d-Val22 containing human big endothelin-1 analog, [d-Val22]Big ET-1[16–38], inhibits the endothelin converting enzyme

AbstractEndothelin converting enzyme (ECE) is essential for generation of the biological effects of endothelin-1 (ET-1) from a precursor, big endothelin-1 (Big ET-1). We synthesized four analogs of human Big ET-1[16–38], substituted with single d-amino acids at P1, P2, P1′and P2′ positions. ECE activity was determined using an ET-1 specific radioimmunoassay system. None of the d-amino acid containing Big ET-1 analogs were apparently cleaved by ECE, however, one of the synthetic peptides, [d-Val22]Big ET-1[16–38], strongly inhibited the ECE activity. Furthermore, when this d-Val22 containing peptide was preadministrated to rat striatum, it was found to inhibit the dopamine release induced by Big ET-1. This result suggests that the d-Val22 containing peptide inhibits the ECE activity in vivo. The d-Val22 containing inhibitor offers hope of developing more potent and highly specific ECE inhibitors of therapeutic significance

A Novel Concept of Fundus-Ovary-Salpinx-Para-Aorta Implantation Promoting Unit during Human Embryo Implantation

Human embryo implantation is mainly regulated by the endocrine system. Since the ovary, fallopian tube, and fundus can directly communicate through the mesosalpinx and ovarian ligament, the local concentration of progesterone in the pathway of the developing embryo is considered to be higher than in systemic blood circulation. The immune system promotes embryo implantation by stimulating progesterone production of the ovary and by inducing endometrial differentiation. The recognition of the developing embryo in the fallopian tube by the immune system is achieved through the para-aortic lymph nodes. On the basis of the above evidence, the autologous immune cells activated in vitro were demonstrated to improve clinical pregnancy rates in patients with repeated implantation failures. In addition, the autonomic nerve system that innervates the fundus, the ovary, and the fallopian tube from the para-aortic region is proposed to regulate the environment of the pathway of the developing embryo. From these findings, we suppose that a unique unilateral functional unit to promote human embryo implantation exists in the pathway of the developing embryo including the para-aortic regions and propose naming this novel functional unit the Fundus-Ovary-Salpinx-Para-aorta Implantation Promoting unit (FOSPa-IP unit)

Placenta Accreta in a Woman with Childhood Uterine Irradiation: A Case Report and Literature Review

The pregnancies of childhood cancer survivors who have received uterine irradiation are associated with a high risk of several obstetrical complications, including placenta accreta. The present case was a 26-year-old pregnant woman with a history of myelodysplastic syndrome treated with umbilical cord blood transplantation following chemotherapy and total body irradiation at the age of 10. Despite every possible measure to prevent preterm labor, uterine contractions became uncontrollable and a female infant weighing 892 g was vaginally delivered at 27⁺⁴ weeks of gestation. Under the postpartum ultrasonographic diagnosis of placenta accreta, we selected to leave the placenta in situ. Although emergency bilateral uterine artery embolization was required, complete resorption of the residual placenta was accomplished on the 115th day postpartum. Our experience highlighted the following points. (1) The expectant management of placenta accreta arising in an irradiated uterus may not only fulfill fertility preservation, but may also reduce possible risks associated with cesarean hysterectomy. (2) Due to extreme thinning of and a poor blood supply to the myometrium, reaching an antepartum diagnosis of placenta accreta in an irradiated uterus is difficult. (3) The recurrence of placenta accreta in subsequent pregnancies needs to be considered after successful preservation of the uterus

Oncofertility care in young women and the outcomes of pregnancy over the last 5 years

Aim: To ascertain the actual outcomes of oncofertility care in young women to provide more appropriate care. Materials & methods: We analyzed the data of 67 female patients under 43 years of age who underwent oncofertility care between January 2015 and September 2019. Results: There were 28 patients with breast cancer, 19 patients with hematologic cancer and 20 patients with other cancer diagnoses. Breast cancer patients tended to take longer than hematologic cancer patients to initiate oncofertility treatment. Despite undergoing oncofertility care, seven of nine pregnant patients did not choose assisted reproductive technology (ART). Conclusion: As spontaneous pregnancies were more common than ART pregnancies in our study, pregnancy by not only ART but also non-ART method is a viable option for young cancer survivors

Development of healthy lifestyle consciousness index for gynecological cancer patients

PURPOSE: Healthy lifestyle is related to quality of life (QOL) after cancer diagnosis and prognosis. However, there are few reports on patients conscious of healthy lifestyle and patients requiring medical providers' attention regarding healthy lifestyle. We aimed to develop a healthy lifestyle consciousness index (HLCI) for cancer patients and evaluated its validity in gynecological cancer patients. METHODS: The HLCI was designed to assess degree of healthy lifestyle consciousness, including items regarding "diet, " "exercise, " "body weight, " and "sleep." Exploratory factor analysis was performed for dimensionality of the scale; Cronbach's alpha was calculated to assess internal-consistency reliability. For criterion-based validity, we calculated proportions of stage III/IV gynecological malignancies in those with categorized HLCI scores based on tertiles. Concurrent validity was evaluated between HLCI and other quality of life (QOL) scales including European Organization for Research and Treatment of Cancer QLQ-C30 in limited patients. RESULTS: HLCI comprised five 10-point items (0-45); higher values implied improved healthy lifestyle consciousness. Data from 108 gynecological malignancy patients at Kyoto University Hospital were analyzed. The mean age of subjects was 55.8 years; 36.1% of them had uterine corpus cancer; 34.3% were at stage III/IV of gynecological malignancy. The factor analysis revealed HLCI was unidimensional; the reliability based on Cronbach's alpha was satisfactory (0.88). The proportions of stage III/IV gynecological malignancies were 25.7%, 33.3%, and 44.4% in those with first (7-24 points), second (25-30 points), and third (31-46 points) tertiles of HLCI score, respectively. For patients with other QOL scales (n = 25), the mean scores of global health status of QLQ-C30 were 33.3, 50.0, and 83.3 for first, second, and third tertiles of HLCI score, respectively. CONCLUSION: HLCI was successfully validated; thus, patients with advanced stages or higher QOL might have strong consciousness regarding healthy lifestyle. HLCI may be useful in precision care for improved lifestyles and QOL

Tertiary lymphoid structures are associated with favorable survival outcomes in patients with endometrial cancer

Immunotherapy has experienced remarkable growth recently. Tertiary lymphoid structures (TLSs) and B cells may play a key role in the immune response and have a survival benefit in some solid tumors, but there have been no reports about their role in endometrial cancer (EC). We investigated the clinicopathological and pathobiological characteristics of the tumor microenvironment (TME) in EC. Patients with EC at Kyoto University Hospital during 2006–2011 were retrospectively included. In 104 patients with EC who met study inclusion criteria, 81 (77.9%) had TLSs, which consisted of areas rich in CD20⁺ B cells, CD8⁺ T cells, CD4⁺ T cells, and CD38⁺ plasma cells. The absence of TLS was independently associated with tumor progression (HR, 0.154; 95% CI, 0.044–0.536; P = 0.003). Patients with TLSs that included CD23⁺ germinal centers had better PFS. All tumor infiltrating lymphocytes were counted in the intratumor site. The number of CD20⁺ B cells was significantly larger in patients with TLSs than in those without TLS (P < 0.001). CD20⁺ B cells numbers were positively correlated with other TLSs. The larger number of CD20⁺ B cell was associated with better PFS (P = 0.015). TLSs and B cell infiltration into tumors are associated with favorable survival outcomes in patients with EC. They may represent an active immune reaction of the TME in endometrial cancer

Low-Grade Endometrial Stromal Sarcoma with a Nodule-in-Nodule Appearance in Preoperative Magnetic Resonance Images

Low-grade endometrial stromal sarcoma (LG-ESS) is a rare malignant disease and demonstrates various patterns in preoperative imaging. Therefore, accurate diagnosis is important. Given its unique form, we report a case of LG-ESS with a nodule-in-nodule appearance on preoperative imaging. A 41-year-old woman was referred to our department for further examination of a 45 mm diameter uterine corpus mass. Preoperative magnetic resonance imaging (MRI) revealed several small nodules within a larger nodule. T2-weighted images showed moderate-to-high signal intensity with focal bands of low signal intensity in the small nodules. The patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Histopathological findings of the small nodules showed densely concentrated endometrial stromal cells reminiscent of a proliferative phase endometrium with a concentric arrangement of small spiral arteriole-like vessels. The small nodules exhibited an expansile growth pattern and were surrounded by less densely concentrated endometrial stromal cells intermingled with the normal uterine myometrium. LG-ESS with smooth muscle differentiation and sex cord-like elements was partially observed. In summary, LG-ESS demonstrating a unique nodule-in-nodule appearance on preoperative imaging histopathologically comprised tumor cells of varying densities. Our current case suggests that preoperative diagnostic imaging with MRI may be useful

A patient with adult extrahepatic portal obstruction, of which distinction from intrahepatic cholangiocarcinoma was difficult

A 51-year-old Japanese male with chief complaints of slightly high fever and epigastralgia was hospitalized at our facility. The inflammatory response was enhanced, and liver dysfunction was observed. Abdominal ultrasonography demonstrated a hyperechoic lesion occupying the left portal vein, and abdominal plain CT indicated a low density of the lesion with a clear boundary, measuring about 3 cm× 2 cm, between the porta hepatis and segment IV of the liver. Contrast CT showed no enhancement in the arterial and portal phases, but a reduction in the density inside the tumor in the equilibration phase was noted. MRI showed hypointensity by T1-weighted imaging and hyperintensity by T2-weighted imaging. Angiography demonstrated an obstruction of the left portal vein and superior mesenteric vein, and endoscopic retrograde cholangiography revealed a constriction in the left intrahepatic bile duct. Since the possibility of intrahepatic cholangiocarcinoma could not be excluded, extended left hepatectomy combined with caudate lobectomy was performed. The tumor, measuring 31 mm× 21 mm×20 mm, was pathohistologically diagnosed as an extrahepatic portal obstruction. Extrahepatic portal obstruction is an important disease that is sometimes difficult to rule out oncologic origin

Ex vivo reconstitution of fetal oocyte development in humans and cynomolgus monkeys

ヒト・サルの胎児卵巣から原始卵胞を体外で作出することに成功. 京都大学プレスリリース. 2022-08-01.New egg recipe to boost fertility research. 京都大学プレスリリース. 2022-08-14.In vitro oogenesis is key to elucidating the mechanism of human female germ-cell development and its anomalies. Accordingly, pluripotent stem cells have been induced into primordial germ cell-like cells and into oogonia with epigenetic reprogramming, yet further reconstitutions remain a challenge. Here, we demonstrate ex vivo reconstitution of fetal oocyte development in both humans and cynomolgus monkeys (Macaca fascicularis). With an optimized culture of fetal ovary reaggregates over three months, human and monkey oogonia enter and complete the first meiotic prophase to differentiate into diplotene oocytes that form primordial follicles, the source for oogenesis in adults. The cytological and transcriptomic progressions of fetal oocyte development in vitro closely recapitulate those in vivo. A comparison of single-cell transcriptomes among humans, monkeys, and mice unravels primate-specific and conserved programs driving fetal oocyte development, the former including a distinct transcriptomic transformation upon oogonia-to-oocyte transition and the latter including two active X chromosomes with little X-chromosome upregulation. Our study provides a critical step forward for realizing human in vitro oogenesis and uncovers salient characteristics of fetal oocyte development in primates

Analysis of different complexes of type IIa sodium-dependent phosphate transporter in rat renal cortex using blue-native polyacrylamide gel electrophoresis

Type IIa sodium-dependent phosphate transporter (NaPi-IIa) can be localized in the apical plasma membrane of renal proximal tubule to carry out a rate-limiting step of phosphate reabsorption. For the apical localization, NaPi-IIa is required to form a macromolecular complex with some adaptor proteins such as Na+/H+ exchanger regulatory factor 1 (NHERF-1) and ezrin. However, the detail of macromolecular complex containing NaPi-IIa in the apical membrane of the renal proximal tubular cells has not been clarified. In this study, we identified at least four different complexes (220, 480, 920, 1,100 kDa) containing NaPi-IIa by using blue-native polyacrylamide gel electrophoresis. Interestingly, LC-MS/MS analysis and immunoprecipitation analysis reveal that megalin is a component of larger complexs (920 and 1,100 kDa). In addition, NaPi-IIa can be heterogeneously co-localized with ezrin and megalin on the apical membrane of renal proximal tubuler cells by fluorescence microscopy analysis. These results suggest that NaPi-IIa can form some different complexes on the apical plasma membrane of renal proximal tubular cells