Four conserved amino acids on human papillomavirus E6 predict clinical high-risk types.

Human papillomavirus (HPV) types included in the genus alpha papillomavirus (alpha-HPVs) are subdivided into high- and low-risk HPVs associated with tumorigenicity. According to conventional risk classification, over 30 alpha-HPVs remain unclassified and HPV groups phylogenetically classified using the L1 gene do not exactly correspond to the conventional risk classification groups. Here, we propose a novel cervical lesion progression risk classification strategy. Using four E6 risk distinguishable amino acids (E6-RDAAs), we successfully expanded the conventional classification to encompass alpha-HPVs and resolve discrepancies. We validated our classification system using alpha-HPV-targeted sequence data of 325 cervical swab specimens from participants in Japan. Clinical outcomes significantly correlated with the E6-RDAA classification. Four of five HPV types in the data set that were not conventionally classified (HPV30, 34, 67, and 69) were high-risk according to our classification criteria. This report sheds light on the carcinogenicity of rare genital HPV types using a novel risk classification strategy.

Discordance of light chain isotypes between serum and glomerular deposits in proliferative glomerulonephritis with monoclonal IgG deposits: a case report and review of the literature.

BACKGROUND: Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMID) is a disease entity with nonorganized granular glomerular deposition with monoclonal proteins of both heavy and light chains. Dysproteinemia was observed in only 30% of the patients with PGNMID. We herein report a case of PGNMID with discrepancy between serum and glomerular deposits. CASE PRESENTATION: The patient was a 50-year-old man who had been followed at a local clinic due to hypertension, type 2 diabetes, hyperlipidemia, hyperuricemia, fatty liver, and obesity. Proteinuria had been noted five years previously, and he had been referred to a hematology department due to hyperproteinemia, high gamma globulin, and κ Bence-Jones protein (BJP) positivity one year previously. Bone marrow aspiration showed 5% plasma cells, and he was referred to the nephrology department to evaluate persistent proteinuria. He was hypertensive, and his estimated glomerular filtration rate was 54.2 ml/min/1.73 m2. His urinary protein level was 0.84 g/g⋅Cr. Urine and serum immunofixation showed BJP-κ type and IgG-κ type, respectively. Kidney biopsy showed an increase in mesangial cells and matrix without nodular lesions under a light microscope. Immunofluorescence microscopy showed granular deposits of IgG and C3 on the capillary wall and weak positivity for C1q. IgG3 was predominant among the IgG subclasses, and intraglomerular κ and λ staining was negative for κ and positive for λ. Direct fast scarlet staining was negative. Electron microscopy showed lumpy deposits without a fibrillar structure in the subepithelial area. Based on the above findings, a diagnosis of membranous nephropathy-type PGNMID was made. Since proteinuria increased gradually after three years of treatment with valsartan (40 mg, daily), oral prednisolone (30 mg, daily) was initiated, which led to decreased proteinuria. The dose of oral prednisolone was gradually tapered to 10 mg per day. At that time, proteinuria was 0.88 g/g⋅Cr. We found 204 cases in 81 articles in the PubMed database, among which 8 showed discrepancy in the heavy and/or light chains between serum and kidney. CONCLUSIONS: We experienced a case of membranous nephropathy-type PGNMID with discrepancy in light chains between serum and kidney that was successfully treated with oral prednisolone.

Simultaneous bilateral mastectomy and RRSO for BRCA2-positive non-invasive breast cancer in Japan: a case report and analysis of initial experience.

BACKGROUND: In Japan, genetic testing, surveillance, and risk-reducing surgery for hereditary breast and ovarian cancer (HBOC) syndrome have been covered by the Japanese national insurance system since April 2020. On the other hand, the current situation is that medical care, including surveillance of undiagnosed (cancer-free) patients, is self-funded even for individuals with HBOC. We report a case in which breast cancer was diagnosed at an early stage during surveillance for cancer-free HBOC at the patient's own expense, and risk-reducing surgery was performed at the same time as treatment for breast cancer. CASE PRESENTATION: The patient was a 63-year-old woman. Her sister had a history of breast cancer in her 30s and was found to be a BRCA2 pathogenic variant carrier by genetic testing. The patient therefore presented to the genetic department of our hospital and underwent genetic testing (out-of-pocket). A pathogenic variant was found at the same site. During annual breast and ovarian surveillance at the patient's own expense, a physician with sufficient expertise in contrast-enhanced breast magnetic resonance imaging (MRI) noticed a change in the contrast enhancement pattern on breast MRI and performed needle biopsy, revealing ductal carcinoma in situ. At the request of the patient, she underwent concurrent contralateral risk-reducing mastectomy and risk-reducing salpingo-oophorectomy in addition to breast cancer treatment. CONCLUSIONS: We encountered a case in which cancer treatment and risk-reducing surgery were performed at the same time for a pathogenic variant carrier who was very anxious about developing cancer. Surveillance of cancer-free BRCA1/2 mutation carriers and expansion of insurance coverage for surgery are important future issues.

Normalizing hyperactivity of the Gunn rat with bilirubin-induced neurological disorders via ketanserin.

BACKGROUND: Severe neonatal hyperbilirubinemia has been known to cause the clinical syndrome of kernicterus and a milder one the syndrome of bilirubin-induced neurologic dysfunction (BIND). BIND clinically manifests itself after the neonatal period as developmental delay, cognitive impairment, and related behavioral and psychiatric disorders. The complete picture of BIND is not clear. METHODS: The Gunn rat is a mutant strain of the Wistar rat with the BIND phenotype, and it demonstrates abnormal behavior. We investigated serotonergic dysfunction in Gunn rats by pharmacological analyses and ex vivo neurochemical analyses. RESULTS: Ketanserin, the 5-HT2AR antagonist, normalizes hyperlocomotion of Gunn rats. Both serotonin and its metabolites in the frontal cortex of Gunn rats were higher in concentrations than in control Wistar rats. The 5-HT2AR mRNA expression was downregulated without alteration of the protein abundance in the Gunn rat frontal cortex. The TPH2 protein level in the Gunn rat raphe region was significantly higher than that in the Wistar rat. CONCLUSIONS: It would be of value to be able to postulate that a therapeutic strategy for BIND disorders would be the restoration of brain regions affected by the serotonergic dysfunction to normal operation to prevent before or to normalize after onset of BIND manifestations. IMPACT: We demonstrated serotonergic dysregulation underlying hyperlocomotion in Gunn rats. This finding suggests that a therapeutic strategy for bilirubin-induced neurologic dysfunction (BIND) would be the restoration of brain regions affected by the serotonergic dysfunction to normal operation to prevent before or to normalize after the onset of the BIND manifestations. Ketanserin normalizes hyperlocomotion of Gunn rats. To our knowledge, this is the first study to demonstrate a hyperlocomotion link to serotonergic dysregulation in Gunn rats.

Effect of speed sintering of monolithic zirconia with different yttria contents on color and crystal phase.

This study evaluated the color and microstructure of monolithic zirconia crowns with different yttrium oxide (Y2 O3 ) contents treated by conventional or speed sintering. Four types of zirconia ceramics were assessed: two monolayer zirconia, and two multilayer zirconia. The monolithic zirconia crowns were fabricated using a dental computer-aided design/computer-aided manufacturing (CAD/CAM) system and in two shades (A2 and BL). After milling, the zirconia crowns were sintered using either speed sintering or conventional sintering. For each combination of zirconia (4), shade (2), and sintering condition (2), the color parameters were determined at three positions of each of nine crowns using a non-contact dental spectrophotometer. In addition, the zirconia phases in the specimens were quantified using X-ray diffractometry. Significant differences in the ΔE00 values at different measurement positions were observed for the Multi2 crown of the BL shade group. The color difference resulting from conventional and speed sintering programs was not affected by the difference in yttria content of Mono1, Mono2, and Multi1. However, in Multi2, containing 3Y-TZP and 5Y-PSZ, a color change was caused by the use of speed sintering. Therefore, when performing speed sintering with Multi2, it is necessary to select the color in consideration of these results or take measures for staining.

Bihormonal dysregulation of insulin and glucagon contributes to glucose intolerance development at one year post-delivery in women with gestational diabetes: a prospective cohort study using an early postpartum 75-g glucose tolerance test.

Gestational diabetes mellitus (GDM) is known to be a significant risk factor for the future development of type 2 diabetes. Here, we investigated whether a precise evaluation of ß- and α-cell functions helps to identify women at high risk of developing glucose intolerance after GDM. Fifty-six women with GDM underwent a 75-g oral glucose tolerance test (OGTT) at early (6-12 weeks) postpartum. We measured their concentrations of glucose, insulin, proinsulin and glucagon at fasting and 30, 60 and 120 min. At 1-year post-delivery, we classified the women into a normal glucose tolerance (NGT) group or an impaired glucose tolerance (IGT)/diabetes mellitus (DM) group. Forty-three of the 56 women completed the study. At 1-year post-delivery, 17 women had developed IGT/DM and 26 women showed NGT. In the early-postpartum OGTTs, the IGT/DM group showed a lower insulinogenic index, a less glucagon suppression evaluated by the change from fasting to 30 min (ΔGlucagon 30 min), and a higher glucagon-to-insulin ratio at 30 min compared to the NGT group. There were no significant between-group differences in proinsulin levels or proinsulin-to-insulin ratios. Insulinogenic index <0.6 and ΔGlucagon 30 min >0 pg/mL were identified as predictors for the development of IGT/DM after GDM, independent of age, body mass index, and lactation intensity. These results suggest that the bihormonal disorder of insulin and glucagon causes the postpartum development of glucose intolerance. The measurement of plasma insulin and glucagon during the initial OGTT at early postpartum period can help to make optimal decisions regarding the postpartum management of women with GDM.

Delirium is associated with high mortality in older adult patients with acute decompensated heart failure.

BACKGROUND: Delirium is associated with high mortality after cardiac surgery. However, evidence on the epidemiology of delirium in patients with acute decompensated heart failure (ADHF) is limited. This study aimed to assess the incidence and prognostic impact of delirium in patients with ADHF. METHODS: This single-center prospective observational study enrolled 132 consecutive patients with ADHF. We utilized the Diagnostic and Statistical Manual of Mental Disorders, fifth edition and classified the patients into two groups according to the presence or absence of delirium. The primary endpoint was 90-day all-cause mortality. The prognostic impact and risk factors of delirium were evaluated using multivariable Cox and logistic regression analyses, respectively. RESULTS: The median patient age was 83 (interquartile range, 75-87) years. Approximately 51.5% were men. Delirium occurred in 36 (27.3%) patients, and hyperactive delirium was the most frequent type (86.1%). The 90-day all-cause mortality was higher in the patients with delirium than in those without (21.6% versus 3.9%, log-rank p = 0.002). Delirium was associated with higher mortality with an adjusted hazard ratio of 6.8 (95% confidence interval, 1.1-42.6, p = 0.042). The risk factors associated with delirium included advanced age, male sex, higher clinical frailty scale score, and dementia. CONCLUSIONS: Delirium was associated with a higher 90-day all-cause mortality in the older adult patients with ADHF. Hyperactive delirium was the most common subtype.

Natural Course of Human T-Cell Leukemia Virus Type 1 Proviral DNA Levels in Carriers During Pregnancy.

The measurement of human T-cell leukemia virus type 1 (HTLV-1) proviral DNA levels by using polymerase chain reaction has been beneficial for confirming HTLV-1 infection during pregnancy. However, the influence of pregnancy on HTLV-1 infection and proviral DNA levels among pregnant women with HTLV-1 has not been clarified. We prospectively gathered blood samples from 36 pregnant women in whom HTLV-1 carriage was previously diagnosed and sequentially measured their proviral DNA levels. The HTLV-1 proviral DNA levels remained at a plateau during pregnancy but were elevated after delivery. Moreover, flow cytometry and serological analyses revealed that the regulatory T-cell population and soluble interleukin 2 receptor levels were similarly elevated after birth in comparison with those in control pregnant women. This study is the first to provide data on sequential changes in HTLV-1 proviral DNA levels during and after pregnancy. These findings will guide the establishment of a better program to prevent mother-to-child transmission of HTLV-1.

Effect of finish line design on stress distribution in bilayer and monolithic zirconia crowns: a three-dimensional finite element analysis study.

This study evaluated the influence of different finish line designs and abutment materials on the stress distribution of bilayer and monolithic zirconia crowns using three-dimensional finite element analysis (FEA). Three-dimensional models of two types of zirconia premolars - a yttria-stabilized zirconia framework with veneering ceramic and a monolithic zirconia ceramic - were used in the analysis. Cylindrical models with the finish line design of the crown abutments were prepared with three types of margin curvature radius (CR): CR = 0 (CR0; shoulder margin), CR = 0.5 (CR0.5; rounded shoulder margin), and CR = 1.0 (CR1.0; deep chamfer margin). Two abutment materials (dentin and brass) were analyzed. In the FEA model, 1 N was loaded perpendicular to the occlusal surface at the center of the crown, and linear static analysis was performed. For all crowns, stress was localized to the occlusal loading area as well as to the axial walls of the proximal region. The lowest maximum principal stress values were observed when the dentin abutment with CR0.5 was used under a monolithic zirconia crown. These results suggest that the rounded shoulder margin and deep chamfer margin, in combination with a monolithic zirconia crown, potentially have optimal geometry to minimize occlusal stress.

Reference values for circulating pregnancy-associated microRNAs in maternal plasma and their clinical usefulness in uncomplicated pregnancy and hypertensive disorder of pregnancy.

AIM: The aim of this study was to establish the reference values for circulating pregnancy-associated placental microRNAs in maternal plasma and clarify their clinical significance in patients with hypertensive disorder of pregnancy (HDP). METHODS: Blood samples were collected from 145 women with uncomplicated pregnancies (24, 26, 31 and 32 women at 12, 23, 30 and 36 weeks of gestation, respectively, and 32 women 1 day after delivery). Plasma concentrations of pregnancy-associated placental microRNAs (miR-515-3p, miR-517a, miR-517c and miR-518b) were measured by quantitative real-time reverse-transcription polymerase chain reaction. Reference values for each microRNA were determined by the line of best fit and 95% prediction interval and are expressed as logarithmic transformation. To clarify the clinical significance of these reference values, we measured the plasma concentrations of pregnancy-associated microRNAs in a different population comprising 33 pregnant women with HDP and 44 women with uncomplicated pregnancies. RESULTS: Reference values for circulating pregnancy-associated placental microRNAs on chromosome 19 miRNA clusters showed an increasing tendency as pregnancy progressed and decreased significantly 1 day after delivery (P < 0.05). The sensitivity and specificity of each reference value were 57.6% and 93.2% for miR-515-3p, 63.6% and 75.0% for miR-517a, 75.8% and 79.5% for miR-517c and 63.6% and 75.0% for miR-518b, respectively. The positive and negative predictive values of each reference value were 86.4% and 74.5% for miR-515-3p, 65.6% and 73.3% for miR-517a, 73.5% and 81.4% for miR-517c and 65.6% and 73.3% for miR-518b, respectively. CONCLUSION: Establishing the reference values for circulating pregnancy-associated placental microRNAs in maternal plasma could be useful for the evaluation of HDP.

Clinical evaluation of zirconia-based all-ceramic single crowns: an up to 12-year retrospective cohort study.

OBJECTIVES: This study aims to investigate the incidence of clinical complications with tooth-supported zirconia-based all-ceramic single crowns and identify pertinent risk parameters. MATERIALS AND METHODS: A retrospective cohort study (May 2004 to April 2016) utilizing clinical records of patients receiving yttrium-oxide-partially stabilized zirconia (Y-TZP)-based all-ceramic crowns placed at Tohoku University Hospital was performed. The length of time of treatment success (complication event-free) and restoration survival (including minor complication events and remaining clinically functional) were estimated using Kaplan-Meier analysis. Multilevel survival analysis was used to identify risk factors. RESULTS: One hundred thirty-seven crowns were evaluated (mean follow-up time, 7.0 years). A total of 21 crowns experienced at least one complication with fracture of veneering ceramic being the most common (16 crowns). Estimated success and survival rates at 5 years (96.9 and 98.5%, respectively) decreased at 10 years to 62.1 and 67.2%, respectively. The risk of complications was significantly higher for molar crowns compared to anterior crowns (p < 0.01). A significant association of complications with metal antagonist restorations was shown by univariate analysis (p < 0.01). CONCLUSIONS: Given the study limitations, Y-TZP single crowns placed on anterior teeth demonstrated encouraging clinical results over a period of up to 10 years. However, there is a substantial risk of complications with posterior teeth within 10 years of restoration placement. CLINICAL RELEVANCE: Treatment with zirconia-based all-ceramic crowns for molar teeth with metal antagonist occlusion should be undertaken with caution.

Three-dimensional finite element analysis of zirconia all-ceramic cantilevered fixed partial dentures with different framework designs.

The purpose of this study were: to perform stress analyses using three-dimensional finite element analysis methods; to analyze the mechanical stress of different framework designs; and to investigate framework designs that will provide for the long-term stability of both cantilevered fixed partial dentures (FPDs) and abutment teeth. An analysis model was prepared for three units of cantilevered FPDs that assume a missing mandibular first molar. Four types of framework design (Design 1, basic type; Design 2, framework width expanded buccolingually by 2 mm; Design 3, framework height expanded by 0.5 mm to the occlusal surface side from the end abutment to the connector area; and Design 4, a combination of Designs 2 and 3) were created. Two types of framework material (yttrium-oxide partially stabilized zirconia and a high precious noble metal gold alloy) and two types of abutment material (dentin and brass) were used. In the framework designs, Design 1 exhibited the highest maximum principal stress value for both zirconia and gold alloy. In the abutment tooth, Design 3 exhibited the highest maximum principal stress value for all abutment teeth. In the present study, Design 4 (the design with expanded framework height and framework width) could contribute to preventing the concentration of stress and protecting abutment teeth.

A significant association between rs8067378 at 17q12 and invasive cervical cancer originally identified by a genome-wide association study in Han Chinese is replicated in a Japanese population.

In this study, associations between invasive cervical cancer and four cervical cancer susceptibility loci (rs13117307 at 4q12, rs8067378 at 17q12, and rs4282438 and rs9277952 at 6p21.32) in the Han Chinese population were investigated in a Japanese population. Human leukocyte antigen (HLA)-DPB1 alleles were also investigated for their association with cervical cancer risk in the Japanese population. After receiving written informed consent, 214 unrelated Japanese women with invasive cervical cancer and 288 cancer-free Japanese women were recruited, and DNA samples were obtained (study protocol approved by Institutional Review Board of Nagasaki University). Of the four single-nucleotide polymorphisms, rs8067378 showed a significant association with invasive cervical cancer (P=0.0071). Under a recessive model, the minor allele G of rs8067378 contributed to the risk of invasive cervical cancer (odds ratio=2.92, 95% confidence interval=1.40-6.36; P=0.0021). No association was detected between HLA-DPB1 alleles and cervical cancer risk in the Japanese population. In conclusion, we show for the first time, to the best of our knowledge, that an association between increased risk of invasive cervical cancer and rs8067378 in the Han Chinese population is replicated in a Japanese population. In addition, Japanese women with the GG genotype of rs8067378 are a candidate high-risk group for invasive cervical carcinoma.

Effect of labor on plasma concentrations and postpartum clearance of cell-free, pregnancy-associated, placenta-specific microRNAs.

OBJECTIVE: This study aimed to investigate the effect of labor on plasma concentrations of cell-free, pregnancy-associated, placenta-specific microRNAs (miRNAs) before and after delivery. METHOD: In the non-labor group (32 women), cesarean section (C/S) was performed before the beginning of labor. In the labor group (32 women), C/S was performed after the beginning of labor. Plasma concentrations of cell-free, pregnancy-associated, placenta-specific miRNAs (miR-515-3p, miR-517a, miR-517c, and miR-518b) were measured by real-time quantitative PCR. Each miRNA concentration was compared between the non-labor and labor groups. RESULTS: Before C/S, plasma concentrations of cell-free, pregnancy-associated, placenta-specific miRNAs in the labor group were significantly higher than those in the non-labor group (P = 0.001 for 515-3p, P = 0.002 for 517a, P = 0.001 for 517c, and P = 0.003 for 518b). Twenty-four hours after delivery, plasma concentrations of cell-free, pregnancy-associated, placenta-specific miRNAs in the labor group were significantly higher than those in the non-labor group (P = 0.002 for 515-3p, P = 0.017 for 517a, P = 0.043 for 517c, and P = 0.009 for 518b). CONCLUSION: The presence of labor affects cell-free, pregnancy-associated, placenta-specific miRNA levels in maternal plasma. Labor also affects postpartum clearance of these miRNAs 24 h after delivery.

Circulating chromosome 19 miRNA cluster microRNAs in pregnant women with severe pre-eclampsia.

AIM: To clarify the association between circulating chromosome 19 miRNA cluster (C19MC) microRNAs in maternal plasma and severe pre-eclampsia. METHOD: Maternal blood samples (7 mL) at 27-34 weeks of gestation were obtained from 20 pregnant women with severe pre-eclampsia (sPE group) and from 20 uncomplicated pregnant women (NP group). Twenty cases of severe pre-eclampsia were classified into late onset (sPELO group; n = 14) and early onset (sPEEO group; n = 6). Plasma concentration of C19MC microRNAs (miR-518b, -1323, -516b, -516a-5p, -525-5p, -515-5p, -520 h, -520a-5p, -519d and -526b) was measured on quantitative real-time reverse transcription-polymerase chain reaction. RESULTS: The circulating levels of all 10 C19MC microRNAs in maternal plasma were significantly increased in the sPE group compared with the NP group. Plasma concentration of all 10 C19MC microRNAs tested was significantly increased in the sPEEO group compared with the NP group, while plasma concentration of nine miRNAs, except for miR-519d, was significantly increased in the sPELO group compared with the NP group. Of the 10 C19MC microRNAs measured, plasma concentration of eight miRNAs, except for miR-518b and miR-519d, was significantly increased in the sPEEO group compared with the sPELO group. CONCLUSIONS: Increased levels of C19MC microRNAs in maternal plasma are a characteristic phenomenon of established severe pre-eclampsia, and it has been shown for the first time that the upregulation of C19MC miRNAs occurred as a consequence of, not in advance of, the onset of pre-eclampsia.

Single human papillomavirus 16 or 52 infection and later cytological findings in Japanese women with NILM or ASC-US.

The relationship between oncogenic human papillomavirus (HPV) infection and later cytological findings in the uterine cervix is unknown in women who were negative for intraepithelial lesion and malignancy (NILM) or atypical squamous cells of undetermined significance (ASC-US). This was investigated in this study in a Japanese population to determine the clinical utility of oncogenic (HPV) genotyping. The relative risk of progressive cytological findings 2 years after identification of oncogenic HPV infection was higher than in cases of non-oncogenic HPV infection (relative risk 3.827; 95% confidence interval (CI): 1.282-11.422), as well as in cases of negative HPV infection (relative risk 2.124; 95% CI: 1.451-3.110). Moreover, the relative risk of progression of cytological findings 2 years later in cases of HPV-16 infection was higher than in cases of HPV-52 infection (relative risk 2.094; 95% CI: 1.005-3.935). Therefore, the initial HPV-DNA genotype may be a potential predictive marker of later progression of cytological findings in the uterine cervix in cases of NILM or ASC-US.

Identification of endometrioid endometrial carcinoma-associated microRNAs in tissue and plasma.

OBJECTIVE: This study aimed to identify a set of endometrioid endometrial carcinoma EEC-associated microRNAs (miRNAs) in tissue and plasma, and evaluate their clinical significance. METHODS: A set of EEC-associated miRNAs in tissue and plasma was identified by next-generation sequencing (NGS), which could enable in-depth characterization of the global repertoire of miRNAs. RESULTS: NGS identified 11 candidate EEC-associated miRNAs. Quantitative reverse-transcriptase PCR identified 8 EEC-associated miRNAs in tissue (upregulated: miR-499, miR-135b, miR-205, downregulated: miR-10b, miR-195, miR-30a-5p, miR-30a-3p and miR-21). Expression of hsa-miR-499 in International Federation of Gynecology and Obstetrics (FIGO) Stage IA and Grade 1 tissues was significantly lower than in others (FIGO Stage IB or more advanced, and Grade 2 or 3). By receiver operating characteristic (ROC) curve analysis, compared with single EEC-associated miRNA, two miRNA signatures (miR135b/miR195 and miR135b/miR30a-3p) could distinguish between EEC and normal endometrial tissue samples yielding a high area under the curve (AUC) of 0.9835 [95% confidence interval (CI): 0.9677-1.0], and 0.9898 (95% CI: 0.9677-1.0), respectively. As possible non-invasive markers for EEC, four EEC-associated miRNAs (increased level: miR-135b and miR-205, decreased-level: miR-30a-3p and miR-21) in plasma were identified. Circulating levels of three EEC-associated miRNAs (miR-135b, miR-205 and miR-30a-3p) in plasma were significantly decreased after hysterectomy. ROC curves analysis revealed that miR-135b and miR-205 levels in plasma yielded AUCs of 0.9722 (95% CI: 0.913-1.0) and 1.0 (95% CI: 1.0-1.0), respectively. CONCLUSION: Measurement of tissue and plasma EEC-associated miRNAs may be useful for early detection, diagnostic, and follow-up tests for EEC.

Predominantly placenta-expressed mRNAs in maternal plasma as predictive markers for twin-twin transfusion syndrome.

OBJECTIVE: This study aimed to identify a set of predominantly placental (PP) mRNAs, which are associated with later-developing twin-to-twin transfusion syndrome (TTTS). METHOD: First, out of 50 PP mRNAs we previously reported, we select target mRNAs that are ordinarily detectable in maternal plasma. Plasma concentrations of these PP mRNAs were measured in monochorionic diamniotic twin (MCDA-T) pregnancies complicated by TTTS later (n = 11) and in uncomplicated MCDA-T pregnancies (n = 17). Finally, the diagnostic values of the PP mRNAs in plasma were evaluated. RESULTS: From 50 PP mRNAs, nine [human placental lactogen (hPL); pregnancy-specific glycoproteins 2 (PSG2); human pregnancy-specific glycoproteins 3 (PSG3); syncytin; syncytin 2; retinoic acid-induced 14; A disintegrin and metalloproteinase domain-containing protein 12 (ADAM12); chorionic glycoprotein hormones, alpha polypeptide; and chorionic glycoprotein hormones, and beta polypeptide] were selected as target mRNAs. Changes in six PP mRNAs [increased hPL, PSG2, and PSG3 and decreased syncytin, syncytin2, and ADAM12] in maternal plasma were detected in MCDA-T pregnant women who subsequently developed TTTS. Finally, mRNA signatures gave elevated AUCs (hPL/PSG2: 0.8717; hPL/PSG3: 0.8449; hPL/ADAM12: 0.8396) compared with single hPL mRNA. CONCLUSION: Quantitative aberration of plural cell-free PP mRNAs in maternal plasma precedes the appearance of clinically apparent TTTS. This suggests that pathophysiological changes in the placenta are associated with morbid conditions of TTTS.