Identification of Tumor Antigens in Ovarian Cancers Using Local and Circulating Tumor-Specific Antibodies.

Ovarian cancers include several disease subtypes and patients often present with advanced metastatic disease and a poor prognosis. New biomarkers for early diagnosis and targeted therapy are, therefore, urgently required. This study uses antibodies produced locally in tumor-draining lymph nodes (ASC probes) of individual ovarian cancer patients to screen two separate protein microarray platforms and identify cognate tumor antigens. The resulting antigen profiles were unique for each individual cancer patient and were used to generate a 50-antigen custom microarray. Serum from a separate cohort of ovarian cancer patients encompassing four disease subtypes was screened on the custom array and we identified 28.8% of all ovarian cancers, with a higher sensitivity for mucinous (50.0%) and serous (40.0%) subtypes. Combining local and circulating antibodies with high-density protein microarrays can identify novel, patient-specific tumor-associated antigens that may have diagnostic, prognostic or therapeutic uses in ovarian cancer.

Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial.

BACKGROUND: Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C) lowering therapy in older individuals, aged ≥75 years, is insufficient. This trial tested whether LDL-C-lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. METHODS: This multicenter, prospective, randomized, open-label, blinded end-point evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥75 years, with elevated LDL-C without history of coronary artery disease. Patients, who all received dietary counseling, were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke. RESULTS: Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50-0.86; P=0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37-0.98; P=0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18-0.79; P=0.007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups. CONCLUSIONS: LDL-C-lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution. Clinical Registration: URL: https://www.umin.ac.jp. Unique identifier: UMIN000001988.

Magnetic Resonance Imaging Grading System for Preoperative Diagnosis of Leiomyomas and Uterine Smooth Muscle Tumors.

STUDY OBJECTIVE: To evaluate a new magnetic resonance imaging (MRI) grading system for preoperative differentiation between benign and variant-type uterine leiomyomas including smooth muscle tumors of uncertain malignant potential (STUMPs). DESIGN: Retrospective analysis (Canadian Task Force classification III). SETTING: Teaching hospital (Teine Keijinkai Hospital). PATIENTS: Three-hundred thirteen patient medical records were retrospectively reviewed if treated for uterine myomas and diagnosed with variant type leiomyomas or STUMPs (n = 27) or benign, typical leiomyomas (n = 286) and treated between January 2012 and December 2014. INTERVENTION: Uterine myoma classifications using MRI findings according to a 5-grade system (grades I-V) based on 3 elements. MEASUREMENTS AND MAIN RESULTS: Uterine myoma MRI classifications were based on 3 elements: T2-weighted imaging (high or low), diffusion-weighted imaging (high or low), and apparent diffusion coefficient values (high or low; apparent diffusion coefficient < 1.5 × 10-3 mm2/sec was considered low). Grades I to II were designated as typical or benign leiomyomas, grade III as degenerated leiomyomas, and grades IV to V as variant type leiomyomas or STUMPs. Accuracy levels were 98.9%, 100%, 94.3%, 58.8%, and 41.9% for grades I through V lesions, respectively. The grades were divided into 2 groups to discriminate benign leiomyomas and STUMPs (grades I-III were considered negative and grades IV-V positive). Grades IV to V scored 85.2% for sensitivity, 91.3% for specificity, 47.9% positive predictive value, 98.5% negative predictive value, a 9.745 positive likelihood ratio, and a .162 negative likelihood ratio. CONCLUSION: This novel MRI grading system for uterine myomas may be beneficial in differentiating benign leiomyomas from STUMPs or variant type leiomyomas and could be a future effective presurgical assessment tool.

UPLC-MS/MS based diagnostics for epithelial ovarian cancer using fully sialylated C4-binding protein.

Serum levels of fully sialylated C4-binding protein (FS-C4BP) are remarkably elevated in patients with epithelial ovarian cancer (EOC) and can be used as a marker to distinguish ovarian clear cell carcinoma from endometrioma. This study aimed to develop a stable, robust and reliable liquid chromatography-hybrid mass spectrometry (UPLC-MS/MS) based diagnostic method that would generalize FS-C4BP as a clinical EOC biomarker. Glycopeptides derived from 20 µL of trypsin-digested serum glycoprotein were analyzed via UPLC equipped with an electrospray ionization time-of-flight mass spectrometer. This UPLC-MS/MS-based diagnostic method was optimized for FS-C4BP and validated using sera from 119 patients with EOC and 127 women without cancer. A1958 (C4BP peptide with two fully sialylated biantennary glycans) was selected as a marker of FS-C4BP because its level in serum was highest among FS-C4BP family members. Preparation and UPLC-MS/MS were optimized for A1958, and performance and robustness were significantly improved relative to our previous method. An area under the curve analysis of the FS-C4BP index receiver operating characteristic curve revealed that the ratio between A1958 and A1813 (C4BP peptide with two partially sialylated biantennary glycans) reached 85%. A combination of the FS-C4BP index and carbohydrate antigen-125 levels further enhanced the sensitivity and specificity.

Fully sialylated alpha-chain of complement 4-binding protein (A2160): a novel prognostic marker for epithelial ovarian carcinoma.

PURPOSE: Fully sialylated alpha-chain of complement 4-binding protein (A2160) is a member of the glycoprotein family and has recently been identified as a diagnostic biomarker for epithelial ovarian cancer. This study examined the utility of A2160 as a prognostic biomarker for this disease. METHODS: This is a retrospective analysis of prospectively collected plasma samples from 93 women with stage I-IV epithelial ovarian cancer who underwent primary cytoreductive surgery between 2009 and 2014. Pretreatment A2160 levels were correlated to clinico-pathological factors and survival outcome. RESULTS: Women with advanced-stage disease had significantly higher 2160 levels compared to those with early stage disease (stage I-II versus III-IV, median 2.17-2.70 versus 5.31-8.70 U/mL, P < 0.01). Women with high-grade serous ovarian carcinoma had higher A2160 levels compared to other histologies (6.60 versus 3.01 U/mL, P = 0.05). Women who had suboptimal cytoreduction had significantly higher A2160 levels than those who achieved optimal/complete cytoreduction (7.02 versus 2.30-3.17 U/mL, P < 0.01). On univariable analysis, higher A2160 levels were significantly associated with decreased progression-free survival (64-100 versus 1-33%ile, 5-year rates 53.4 versus 78.9%, P = 0.029). After controlling for age, CA-125 level, cytoreductive status, histology, and stage, higher A2160 levels remained an independent prognostic factor for decreased progression-free survival (adjusted-hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.01-6.11, P = 0.049). Similarly, higher A2160 levels were independently associated with decreased cause-specific survival on multivariable analysis (adjusted-HR 3.07, 95% CI 1.19-7.93, P = 0.021). CONCLUSION: Our study suggests that A2160 may be a useful prognostic biomarker for epithelial ovarian cancer, and higher pretreatment levels of A2160 predicts poor survival outcome.

Developmental Changes in Neonatal and Infant Skin Structures During the First 6 Months: In Vivo Observation.

BACKGROUND/OBJECTIVES: Developmental changes of structures in neonatal and infant skin have not been well characterized. The purpose of this study was to clarify changes in skin structures during neonatal and infant growth in vivo. METHODS: Fifteen healthy, full-term neonates (seven girls, eight boys) were studied. The measurements were performed 4 to 7 days (neonate) and 1, 3, and 6 months after birth on the buttock, upper thigh, and ventral forearm skin using a confocal laser scanning microscope. Developmental changes in dermoepidermal junction structures, stratum corneum thickness, epidermal thickness, and microvascular development were investigated. RESULTS: A significant decrease in stratum corneum thickness was observed over the 3 months after birth. Dermal papillae were not observed in neonatal skin but were observed gradually over the next 3 months. Epidermal thickness, determined from the skin surface to the bottom of the epidermal layer, increased significantly from 4 to 7 days to 1 month of age, indicating the formation of dermal papillae and rete ridges. Complicated microvascular structures were observed in neonatal skin but disappeared gradually and were observed only at the dermal papillae at 3 months of age. CONCLUSIONS: Our results reveal that infant skin is in a developmental stage structurally up to 3 months of age, paralleling skin functional and developmental maturation.

Fully-sialylated alpha-chain of complement 4-binding protein: Diagnostic utility for ovarian clear cell carcinoma.

OBJECTIVE: While a certain fraction of endometriomas can develop de novo epithelial ovarian cancer (EOC) such as clear cell carcinoma (OCCC), there is currently no useful biomarker available for early detection of OCCC from endometriomas. The aim of this study was to describe the diagnostic utility of a novel biomarker for EOC especially for OCCC to distinguish from endometrioma. METHODS: More than 100,000 glycan structures of serum glycoproteins obtained from 134 pretreatment all stage EOC patients (including 45 OCCCs) and 159 non-cancer control women (including 36 endometriomas) were explored for a mass spectrum approach. Diagnostic accuracy of identified biomarker was compared to the one of CA-125 by comparing area under curve (AUC) and positive/negative predictive values (PPV and NPV). RESULTS: A2160, a fully-sialylated alpha-chain of complement 4-binding protein, was identified as a candidate target marker. A2160 was significantly elevated in all stages of OCCC compared to with endometriomas. Diagnostic accuracy of A2160 (cutoff 1.6U/mL) to distinguish early stage OCCC from endometrioma is significantly higher than that of CA-125 (cutoff 35IU/L): AUC for A2160 versus CA-125, 0.92 versus 0.67; PPV 95% versus 64%; and NPV 85% versus 58%. In addition, fully-sialylated glycans had a higher accuracy for diagnosing EOC as compared to partially-sialylated glycans of alpha-chain of complement 4-binding protein. CONCLUSION: Our study suggested that A2160 may be a useful biomarker to distinguish early-stage OCCC from endometrioma. This new biomarker can be potentially applied for the monitoring of endometrioma patients, making possible the early diagnosis of OCCC.

A Novel Method for Acquired Sex Chromosome Mosaicism.

The phenomenon of sex chromosome loss from hematopoietic cells is an emerging indicator of biological aging. While many methods to detect this loss have been developed, enhancing the field, these existing methods often suffer from being labor-intensive, expensive, and not sufficiently sensitive. To bridge this gap, a novel and more efficient technique is developed, named the SinChro assay. This method employs multiplexed single-cell droplet PCR, designed to detect cells with sex chromosome loss at single-cell resolution. Through the SinChro assay, the age-dependent increase in Y chromosome loss in male blood is successfully mapped. The age-dependent loss of the X chromosome in female blood is also identified, a finding that has been challenging with existing methods. The advent of the SinChro assay marks a significant breakthrough in the study of age-related sex mosaicism. Its utility extends beyond blood analysis, applicable to a variety of tissues, and it holds the potential to deepen the understanding of biological aging and related diseases.

Diffuse Non-obstructive Bowel Dilatation in utero: Report of a Case with a Unique Presentation.

Thus far, few reports have described the rare, non-obstructive type of fetal diffuse bowel dilatation. We describe such a case in the fetus of a 31-year-old Pakistani pregnant woman, gravida 3, para 2. A series of ultrasonographic examinations in the third trimester showed a "honeycomb" appearance of fetal d iffuse dilated bowel loops, a mildly enlarged stomach, and mild polyhydramnios. Magnetic resonance imaging further revealed fluid-filled dilated bowel loops extending to the colon and rectum. The male neonate was born at 36 weeks and had marked abdominal distension but did not show signs of mechanical bowel obstruction. He passed a profuse amount of liquid with meconium at 4 h of life. Thereafter, his distended abdomen and bowel dilatation subsided, and he became asymptomatic within a week of life. Taken together with previous case reports, among infants who show the "honeycomb" sign in utero, there definitely exists a subset with a favorable outcome and an unknown etiology. This case alerts physicians who are responsible for perinatal care to the fact that careful assessment is required for a newborn when the "honeycomb" sign is observed via fetal imaging. Without evidence of mechanical bowel obstruction, alternative etiologies should be sought to avoid unnecessary laparotomy.

Piezo-ICSI for Human Oocytes.

Since the first successful pregnancies achieved by intracytoplasmic sperm injection (ICSI) were reported, ICSI has become an essential technique in assisted reproductive technology (ART). ICSI uses micropipettes with a spiking tip to penetrate the zona pellucida and membrane. Then, the cytoplasm is usually aspirated into the micropipette for membrane breakage (conventional-ICSI). The survival and fertilization rates of mouse oocytes after conventional-ICSI were as low as 16% and 8%, respectively. Kimura and Yanagimachi applied a piezo drive unit, mercury, and a micropipette with a flat tip for mouse ICSI. The membrane breakage could be performed semi-automatically by combining these types of equipment without cytoplasmic aspiration into the micropipette (piezo-ICSI). These authors reported significantly higher survival and fertilization rates (80% and 78%) compared to those of conventional-ICSI (16% and 8%). Therefore, the piezo-ICSI may be effective not only for mouse oocytes but also for human oocyte ICSI. However, only five papers are available that assessed the effectiveness of piezo-ICSI compared to conventional-ICSI for human oocytes. All of these five papers reported significantly higher fertilization rates compared to those of conventional-ICSI. The goal of the piezo-ICSI protocol described here is to improve the clinical results of ICSI compared to the conventional-ICSI.

Retained Products of Conception Fed by the Inferior Mesenteric Artery: A Case Report.

Retained products of conception (RPOC) refer to the persistence of placental or fetal tissue in the uterus following delivery or miscarriage. RPOC may cause massive postpartum or post-abortion hemorrhage. Arterial embolization (AE) is an effective choice of management for postpartum hemorrhage including RPOC. We report a case of hemorrhagic RPOC, in which uterine artery embolization with transcervical resection did not achieve hemostasis, and laparotomy with uterine compression sutures was subsequently required. The RPOC was apparently fed by an aberrant branch derived from the inferior mesenteric artery (IMA). AE of IMA was not performed because of possible necrosis of the descending colon and rectum. A physician should be aware that AE is not an all-encompassing hemostatic technique for postpartum bleeding, such as with RPOC, and should keep alternatives in mind.

Acquired Factor XI Deficiency with Lupus Anticoagulant in a Pregnant Woman Diagnosed by the Eruptions and Pain in Fingers.

We report a case of acquired factor XI deficiency with lupus anticoagulant (LA) in a 28-year-old primigravida who presented with finger pain and eruptions on her palms and fingers during the 3rd trimester of pregnancy. The patient complained of pain and reddening of the fingers at 30 weeks of gestation. She was referred to our tertiary center with a diagnosis of preeclampsia and suspected collagen disease at 35 weeks of gestation. Erythema was seen on the fingers and palms, and she presented with pain and cryesthesia on the fingers. Laboratory investigations revealed an activated partial thromboplastin time of 51 s (normal, 23-40 s), although it was normal during the 30th and 34th gestational weeks, LA with an anticardiolipin-beta2-glycoprotein I complex antibody, and low level of clotting XI activity (25 U/mL). On week 37 day 0 of gestation, the patient presented with severe hypertension. An urgent Cesarean section was performed after transfusion of two units of fresh frozen plasma. There was no excessive bleeding during the surgery or the postpartum period. The symptoms on her fingers and palms gradually improved after surgery. Our case indicates that dermatoses of pregnancy may become a starting point for the diagnosis of autoimmune diseases and coagulation abnormalities. When a patient presents with an atypical symptom, as in our case, the possibility of various diseases should be considered.

Monochorionic Diamniotic Twin Pregnancy; a Retrospective Study on Twintwin Transfusion Syndrome and Related Disorders.

OBJECTIVE: We assessed the clinical characteristics and perinatal outcome of disorders specific to monochorionic diamniotic (MD) twin pregnancies, focusing on twin-twin transfusion syndrome (TTTS) and related disorders, such as selective intrauterine growth restriction (sIUGR), inter-twin amniotic fluid discordance (AFD), and twin anemia polycythemia sequence (TAPS). METHODS: We retrospectively reviewed 69 cases of MD twin pregnancies delivered after 22 weeks at our institution from January 2009 to September 2013. RESULTS: TTTS occurred in 9 cases (13%). There was a total of 11 cases (16%) of MD twins with sIUGR in this period. One case developed TTTS. All 3 cases (4%) of AFD in this study developed TTTS or sIUGR. CONCLUSION: AFD should be recognized as predictors of TTTS or sIUGR. Further studies on TTTS-related disorders allow a more precise subgroup categorization that enables optimal management.

Utility of Comprehensive Serum Glycopeptide Spectra Analysis (CSGSA) for the Detection of Early Stage Epithelial Ovarian Cancer.

Comprehensive serum glycopeptide spectra analysis (CSGSA) evaluates >10,000 serum glycopeptides and identifies unique glycopeptide peaks and patterns via supervised orthogonal partial least-squares discriminant modeling. CSGSA was more accurate than cancer antigen 125 (CA125) or human epididymis protein 4 (HE4) for detecting early stage epithelial ovarian cancer. Combined CSGSA, CA125, and HE4 had improved diagnostic performance. Thus, CSGSA may be a useful screening tool for detecting early stage epithelial ovarian cancer.

Comprehensive Serum Glycopeptide Spectra Analysis Combined with Artificial Intelligence (CSGSA-AI) to Diagnose Early-Stage Ovarian Cancer.

Ovarian cancer is a leading cause of deaths among gynecological cancers, and a method to detect early-stage epithelial ovarian cancer (EOC) is urgently needed. We aimed to develop an artificial intelligence (AI)-based comprehensive serum glycopeptide spectra analysis (CSGSA-AI) method in combination with convolutional neural network (CNN) to detect aberrant glycans in serum samples of patients with EOC. We converted serum glycopeptide expression patterns into two-dimensional (2D) barcodes to let CNN learn and distinguish between EOC and non-EOC. CNN was trained using 60% samples and validated using 40% samples. We observed that principal component analysis-based alignment of glycopeptides to generate 2D barcodes significantly increased the diagnostic accuracy (88%) of the method. When CNN was trained with 2D barcodes colored on the basis of serum levels of CA125 and HE4, a diagnostic accuracy of 95% was achieved. We believe that this simple and low-cost method will increase the detection of EOC.

Large angioleiomyoma, rich of mast cell and sex hormone receptor expression.

BACKGROUND: Angioleiomyoma is a rare benign solitary tumor, arising from the vascular smooth muscle. This tumor usually occurs in the subcutis of extremities, uncommonly in abdomen, often presents as a small (<2 cm) and is treated with excision. CASE: We report an extremely rare case of unusually large angioleiomyoma, first diagnosed as an ovarian tumor with some malignant possibilities by diagnostic imaging. We resected 1.7 kg of tumor from the extra-peritoneal cavity in the lower abdomen. Histological study revealed that this case's angioleiomyoma had abundant mast cells and sex hormone receptor expression. CONCLUSION: This angioleiomyoma is not an obvious malignant tumor because of low mitosis, coagulative necrosis and cellular atypia. However, it seems to have low potential malignancy, because it has massive size, marked degeneration and abundant mast cells. There are some possibilities that sex hormones are related with the growth and degeneration of this case's tumor, because those receptors are strongly expressed in the nucleus of tumor cells.

Atypical Presentation of Duodenal Atresia Concomitant with Type-A Esophageal Atresia in Fetal Life: A Case Report.

Duodenal atresia concomitant with type-A esophageal atresia (DA + TA-EA) is rare. A pronounced enlargement of a closed loop of the upper gastrointestinal tract serves as an early clue for its prenatal detection. We describe an atypical case of DA + TA-EA in which the dilatation of the upper gastrointestinal tract remained mild. Ultrasonographic examination at 28 weeks of gestation showed mild polyhydramnios. Subsequent detailed sonographic and magnetic resonance imaging studies revealed a mildly enlarged stomach and duodenum that resembled a "double bubble," mild ascites, and polydactyly of the right thumb. Fetal abdominal circumference measurements were within normal range. A female neonate born at 36 weeks gestation did not show abdominal distension. DA + TA-EA was diagnosed based on clinical characteristics and X-ray studies of the neonate; the diagnosis was confirmed by surgery. Duodenoduodenostomy and gastrostomy in the first week of life and esophagoesophagostomy at six months of age were performed with satisfactory results, and the infant developed well. Prominent and/or increasing C-shaped fluid collection in the upper abdomen is a highly useful diagnostic sign for DA + TA-EA, but it is not applicable for all fetuses with this disease. Physicians should bear this caveat in mind to avoid diagnostic delays and initiate prompt postnatal therapy.

Comprehensive Serum Glycopeptide Spectra Analysis (CSGSA): A Potential New Tool for Early Detection of Ovarian Cancer.

OBJECTIVES: To conduct a comprehensive glycopeptide spectra analysis of serum between cancer and non-cancer patients to identify early biomarkers of epithelial ovarian cancer (EOC). METHODS: Approximately 30,000 glycopeptide peaks were detected from the digested serum glycoproteins of 39 EOC patients (23 early-stage, 16 advanced-stage) and 45 non-cancer patients (27 leiomyoma and ovarian cyst cases, 18 endometrioma cases) by liquid chromatography mass spectrometry (LC-MS). The differential glycopeptide peak spectra were analyzed to distinguish between cancer and non-cancer groups by employing multivariate analysis including principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA) and heat maps. RESULTS: Examined spectral peaks were filtered down to 2281 serum quantitative glycopeptide signatures for differentiation between ovarian cancer and controls using multivariate analysis. The OPLS-DA model using cross-validation parameters R2 and Q2 and score plots of the serum samples significantly differentiated the EOC group from the non-cancer control group. In addition, women with early-stage clear cell carcinoma and endometriomas were clearly distinguished from each other by OPLS-DA as well as by PCA and heat maps. CONCLUSIONS: Our study demonstrates the potential of comprehensive serum glycoprotein analysis as a useful tool for ovarian cancer detection.

Enhanced expression of hydroxylated ceramide in well-differentiated endometrial adenocarcinoma.

Based on our previous analysis of neutral glycolipids in the human endometrium, the present authors already reported that the concentrations of glucosylceramide, lactosylceramide and globotriaosylceramide (Gb3Cer), in which both fatty acids and sphingosines in the ceramides are hydroxylated, exhibit a marked increase during the luteal phase of the menstrual cycle. It is also well known that poorly differentiated endometrial adenocarcinoma exhibits a more rapid progression and a worse response to therapy than well-differentiated endometrial adenocarcinoma. To examine the molecular background of well-differentiated and poorly differentiated cancers, the levels of neutral glycolipids in tumor tissues from endometrial carcinoma displaying different degrees of differentiation were measured. The composition of neutral glycolipids in tumor tissues was determined, and ceramide structures that were specifically expressed in well-differentiated endometrial carcinomas were investigated using biochemical analytical methods, including lipid extraction, enzyme digestion, thin-layer chromatography (TLC), gas-liquid chromatography and mass spectrometry. Well-differentiated adenocarcinoma contained numerous structurally unknown glycolipids that exhibited slower migration than globotetraosylceramide (Gb4Cer). In the case of Gb3Cer, three bands appeared on TLC in well-differentiated cancer, but only two bands appeared in the poorly-differentiated cancer. This difference was associated with the fatty acid composition of ceramide, since non-hydroxy fatty acids with ≥20 carbon atoms were increased in well-differentiated cancer, while α-hydroxy fatty acids were increased in poorly differentiated cancer. Similarly, there were two bands on TLC of Gb4Cer from well-differentiated cancer, but only one band in poorly differentiated cancer, and the long-chain base of ceramide was observed to contain phytosphingosine in well-differentiated cancer. It was demonstrated in endometrial cancer that the structure of ceramide molecules changes with the extent of tumor differentiation. These findings suggest that hydroxylated ceramides contribute to the well-differentiated phenotype of endometrial adenocarcinoma.

Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction.

BACKGROUND: Aldosterone (ALD) has been shown to stimulate cardiac collagen synthesis and fibroblast proliferation via activation of local mineralocorticoid receptors. In patients with acute myocardial infarction, we demonstrated that ALD was extracted through the infarct heart and extracting ALD-stimulated post-infarct left ventricular (LV) remodeling. METHODS AND RESULTS: To evaluate the effect of mineralocorticoid receptor antagonist (MRA) spironolactone on post-infarct LV remodeling, 134 patients with first anterior acute myocardial infarction were randomly divided into the MRA (n=65) or non-MRA (n=69) groups after revascularization. All patients were administered angiotensin-converting enzyme (ACE) inhibitor and study drug just after revascularization. Left ventriculography with contrast medium was performed at the acute stage and after 1 month to evaluate LV remodeling. ALD was measured at aortic root and coronary sinus. There was no difference in the baseline characteristics including infarct size and LV performance between the two groups. However, LV ejection fraction was significantly improved in the MRA group compared with that in the non-MRA group (46.0+/-0.6% to 53.2+/-0.8% versus 46.5+/-0.8% to 51.0+/-0.8%, Pinteraction=0.012). LV end-diastolic volume index was significantly suppressed in the MRA group compared with that in non-MRA group (86.5+/-1.0 to 90.6+/-2.4 versus 87.5+/-1.3 to 106.8+/-3.5 mL/m2, Pinteraction=0.002). Transcardiac extraction of ALD through the heart was significantly suppressed in the MRA group (Pinteraction=0.001), and plasma procollagen type III aminoterminal peptide level, a biochemical marker of fibrosis, was significant lower in the MRA group compared with the non-MRA group (Pinteraction=0.002). CONCLUSIONS: These findings indicate that MRA combined with ACE inhibitor can prevent post-infarct LV remodeling better than ACE inhibitor alone in association with the suppression of a marker of collagen synthesis.