenofibromasarcoma originating from a mural nodule of ovarian serous cystadenoma.

A 83-year-old woman received bilateral salpingo-oophorectomy and hysterectomy due to a provisional diagnosis of ovarian cystic tumor. The tumor had a unilocular cystic cavity demonstrating serous cystadenoma and a solid mural nodule representing a biphasic pattern with mesenchymal and glandular components. The glandular elements were composed of benign serous cells, whereas the mesenchymal components consisted of an admixture of fibromatous stromal cells without atypia and sarcomatous overgrowth. The area of transition from a fibromatous component to sarcomatous overgrowth was identified. After a 2-year follow-up, there were no signs of tumor recurrence or systemic disease. To the authors' knowledge, this is the first reported case of adenofibrosarcoma originating from a mural nodule of ovarian serous cystadenoma.

Coexistence of brenner tumor and struma ovarii: case report.

BACKGROUND: There has been controversy regarding the histogenesis of Brenner tumors. It is generally accepted that Brenner tumors are derived directly from ovarian surface epithelium, which undergoes metaplasia to form the typical urothelial-like components, whereas some investigators assume that Brenner tumors arise from immature germ cells. CASE: We describe a well-documented case of the coexistence of struma ovarii regarded as a form of teratoma and Brenner tumor in the same ovary. Immunohistologically, not only columnar cells of thyroid follicles, but also transitional cells of Brenner nests were positive for thyroglobulin. CONCLUSIONS: In the present case, Brenner tumors and thyroid elements coexisted and were positive for thyroglobulin. While there is strong evidence that pure Brenner tumors originate mostly from the ovarian surface, at least Brenner tumors associated with teratomatous elements may have a germ cell origin.

Pregnancy complicated with pulmonary lymphangioleiomyomatosis: case report.

A case of a 30-year-old primiparous woman with pulmonary lymphangioleiomyomatosis is described. The patient had experienced six episodes of spontaneous pneumothorax at the age of 27 years and had been diagnosed as having pulmonary lymphangioleiomyomatosis based on histological findings of specimens obtained by transbronchial biopsy. She had undertaken open lung surgery and thoracoscopy. Thereafter, she became pregnant spontaneously. Her antenatal course was uneventful with no exacerbation of respiratory status. At 38 weeks of gestation, she underwent a selective cesarean section and myomectomy under combined spinal and epidural anesthesia. Her postoperative course was uneventful. No remarkable changes in computed tomographic findings of the lung were noted on the 20th day of postoperation compared with those before pregnancy. She has been followed-up in the pulmonary outpatient clinic with no deterioration of the disease.

Consumptive coagulopathy that developed in a pregnant woman with degenerated uterine leiomyoma: case report.

A case of consumptive coagulopathy in a 30-year-old pregnant woman with degenerated uterine leiomyoma is described. She developed lower abdominal pain at 21 weeks of gestation. Laboratory profiles revealed coagulation abnormalities. Magnetic resonance imaging diagnosed degenerated uterine leiomyoma. At 34 weeks, she underwent cesarean section and myomectomy. Pathological examination showed the presence of organized thrombi in the vessels of leiomyoma. The consumption of platelets and coagulation factors in degenerated uterine leiomyoma may result in consumptive coagulopathy.

A pregnant woman with anti-Gregory antigen: case report.

Negative Gregory antigen (Gy(a-)) remains an extremely uncommon blood phenotype. We describe a 32-year-old pregnant woman with (Gy(a-)) and anti-Gregory antigen (anti-Gy(a)). There was no evidence of consanguineous mating in her family. Blood typing study revealed that only her father was Gy(a-) among the family. Anti-Gy(a) had a titer of 16 before pregnancy, but increased to 1024 at 33 weeks of gestation with a titer of 512 at 34 weeks. Her own blood stores were collected starting at 14 weeks, amounting to 1800 g totally. She underwent an emergency cesarean section at 35 weeks due to a non-reassuring fetal status. Blood loss was approximately 1090 g. Cord blood type was found to be Gy(a-). The indirect Coombs test of cord blood was positive, while the direct Coombs test was negative. No neonatal hemorrhagic disease developed. The storage of a sufficient amount of crossmatch-compatible Gy(a-) blood during pregnancy is important in case of possible need of blood transfusion at delivery for women with anti-Gy(a).

Differential modulation of chorionic gonadotropin (CG) subunit messenger ribonucleic acid levels and CG secretion by progesterone in normal placenta and choriocarcinoma cultured in vitro.

The ability of progesterone to modulate the production and secretion of human CG (hCG) in both normal placenta and choriocarcinoma was compared by culturing explants of each trophoblastic tissue in the presence or absence of progesterone. The cellular level of messenger RNAs (mRNAs) encoding hCG alpha, hCG beta, and human placental lactogen (hPL) were quantitatively estimated by mean grain count per syncytial nucleus on the tissue sections hybridized in situ with labeled complementary DNA probes corresponding to these mRNAs. Immunoreactive hCG, hCG alpha, and hCG beta in the media and explanted tissues were measured by the homologous RIAs, and hPL was assayed by hPL-RIA kit. Addition of progesterone at concentrations of 5-20 micrograms/ml into the culture of normal early placenta caused a decrease in the cellular levels of hCG alpha mRNA and hCG beta mRNA after a 24-h culture, and exhibited a decline in immunoreactive hCG and hCG alpha levels released into the media together with a decrease in immunoreactive hCG alpha and hCG beta levels in the explanted tissues after a 48-h culture. The addition of progesterone neither affected the cellular levels of hPL mRNA nor immunoreactive hPL levels in the media and tissues. On the other hand, addition of 17 beta-estradiol at concentrations similar to those used with progesterone did not alter the levels of immunoreactive hCG and hCG alpha in the media or explanted placental tissues, while lower concentrations (1-10 ng/ml) of 17 beta-estradiol caused an increase in immunoreactive hCG alpha levels in the media and cultured tissues. These findings suggest that the suppressive effect observed with progesterone is not likely to be a toxic effect of steroid, but is rather selective on hCG production and secretion by normal placenta. Thus, progesterone may be a factor responsible for the inhibitory regulation of hCG production and secretion by normal placenta. However, in contrast to normal placenta, the choriocarcinoma culture in vitro did not respond to progesterone. The steroid was without significant effect on the cellular levels of hCG alpha mRNA and hCG beta mRNA, and on the levels of immunoreactive hCG and hCG alpha in the media and explanted tissues. These results suggest that the inhibitory regulation of hCG production and secretion in choriocarcinoma is different from that in normal early placenta.

The role of thyroid hormone as a biological amplifier of the actions of follicle-stimulating hormone in the functional differentiation of cultured porcine granulosa cells.

To characterize thyroid hormone action on the ovary, the direct effects of T4 or T3 were investigated in vitro using a monolayer culture system of porcine granulosa cells. Monolayer cultures were maintained for 6 days in 4% serum-supplemented medium in the absence or presence of porcine FSH (20 ng/ml), with or without graded doses of T4 or T3. Combined treatment with FSH and T4 (10(-7) M) induced morphological alternation resembling epithelioid cells, while FSH alone or T4 alone failed to bring about the epithelioid morphology. Concomitant treatment with FSH and T4 (10(-7) M) markedly increased FSH-stimulated induction of [125I]iodo-human CG binding to cultured granulosa cells obtained from small follicles. The combined treatment with FSH and T4 (10(-7) M) also resulted in a significant increase in progesterone and estrogen secretion by the cultured cells relative to treatment with FSH alone. Increases in progesterone, 17 beta-estradiol, and estrone secretion caused by the combined treatment with FSH and T4 (10(-7) M) were further augmented in response to the addition of exogenously provided substrate pregnenolone, testosterone, and androstenedione, respectively. Furthermore, aromatase activity assessed by the release of [3H]water from [1 beta-3H, 4-14C]androstenedione was significantly higher in cells treated concomitantly with FSH and T4 (10(-7) M) than that in cells treated with FSH alone. All the stimulatory effects of T4 (10(-7) M) on the morphological and functional differentiation of cultured granulosa cells were also found in combined treatment with FSH and T3 (10(-9) M). Either treatment with higher or lower concentrations of T4 or T3 gave attenuated effects, and T4 or T3 alone without FSH was incapable of exhibiting these stimulatory effects. These findings suggest that thyroid hormones synergize with FSH to exert direct stimulatory effects on granulosa cell functions, including morphological differentiation, LH/human CG receptor formation and steroidogenic enzyme (3 beta-hydroxysteroid dehydrogenase and aromatase) induction. Hence, decreases in ovarian functions during the states of hypo- or hyperthyroidism may account for diminished responsiveness of the granulosa cells to FSH.

Expression of epidermal growth factor and its receptor in the human ovary during follicular growth and regression.

Immunohistochemical studies were performed using specific antibodies to epidermal growth factor (EGF) and EGF receptor to determine their presence and cellular localization in the human ovary during follicular growth and regression. There was no immunostaining for EGF or EGF receptor in primordial follicles. In the preantral follicle stage, immunostaining for EGF and EGF receptor was observed only in the oocyte. The staining intensity of the oocyte increased as the oocyte reached the preovulatory stage. In the antral follicle stage, immunostaining for EGF and EGF receptor became apparent in the granulosa and theca interna cell layers, without appreciable staining in the surrounding stromal cells. The immunostaining for EGF and EGF receptor in the granulosa cells and theca interna cells persisted in preovulatory follicles and corpus luteum, and intensified in the midluteal phase. The stromal cells surrounding the corpus luteum were negative for EGF and EGF receptor staining. In the regressing corpus luteum, immunostaining for EGF and EGF receptor was present in the peripheral lutein cells adjacent to the central core of scar tissue, but absent in the scar tissue of the central core. Corpus albicans showed no staining for EGF and EGF receptor. By contrast, the stromal cells surrounding the corpus albicans in the cortex region demonstrated intense staining for EGF and EGF receptor, while the stromal cells surrounding the corpus albicans in the medullary region were negative for immunostaining. In the case of atretic follicles, the theca interna cells showed intense staining for EGF and EGF receptor, but immunostaining in the scattered granulosa cells was negligible. This is the first study to demonstrate a remarkable change in the expression of EGF and EGF receptor in the oocyte, granulosa cells, thecal cells, and surrounding stromal cells over the course of follicular growth and regression. The results obtained support EGF participation in oocyte maturation and in follicular growth and atresia. The intense immunostaining for EGF and EGF receptor observed in the theca interna cells in atretic follicles and the stromal cells surrounding corpus albicans in the cortex region raises the possibility of EGF involvement in transformation of thecal cells into stromal cells. Furthermore, the cell type-specific simultaneous expression of EGF and EGF receptor in follicular and stromal compartments in the various stages of follicular development suggests that an autocrine mode of EGF action may exist to regulate follicular growth and regression in the human ovary.

Increased expression of Bcl-2 protein in human uterine leiomyoma and its up-regulation by progesterone.

Uterine leiomyoma is the most common benign smooth muscle cell tumor of the myometrium. Although Bcl-2 protein is known to be an apoptosis-inhibiting gene product and to prevent apoptotic cell death in a variety of cells, there are no published data regarding whether human leiomyomas express Bcl-2 protein. In the present study, we examined the expression of Bcl-2 protein in leiomyomas in comparison with that in the normal myometrium using an immunohistochemical method and immunoblot analysis with a monoclonal antibody to human Bcl-2 protein. Furthermore, we investigated whether sex steroid hormones could influence the levels of Bcl-2 protein expression in leiomyoma cells cultured in vitro under serum-free, phenol red-free conditions. Immunohistochemical staining for Bcl-2 protein was prominent in leiomyoma cells, but was scarcely present in normal myometrial smooth muscle cells. The expression of Bcl-2 protein in leiomyoma cells was most abundant in the secretory, progesterone-dominated, phase of the menstrual cycle, but was less abundant in the proliferative phase of the menstrual cycle. Western blot analyses of leiomyoma and myometrium tissue extracts revealed that Bcl-2 protein, with a molecular mass estimated at approximately 26 kDa, was abundantly present in leiomyoma tissue extracts, but was undetectable in normal myometrial tissue extracts. In monolayer cultures of uterine leiomyoma cells under a serum-free condition, the addition of progesterone (100 ng/mL) resulted in a striking increase in Bcl-2 protein expression in the cultured leiomyoma cells relative to that in control cultures, whereas the addition of 17 beta-estradiol (10 ng/mL) resulted in a reduction in Bcl-2 protein expression in the cells. The concentrations of sex steroids used were within the physiological tissue concentrations found in leiomyomas and myometrium. The present results suggest that the abundant expression of Bcl-2 protein may have a molecular basis characteristic of leiomyomas in the human uterus and that progesterone may play a vital role in the enhanced expression of Bcl-2 protein in human uterine leiomyoma cells.

Expression of adrenomedullin by human placental cytotrophoblasts and choriocarcinoma JAr cells.

Adrenomedullin is a multifunctional peptide expressed in a variety of tissues. This study was conducted to investigate the expression of adrenomedullin and its mRNA by human trophoblasts and the possible existence of adrenomedullin receptor in those cells. Human placentas in all three trimesters were obtained from patients undergoing therapeutic abortions and deliveries. Total RNA was extracted from placental trophoblastic tissues and JAr choriocarcinoma cells, and the expression of adrenomedullin mRNA was determined by RT-PCR. Immunohistochemical analysis was performed by the avidin/biotin immunoperoxidase method using a specific antibody to adrenomedullin. The secretion of adrenomedullin by JAr cells cultured in medium containing [35S]cysteine-[35S]methionine was determined by immunoprecipitation followed by PAGE. The presence of adrenomedullin receptor in JAr cells was examined using a binding assay with [125I]rat adrenomedullin. Adrenomedullin mRNA was expressed by human placental trophoblastic tissues in all three trimesters and by JAr cells. Immunohistochemical analysis revealed that adrenomedullin is expressed by cytotrophoblasts in placentas in all three trimesters, but not by syncytiotrophoblasts. The expression of adrenomedullin in the cytotrophoblast was most abundant in first trimester placenta and became less abundant during the course of pregnancy. JAr cells synthesized and secreted immunoreactive adrenomedullin. Binding assay with [125I]rat adrenomedullin demonstrated specific binding of adrenomedullin to JAr cells, indicating the existence of a specific receptor for adrenomedullin in trophoblastic cells. Adrenomedullin is transcribed and secreted by cytotrophoblastic cells that possess adrenomedullin receptor. Adrenomedullin may play a potential role as an autocrine/paracrine factor in the growth of cytotrophoblasts, especially in early gestation.