Akihiro Nawa

Nitric Oxide and Reactive Oxygen Species in the Pathogenesis of Preeclampsia

Preeclampsia (PE) is characterized by disturbed extravillous trophoblast migration toward uterine spiral arteries leading to increased uteroplacental vascular resistance and by vascular dysfunction resulting in reduced systemic vasodilatory properties. Its pathogenesis is mediated by an altered bioavailability of nitric oxide (NO) and tissue damage caused by increased levels of reactive oxygen species (ROS). Furthermore, superoxide (O2−) rapidly inactivates NO and forms peroxynitrite (ONOO−). It is known that ONOO− accumulates in the placental tissues and injures the placental function in PE. In addition, ROS could stimulate platelet adhesion and aggregation leading to intravascular coagulopathy. ROS-induced coagulopathy causes placental infarction and impairs the uteroplacental blood flow in PE. The disorders could lead to the reduction of oxygen and nutrients required for normal fetal development resulting in fetal growth restriction. On the other hand, several antioxidants scavenge ROS and protect tissues against oxidative damage. Placental antioxidants including catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx) protect the vasculature from ROS and maintain the vascular function. However, placental ischemia in PE decreases the antioxidant activity resulting in further elevated oxidative stress, which leads to the appearance of the pathological conditions of PE including hypertension and proteinuria. Oxidative stress is defined as an imbalance between ROS and antioxidant activity. This review provides new insights about roles of oxidative stress in the pathophysiology of PE.

Role of the renin-angiotensin system in gynecologic cancers.

Recent studies have shown an activation of the local renin-angiotensin system (RAS) in various tumor tissues, including the abundant generation of angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) and the upregulation of angiotensin II type 1 receptor (AT1R) expression. Thus, considerable attention has been paid not only to the role of the RAS in cancer progression, but also to the blockade of RAS as a new approach to the treatment of human cancer. There is increasing evidence that the Ang II-AT1R pathway is involved in tumor growth, angiogenesis and metastasis in various experimental animal models, suggesting the therapeutic potential of an ACE inhibitor and AT1R blocker. In addition, specific Ang II-degrading enzymes are also expressed in tumors and play a regulatory role in tumor cell proliferation and invasion. This review focuses on the role of the RAS in the progression of gynecologic cancers, such as cervical cancer, endometrial cancer, ovarian cancer, and gestational choriocarcinoma. We present here the clinical potential of blocking the RAS as a novel and promising strategy for the treatment of gynecologic cancers.

Lgr4 Controls Specialization of Female Gonads in Mice

ABSTRACT Leucine-rich repeat-containing G protein-coupled receptor 4 (Lgr4) is a type of membrane receptor with a seven-transmembrane structure. LGR4 is homologous to gonadotropin receptors, such as follicle-stimulating hormone receptor (Fshr) and luteinizing hormone/choriogonadotropin receptor (Lhcgr). Recently, it has been reported that Lgr4 is a membrane receptor for R-spondin ligands, which mediate Wnt/beta-catenin signaling. Defects of R-spondin homolog (Rspo1) and wingless-type MMTV integration site family, member 4 (Wnt4) cause masculinization of female gonads. We observed that Lgr4−/− female mice show abnormal development of the Wolffian ducts and somatic cells similar to that in the male gonads. Lgr4−/− female mice exhibited masculinization similar to that observed in Rspo1-deficient mice. In Lgr4−/− ovarian somatic cells, the expression levels of lymphoid enhancer-binding factor 1 (Lefl) and Axin2 (Axin2), which are target genes of Wnt/beta-catenin signaling, were lower than they were in wild-type mice. This study suggests that Lgr4 is critical for ovarian somatic cell specialization via the cooperative signaling of Rspo1 and Wnt/beta-catenin.

Survival Impact of Adjuvant Paclitaxel and Carboplatin for Early-Stage Ovarian Clear-Cell Carcinoma with Complete Surgical Staging

Objectives: The aim of this study was to estimate the survival impact of adjuvant paclitaxel and carboplatin (TC) compared to cisplatin (CDDP)-based chemotherapies for early-stage ovarian clear-cell carcinoma (CCC). Methods: Clinicopathologic information on 99 stage I–II CCC patients was obtained between 1987 and 2005. All patients underwent complete surgical staging including systemic lymphadenectomy, followed by TC or various CDDP-based regimens. In the present study, only CCC patients with no residual tumor were enrolled. Results: The median age was 53 years and ranged from 30 to 69 years. Fifty-three (53.5%) patients received TC and 46 (46.5%) patients underwent various CDDP-based chemotherapies after initial surgery. Five-year progression-free survival (PFS) rates of TC and various CDDP groups were 66.5 and 75.8%, respectively (n.s., p = 0.933). In addition, 5-year overall survival (OS) rates of TC and various CDDP groups were 82.4 and 82.3%, respectively (n.s., p = 0.583). In multivariate analyses of OS and PFS, the regimen of chemotherapywas not a significant prognostic factor (OS, p = 0.502; PFS, p = 0.977. Conclusions: In our current examination of the long-term survival of early-stage CCC patients, we did not identify a superiority of TC over various CDDP-based regimens as frontline adjuvant chemotherapy.

Atypical carcinoid of the uterine cervix with aggressive clinical behavior: A case report

Highlights • We herein report a case of a 44-year-old Japanese woman diagnosed with stage IB1 atypical carcinoid of the uterine cervix.• After radical hysterectomy, she developed recurrence with aggressive clinical behavior, resistance to CPT-11 + cisplatin and paclitaxel + CBDCA chemotherapy.

437. Biosafety After the Injection of Carrier Cells Infected With Oncolytic Adenovirus

Although replication-competent viruses have been developed to treat cancers, their cytotoxic effects are insufficient, since infection with them is inhibited by generation of neutralizing antibodies. To address this limitation, we developed a carrier cell system to deliver a replication-competent adenovirus. Carrier cells infected with oncolytic adenovirus were injected into syngeneic subcutaneous ovarian tumors after immunization with adenovirus and induced complete tumor regression by the induction of antiadenoviral and antitumoral CTL responses. To start clinical trial, toxicity and biodistribution study were carried out in nude mice, rabbits and beagle dogs. Acute toxicity and distribution test were carried out after the single injection of carrier cells into ovarian tumor in nude mice. Chronic toxicity test was carried out by 8 injections of carrier cells into rabbits for 4 weeks. Excretion study was carried out to determine whether oncolytic adenovirus was excreted from the beagle dogs after the single injection of carrier cells. Acute toxicity test did not show any lethal side effects in nude mice. In biodistribution test, single injection of carrier cells into ovarian tumor induced the peak levels of oncolytic adenovirus the next day but did not show any significant levels of that in nude mice 14 days after injection. In chronic toxicity test, 8 injections of 1.25×107 cells/kg or less did not show any significant toxicity in rabbits. In excretion test, oncolytic adenovirus was not excreted into the urine and the stool of beagle dogs. This oncolytic adenovirus-infected carrier cell system might prove effective and safe in the preclinical efficacy and the biosafety test, respectively. Clinical trial is being scheduled to treat recurrent solid cancers.