Adipocyte pyroptosis occurs in omental tumor microenvironment and is associated with chemoresistance of ovarian cancer.

BACKGROUND: Ovarian carcinoma (OC) is a fatal malignancy, with most patients experiencing recurrence and resistance to chemotherapy. In contrast to hematogenous metastasizing tumors, ovarian cancer cells disseminate within the peritoneal cavity, especially the omentum. Previously, we reported omental crown-like structure (CLS) number is associated with poor prognosis of advanced-stage OC. CLS that have pathologic features of a dead or dying adipocyte was surrounded by several macrophages is well known a histologic hallmark for inflammatory adipose tissue. In this study, we attempted to clarify the interaction between metastatic ovarian cancer cells and omental CLS, and to formulate a therapeutic strategy for advanced-stage ovarian cancer. METHODS: A three-cell (including OC cells, adipocytes and macrophages) coculture model was established to mimic the omental tumor microenvironment (TME) of ovarian cancer. Caspase-1 activity, ATP and free fatty acids (FFA) levels were detected by commercial kits. An adipocyte organoid model was established to assess macrophages migration and infiltration. In vitro and in vivo experiments were performed for functional assays and therapeutic effect evaluations. Clinical OC tissue samples were collected for immunochemistry stain and statistics analysis. RESULTS: In three-cell coculture model, OC cells-derived IL-6 and IL-8 could induce the occurrence of pyroptosis in omental adipocytes. The pyroptotic adipocytes release ATP to increase macrophage infiltration, release FFA into TME, uptake by OC cells to increase chemoresistance. From OC tumor samples study, we demonstrated patients with high gasdermin D (GSDMD) expression in omental adipocytes is highly correlated with chemoresistance and poor outcome in advanced-stage OC. In animal model, by pyroptosis inhibitor, DSF, effectively retarded tumor growth and prolonged mice survival. CONCLUSIONS: Omental adipocyte pyroptosis may contribute the chemoresistance in advanced stage OC. Omental adipocytes could release FFA and ATP through the GSDMD-mediate pyroptosis to induce chemoresistance and macrophages infiltration resulting the poor prognosis in advanced-stage OC. Inhibition of adipocyte pyroptosis may be a potential therapeutic modality in advanced-stage OC with omentum metastasis.

Setting up a specialized maternity unit in a tertiary hospital: An oasis for pregnant women with COVID-19 during the pandemic.

OBJECTIVE: The COVID-19 pandemic has had an enormous impact on society and the medical environment in Taiwan in 2022. As pregnant women with COVID-19 are at higher risk for multiple complications, Taiwan needs a COVID-19 specialized maternity unit to improve the quality of maternal and neonatal care. MATERIALS AND METHODS: We share our experience with specialized maternity unit for pregnant women with COVID-19 at the National Cheng Kung University Hospital, where we can have careful evaluation, safe birth, and comprehensive postpartum care. RESULTS: Our COVID-19 specialized maternity unit enrolled 253 pregnant women with COVID-19, 90 (35.6%) pregnant women were admitted to the specialized maternity unit, and 71 (28.1%) pregnant women gave birth during hospitalization in two months. All pregnant women recovery well and real-time polymerase chain reaction tests on all infants were negative for COVID-19. CONCLUSION: A specialized maternity unit can provide pregnant women with a safe birth environment, immediate maternity care, and high medical quality. It can also help health workers in non-specialized maternity units deal with COVID-19-related psychological stress. Therefore, setting up one specialized maternity unit in the city during the pandemic should be guardedly considered.

Downregulation of Salt-Inducible Kinase 3 Enhances CCL24 Activation in the Placental Environment with Preeclampsia.

Preeclampsia (PE) remains one of the leading causes of maternal and perinatal morbidity and mortality. However, the exact pathophysiology of PE is still unclear. The recent widely accepted notion that successful pregnancy relies on maternal immunological adaptation is of utmost importance. Moreover, salt-inducible kinase 3 (SIK3) is an AMP-activated protein kinase-related kinase, and it has reported a novel regulator of energy and inflammation, and its expression related with some diseases. To explore whether SIK3 expression correlated with PE, we analyzed SIK3 gene expression and its association with PE through GEO datasets. We identified that SIK3 was significantly downregulated in PE across four datasets (p < 0.05), suggesting that SIK3 participated in the pathogenesis of PE. We initially demonstrated the significant downregulation of SIK3 in trophoblast cells of PE. SIK3 downregulation was positively correlated with the increased number of CD204(+) cells in in vivo and in vitro experiments. The increased number of CD204(+) cells could inhibit the migration and invasion of trophoblast cells. We then clarified the potential mechanism of PE with SIK3 downregulation: M2 skewing was triggered by trophoblast cells derived via the CCL24/CCR3 axis, leading to an increase in CD204(+) cells, a decrease in phagocytosis, and the production of IL-10 at the maternal-fetal interface of the placenta with PE. IL-10 further contributed to a reduction in the migration and invasion of trophoblast cells. It also established a feedback loop wherein trophoblast cells increased CCL24 production to maintain M2 dominance in the placental environments of PE.

Omental Macrophagic "Crown-like Structures" Are Associated with Poor Prognosis in Advanced-Stage Serous Ovarian Cancer.

The tumor microenvironment is a well-recognized framework in which immune cells present in the tumor microenvironment promote or inhibit cancer formation and development. A crown-like structure (CLS) has been reported as a dying or dead adipocyte surrounded by a 'crown' of macrophages within adipose tissue, which is a histologic hallmark of the inflammatory process in this tissue. CLSs have also been found to be related to formation, progression and prognosis of some types of cancer. However, the presence of CLSs in the omentum of advanced-stage high-grade serous ovarian carcinoma (HGSOC) has not been thoroughly investigated. By using CD68, a pan-macrophage marker, and CD163, an M2-like polarization macrophage marker, immunohistochemistry (IHC) was performed to identify tumor-associated macrophages (TAMs) and CLSs. This retrospective study analyzed 116 patients with advanced-stage HGSOC who received complete treatment and had available clinical data from July 2008 through December 2016 at National Cheng Kung University Hospital (NCKUH) (Tainan, Taiwan). Based on multivariate Cox regression analysis, patients with omental CD68+ CLSs had poor OS (median survival: 24 vs. 38 months, p = 0.001, hazard ratio (HR): 2.26, 95% confidence interval (CI): 1.41-3.61); patients with omental CD163+ CLSs also had poor OS (median survival: 22 vs. 36 months, HR: 2.14, 95%CI: 1.33-3.44, p = 0.002). Additionally, patients with omental CD68+ or CD163+ CLSs showed poor PFS (median survival: 11 vs. 15 months, HR: 2.28, 95%CI: 1.43-3.64, p = 0.001; median survival: 11 vs. 15 months, HR: 2.17, 95%CI: 1.35-3.47, respectively, p = 0.001). Conversely, the density of CD68+ or CD163+ TAMs in ovarian tumors was not associated with patient prognosis in advanced-stage HGSOC in our cohort. In conclusion, we, for the first time, demonstrate that the presence of omental CLSs is associated with poor prognosis in advanced-stage HGSOC.

Synthesis of stable isotopically labeled peptides with filter-assisted enzymatic labeling for the diagnosis of hepatitis B virus infection utilizing mass spectrometry-based proteomics strategy.

A facile method for the preparation of stable isotopically labeled peptides was developed by means of filter-assisted tryptic 16O/18O water labeling, which could be directly applied to the determination of hepatitis B virus infection from human serum with tandem mass spectrometry. Tryptic peptides of hepatitis B surface antigen or hepatitis B e antigen from different subtypes of hepatitis B virus were synthesized with traditional solid-phase peptide synthesis as potential biomarkers. Trypsin catalyzed oxygen-18 exchange at their amidated c-terminus of arginine or lysine residue. The protease catalyzed oxygen-18 to oxygen-16 back exchange reaction was eliminated due to the complete removal of trypsin by the centrifugal filter containing a thin membrane associated with molecular weight cut-off of 10 KDa. The synthetic isotopic peptides were spiked into trichloroacetic acid/acetone precipitated human serum as internal standards and were selectively detected with multiplexed parallel reaction monitoring on a hybrid quadrupole-orbitrap mass spectrometer. The limit of detection for all synthetic peptides were in the range of 0.09 fmol-1.13 fmol. The results indicated that the peptide YLWEWASVR derived from hepatitis B surface antigen was quantified approximately 200 fmol per µl serum and may serve as a diagnostic biomarker for the detection of hepatitis B virus infected disease.

Prenatal sonographic diagnosis of single umbilical artery: Emphasis on the absent side and its relation to associated anomalies.

OBJECTIVE: To determine the absent side of a single umbilical artery (SUA) and to evaluate whether associated anomalies are related to the side of the missing artery in a Taiwanese population. MATERIALS AND METHODS: We retrospectively studied SUA fetuses from our computer database of fetal ultrasound in a tertiary medical center in Southern Taiwan. All cases were diagnosed as SUA prenatally using conventional scanners of two- and three-dimensional (2D and 3D, respectively) ultrasound, as well as color, power, and high-definition Doppler. The absent side of UA and associated anomalies were analyzed. RESULTS: From September 2006 to November 2011, 31 fetuses with SUA were diagnosed prenatally by ultrasound and all were enrolled for this series. The incidence was estimated to be 1:556 (0.18% = 31/17,086). The mean maternal age was 29.2 years (range, 15-36 years) and the mean fetal age was 30.0 weeks of gestation (range 18-36 weeks). Notably, the left-absent UA was detected in 16/31 (52%) fetuses, compared with the right-absent UA in 15/31 (48%) cases. In addition, congenital anomalies were noted prenatally in 2/16 (13%) fetuses with left-absent UA and in 3/15 (20%) fetuses with right-absent UA. CONCLUSION: In SUA fetuses, the absence of UA appears to occur equally at each side. Moreover, this study showed no significant difference between either side of missing UA and associated anomalies after statistical examination.

Prenatal ultrasonography and postnatal follow-up of a case of McKusick-Kaufman syndrome.

OBJECTIVE: McKusick-Kaufman syndrome (MKS) is a rare autosomal recessive syndrome characterized by hydrometrocolpos (HMC) and postaxial polydactyly (PAP). It is very difficult to diagnose MKS prenatally because of overlapping manifestations and associated anomalies with other syndromes. Herein, we present a case of MKS with prenatal ultrasound illustrating a fetal abdominal cystic mass. CASE REPORT: A 33-year-old woman, gravida 3 para 2, was referred to our obstetrics clinic at 34 weeks' gestation for fetal abdominal cyst detected by prenatal ultrasound. Our ultrasound illustrated a fetal abdominal cystic mass with two communicating components (suspected HMC) and polydactyly involving both hands and feet. At birth, the gross appearance revealed abdominal distention, vulva edema, and PAP. MKS was highly suspected. Abdominal computed tomography (CT) at 3 days of life showed HMC with a transverse vaginal septum. At 3 months of age, she received colpotomy and vaginal reconstruction to relieve the abdominal distension by HMC. Then she accepted corrections of PAP of both hands and feet at 8 months and 10 months. At 5 years of age, her body and mental development did not show any retardation. Pediatric ophthalmologic examination revealed no specific findings. Given the above evidences, the diagnosis of MKS was finally made at 5 years of age. CONCLUSION: Rare syndromes like MKS may need early comprehensive evaluations and consultations. Although prenatal diagnosis might be impossible for MKS, prenatal awareness by fetal ultrasound is very helpful to assist early management and maternal transfer. The final diagnosis and appropriate management of MKS requires the collaboration of obstetricians, geneticists, pediatricians, and ophthalmologists as soon as abnormal signs are detected in utero.

Delayed uterine rupture occurred 4 weeks after cesarean section following sexual intercourse: a case report and literature review.

OBJECTIVE: Spontaneous delayed uterine rupture is life-threatening and extremely rare following sexual intercourse in postpartum. Here, we present a case of delayed uterine rupture that occurred 4 weeks after cesarean section following intercourse. CASE REPORT: A 31-year-old postpartum woman, gravida 4, para 1, abortion 3, underwent a cesarean section for prolonged labor. She was transferred to our hospital in shock status with brisk vaginal bleeding following intercourse 4 weeks after delivery. An emergency subtotal hysterectomy was performed to stop the bleeding. The pathology confirmed tissue necrosis and suture granuloma at the previous surgical wound. CONCLUSION: The presented case demonstrated that delayed uterine rupture may occur even 4 weeks after delivery following intercourse, without any obvious abdominal pain or infection signs, which deserved the attention of obstetricians.

Prenatal diagnosis of fetal gastroschisis using three-dimensional ultrasound: comparison between the 20th and 21st centuries.

OBJECTIVE: In order to compare the trends and improvements of prenatal diagnosis of gastroschisis, we herein retrospectively reviewed our cases of fetal gastroschisis detected by three-dimensional ultrasound (3D US) between the two centuries. MATERIALS AND METHODS: We reviewed our computer database of prenatal diagnosis on gastroschisis in National Cheng Kung University Hospital from October 1994 to November 2011. All the fetuses were initially scanned by two-dimensional (2D) US to locate the region of interest (ROI). Then, the 3D probe was used to scan all the ROI systematically and mechanically, and all the images were stored on laser discs for further 3D visualization and reconstruction. To compare the characteristics at prenatal diagnosis of gastroschisis between the 20th and 21st centuries in our hospital, the Chi-square test and Student t test were used. The p values less than 0.05 and 0.1 were considered statistically significant. RESULTS: In total, 26 fetuses with gastroschisis were depicted by 3D US in utero (10 cases were diagnosed in the 20th century and 16 cases in the 21st century). The ranges of gestational age at prenatal diagnosis of gastroschisis by 3D US in the 20th century were between 14 and 34 weeks (mean: 21.6 weeks) and between 14 and 33 weeks (mean: 21.9 weeks) in the 21st century. Moreover, seven cases (70%) were diagnosed before the third trimester in the 20th century, whereas 13 cases (81%) were diagnosed before the third trimester in the 21st century. CONCLUSION: Although without statistical significance, higher prenatal diagnosis rate before the third trimester in the 21st century was noted. The improvement of 3D US has remarkable advantages in adding novel visual depiction of a 3D lesion of a 3D fetus in 3D US after reconstruction and thus assists substantially in prenatal diagnosis, genetic consultation, and perinatal management of gastroschisis.

Prenatal diagnosis of fetal congenital cystic adenomatoid malformation of the lung using three-dimensional ultrasound: comparison between the 20th and 21st centuries.

OBJECTIVE: Congenital cystic adenomatoid malformation of the lung (CCAML) is one of the most common lung lesions diagnosed prenatally. In order to compare the trends and improvements of prenatal diagnosis of CCAML, we herein retrospectively reviewed our cases of fetal CCAML detected by three-dimensional ultrasound (3-D US) between two centuries. MATERIALS AND METHODS: We reviewed our computer database of prenatal diagnosis of CCAML in National Cheng Kung University Hospital from October 1994 to November 2011. All of the fetuses were initially scanned by two-dimensional (2-D) US to locate the region-of-interest (ROI). Then, the 3-D probe was used to scan all of the ROI systematically and mechanically, and the images were stored in the laser discs for further 3-D visualization and reconstruction. To compare the characteristics at prenatal diagnosis of CCAML between the 20th and 21st centuries in our hospital, Chi-square tests were undertaken. A p value <0.05 was considered as statistically significant. RESULTS: In total, 58 fetuses with CCAML were depicted by 3-D US in utero (12 cases were diagnosed in the 20th century and 46 cases in the 21st century). The ranges of gestational age at prenatal diagnosis of CCAML by 3-D US in the 20th century were between 15 and 36 weeks (mean=24 weeks), and were between 16 and 31 weeks (mean=22 weeks) in the 21st century. Moreover, nine cases (75%) were diagnosed at the second trimester in the 20th century, whereas 44 cases (96%) were diagnosed at the second trimester in the 21st century. CONCLUSION: The advancement of 3-D US has remarkable advantages in adding novel visual depiction of a 3-D lesion of a 3-D fetus in 3-D US after reconstruction, and thus assists substantially in the prenatal diagnosis and genetic consultation of CCAML. Furthermore, the trend analysis in this series showed a significantly earlier gestational age at prenatal diagnosis of CCAML in the 21st century than that in the 20th century.