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AIM To evaluate whether embryo selection using the early embryo viability assessment (EEVA) score increases the ongoing pregnancy rate of in vitro fertilization and intracytoplasmic sperm injection patients. METHODS One hundred eighty-one patients whose serum anti mullerian hormone (AMH) level was greater than 0.5 ng/μL were enrolled in the study. All patients received oocyte retrieval repeatedly from June 2017 to January 2019. Transferred embryos were selected using the EEVA score and Veeck's criteria. We investigated the blastocyst rate according to the EEVA score and Veeck's criteria and also evaluated the clinical outcome following embryo transfer of the blastocysts. RESULTS Blastocyst development rate (48.7%) and high-quality blastocyst (42.4%) of Veeck 1 was statistically higher than others. The blastocyst rate (71.4%) and high-quality blastocyst rate (60.0%) for EEVA 1 was the highest, and a correlation between the EEVA score and the blastocyst rate was also identified in cases younger than 40 years. Blastocyst rate of EEVA 1 + 2 (69.8% 208/298) was statistically higher than that of Veeck 1 + 2 (40.1% 317/791) (p

To study the relationship between the migration speed of nucleolus precursor bodies (NPBs) in male and female pronuclei (mPN; fPN) and human embryo development during assisted reproduction. The migration speed of 263 NPBs from 47 zygotes was quantitated, and embryonic development was observed until the blastocyst stage. The central coordinates of mPN, fPN, and NPBs were noted at multiple timepoints. Then, the distance traveled by the NPBs between two sequential images was measured, and migration speed was calculated. Additionally, we investigated the relationship between NPB migration speed and ploidy status (N = 33) or live birth/ongoing pregnancy (LB/OP) (N = 60) after assisted reproduction. The NPB migration speed in both mPN and fPN was significantly faster in the zygotes that developed into blastocysts (N = 25) than that in the zygotes that arrested (N = 22). The timing of blastulation was negatively correlated with NPB migration speed in the mPN. Faster NPB migration was significantly correlated with LB/OP. In multivariate logistic analysis, NPB migration speed in the mPN was the only morphokinetic parameter associated with LB/OP. In a receiver-operating characteristic curve analysis of LB/OP by the NPB migration speed in the mPN, the cut-off value was 4.56 μm/h. When this cut-off value was applied to blastocysts with preimplantation genetic testing for aneuploidy, 100% of the blastocysts faster than or equal to the cut-off value were euploid. The NPBs migrated faster in zygotes having the potential to develop into a blastocyst, and eventually into a baby. This predictor could be an attractive marker for non-invasive embryo selection.

Object: Although thrombin burst has attracted attention as a physiological coagulation mechanism, clinical evidence from a routine assay for it is scarce. This mechanism was therefore evaluated by a clot waveform analysis (CWA) to assess the thrombin time (TT). Material and Methods: The TT with a low concentration of thrombin was evaluated using a CWA. We evaluated the CWA-TT of plasma deficient in various clotting factors, calibration plasma, platelet-poor plasma (PPP), and platelet-rich plasma (PRP) obtained from healthy volunteers, patients with thrombocytopenia, and patients with malignant disease. Results: Although the TT-CWA of calibration plasma was able to be evaluated with 0.01 IU/mL of thrombin, that of FVIII-deficient plasma could not be evaluated. The peak time of CWA-TT was significantly longer, and the peak height significantly lower, in various deficient plasma, especially in FVIII-deficient plasma compared to calibration plasma. The second peak of the first derivative (1st DP-2) was detected in PPP from healthy volunteers, and was shorter and higher in PRP than in PPP. The 1st DP-2 was not detected in PPP from patients with thrombocytopenia, and the 1st DP-2 in PRP was significantly lower in patients with thrombocytopenia and significantly higher in patients with malignant disease than in healthy volunteers. Conclusion: The CWA-TT became abnormal in plasma deficient in various clotting factors, and was significantly affected by platelets, suggesting that the CWA-TT may be a useful test for hemostatic abnormalities.

PURPOSE: To assess the effect of intracytoplasmic sperm injection (ICSI) on embryo hatching and visualise the effects of zona thinning (ZT) on the embryo using time-lapse monitoring. METHODS: In vitro fertilisation (IVF) (n = 178) and ICSI (n = 110)-derived cryopreserved blastocysts were donated by patients who previously had a baby. This study investigated the impacts of IVF, ICSI, laser-assisted hatching by ZT and formation of ICSI penetration trace on zona pellucida of IVF-derived blastocyst on blastcyst diameter, the estimated number of trophectoderm (TE) cells and completed hatching rate. RESULTS: The completed hatching rate and diameters of the completely hatched blastocysts at hatching commencement and at the maximum expansion were significantly greater in the IVF than in ICSI groups. The completed hatching rate significantly increased with ZT in both groups. The maximum diameters of the completely hatched blastocysts were significantly smaller in the ZT than in non-ZT groups. The estimated TE cell numbers increased from hatching commencement to their maximum expansion points. The incompletely hatched ICSI-derived blastocysts intermittently herniated cells via small slits until degeneration. The completed hatching rate significantly decreased by the formation of ICSI penetration trace on zona pellucida of IVF-derived blastocyst. CONCLUSION: ICSI-derived blastocysts intermittently release proliferating cells and extracted TE cells and/or inner cell masses via a small slit; thus, blastocyst expansion is not sufficiently increased, leading to a reduced complete hatching rate. Therefore, the ICSI penetration trace potentially has negative effects on blastocyst expansion process in vitro and is a risk factor for the failure of completed hatching.

Introduction: Cytokine release syndrome (CRS) is a potentially life-threatening systemic disease that has been observed after treatment with antibodies and adoptive T cell therapies. In this case, we observed nivolumab-induced CRS in a patient with gastric cancer. Case Presentation: A 43-year-old male with advanced gastric cancer was treated with nivolumab as a third-line chemotherapy. He had no history of allergies. Eight days after the first administration of nivolumab, fever, tachycardia, appetite loss and increases in liver and biliary enzymes were observed. Computed tomography revealed neither bile duct obstruction nor progression of liver metastases but showed that there was edema of the Gleason sheath. Histopathological analysis of the liver revealed cholestatic liver injury with CD8+ T lymphocyte and macrophage infiltration. Neither viral infection nor autoimmune disease was revealed. His symptoms were similar to those of CRS observed after T cell therapy. We diagnosed his disease as nivolumab-induced liver injury and cholangitis accompanied by CRS based on his serum cytokine levels. Discussion/Conclusion: To the best of our knowledge, this is the first report of nivolumab-induced CRS in a patient with gastric cancer.

This paper presents a design of one-sided directional dual band slot array antenna for both 10GHz and 24GHz application. The antenna element is composed of a top metal, a dielectric substrate, and a bottom metal layer. This antenna is divided into a part corresponding to the upper X-band 2 array and to the lower K-band 4 array antenna. The antenna element is connected to the coplanar waveguide (CPW) feed line. From the simulation and measurement result of the return loss and antenna gain are presented in this paper. The peak gain of proposed antenna is 6.32 dBi at 9.6 GHz and 10.40 dBi at 24 GHz.

Background: Although weekly paclitaxel and trastuzumab is generally considered to be less cardiotoxic than an anthracycline regimen, low baseline left ventricular ejection fraction (LVEF) of ≤55%, hypertension, and high body mass index (BMI) have been reported as risk factors for cardiotoxicity. Without these risk factors, the incidence of cardiotoxicity is expected to be minimal. Method: We retrospectively reviewed the medical records of 86 patients with HER2-positive, node-negative breast cancer between February 2012 and December 2018. Patients were selected for this study according to the following criteria: (1) patients were administered weekly treatment with paclitaxel and trastuzumab for 12 weeks, followed by trastuzumab; (2) baseline LVEF was 60% or more; (3) echocardiography was performed before, during, and at the end of treatment; (4) no hypertension or well-controlled with medication; and (5) BMI was < 30. We investigated the occurrence of cardiotoxicity. A decline in LVEF was defined as a decrease of 15% or more from baseline, or < 50% decrease in LVEF.Results: A total of 40 patients fulfilled the eligibility criteria. The median age was 55.5 (35 to 72) and median baseline LVEF was 68% (60 to 77). The median number of echocardiograms was five (3-7). Out of 40, trastuzumab were completed in 39. Among the 39 patients, no symptomatic congestive heart failure or asymptomatic LVEF decline was observed. Conclusion: In our study, no cardiotoxicity was observed in paclitaxel and trastuzumab. Assessment of cardiac function during treatment may be simplified in patients without risk factors for cardiotoxicity.

Background MicroRNAs (miRNAs) have been implicated to play a vital role in development, differentiation, cell proliferation and apoptosis. However, which miRNAs are actually associated with endometriosis-associated ovarian cancer remains controversial. Methods Serum and ascites samples were obtained from all patients. Serum samples from 5 cases of ovarian endometrioma and endometriosis-associated ovarian cancer each were submitted for comprehensive miRNA microarray profiling. We investigated the differential expression of miRNAs between the two groups to confirm the pivotal role of miRNAs. Quantitative reverse transcription-polymerase chain reaction validation of five selected miRNAs [miR-92a-3p, miR-486-5p, miR-4484, miR-6821-5p, and miR-7108-5p] was performed, and miR-486-5p expression analysis was followed by proliferation and wound healing assays, depending on the expression of miR-486-5p. Result miR-486-5p expression in serum and ascites samples from endometriosis-associated ovarian cancer patients was significantly higher than that from ovarian endometrioma patients. Moreover, the miR-486-5p level in serum and ascites samples was significantly correlated with the severity of the endometriosis. The upregulation of miR-486-5p in immortalized ovarian endometrioma cells significantly increased proliferation and migration. In contrast, the downregulation of miR-486-5p in these cells significantly decreased proliferation and migration. Conclusion miR-486-5p might function as an oncogenic miRNA in endometriosis-associated ovarian cancer and could be a noninvasive biomarker to prospect the severity of ovarian endometrioma.

We explored the relationship between abdominal vein thromboses, including portal vein thrombosis (PVT) and superior mesenteric vein thrombosis (SMVT), and thrombophilia. The frequency of thrombophilia, such as antithrombin (AT), protein C (PC), or protein S (PS) gene mutations, was examined in 21 patients with PVT, 6 patients with SMVT, and 6 patients with both PVT and SMVT. Low levels of AT, PC, or PS were frequently detected in patients with PVT or mesenteric vein thrombosis, and 4 mutations in the PS gene, 3 mutations in the PC gene, and 2 mutations in AT the gene were detected. Protein S Tokushima was detected in 3 of 4 patients with a PS gene mutation and was associated with 2 other PS gene mutations. The onset of PVT or SMVT was almost idiopathic in patients with congenital thrombophilia. Both PVT and SMVT were frequently caused by an AT, a PC, or a PS mutation, and the onset of these thromboses due to thrombophilia was frequently idiopathic.

Purpose The authors previously revealed the association of the follicular fluid (FF) volume with oolemma stretchability following the gonadotropin‐releasing hormone (GnRH) antagonist protocol during intracytoplasmic sperm injection (ICSI). However, the impact of the GnRH agonist protocol on oolemma stretchability remains unclear. Methods Data that were obtained from 74 ICSI cycles were reviewed retrospectively. Controlled ovarian stimulation was performed in accordance with the short GnRH agonist protocol. Each follicle was individually aspirated and assigned to one of six groups, according to the FF volume. The oolemma stretchability during ICSI was evaluated by using a mechanical stimulus for oolemma penetration; that is, oolemma penetration with or without aspiration (high vs low stretchability, respectively). Results The incidence of low oolemma stretchability was significantly higher in the

Ionic scattering factors of atoms that compose biological molecules have been computed by the multi-configuration Dirac–Fock method and parameterized for major curve models in X-ray and electron protein crystallography and single-particle cryo-EM., Ionic scattering factors of atoms that compose biological molecules have been computed by the multi-configuration Dirac–Fock method. These ions are chemically unstable and their scattering factors had not been reported except for O−. Yet these factors are required for the estimation of partial charges in protein molecules and nucleic acids. The electron scattering factors of these ions are particularly important as the electron scattering curves vary considerably between neutral and charged atoms in the spatial-resolution range explored in structural biology. The calculated X-ray and electron scattering factors have then been parameterized for the major scattering curve models used in X-ray and electron protein crystallography and single-particle cryo-EM. The X-ray and electron scattering factors and the fitting parameters are presented for future reference.

// Yasutaka Tono 1, 2 , Mikiya Ishihara 2 , Yoshihiro Miyahara 3 , Satoshi Tamaru 2 , Hiroyasu Oda 2 , Yoshiki Yamashita 2 , Isao Tawara 1 , Hiroaki Ikeda 3, 4 , Hiroshi Shiku 3 , Toshiro Mizuno 2 and Naoyuki Katayama 1, 2 1 Department of Hematology and Oncology, Mie University Graduate School of Medicine, 514-8507 Mie, Japan 2 Department of Medical Oncology, Mie University Hospital, 514-8507 Mie, Japan 3 Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, 514-8507 Mie, Japan 4 Department of Oncology, Nagasaki University Graduate School of Biomedical Sciences, 852-8523 Nagasaki, Japan Correspondence to: Mikiya Ishihara, email: mishihara@clin.medic.mie-u.ac.jp Keywords: breast cancer; eribulin mesylate; HER2-positive; trastuzumab; pertuzumab Received: May 09, 2017 Accepted: February 07, 2018 Epub: February 16, 2018 Published: March 13, 2018 ABSTRACT The standard treatment for advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer is the triple combination of pertuzumab, trastuzumab and docetaxel, but some patients cannot tolerate taxane. To explore a non-taxane triple therapy, we conducted a feasibility study of pertuzumab, trastuzumab and eribulin mesylate (PTE) therapy for previously treated advanced HER2-positive breast cancer with analyses of quality of life and biomarkers. Ten patients were enrolled, two of whom had a history of docetaxel allergy. The median number of prior regimens was 3. The most common Grade 3 toxicities were leukopenia (70%) and neutropenia (70%). Grade 4 or 5 adverse events were not observed. An improving trend for the Functional Assessment of Cancer Therapy-Breast (FACT-B) score at 3 months was observed. Eight cases were included in the biomarker analysis. The peripheral CD8+ T cell/ CD4+Foxp3+ regulatory T cells (Tregs) ratio was significantly increased ( p = 0.039). The frequency of peripheral Tregs was associated with the trastuzumab trough concentration ( p = 0.019). In a non-clinical analysis, Eribulin mesylate significantly inhibited Ser473 Akt phosphorylation in PIK3CA wild-type cells and mutated cells. These results suggest that PTE therapy is a feasible and promising option for advanced HER2-positive breast cancer. Further investigation is warranted.

The usefulness of the waveform of activated partial thromboplastin time (APTT) in various diseases has been evaluated in recent years. The APTT waveform was examined in patients with hemophilia and patients positive for lupus anticoagulant (LA). The correlation with the FVIII activity was highest for the height of acceleration peak. The peak time of acceleration, velocity, and ½ fibrin formation, and the width of acceleration and velocity were significantly long and the height of acceleration was significantly low in patients with hemophilia. The height of velocity was significantly low in patients with hemophilia with inhibitor. There were no significant differences in the APTT waveform between patients with hemophilia and patients with LA, but the peak of acceleration and ½ fibrin formation were significantly longer and the height of acceleration and velocity were significantly lower in patients with hemophilia with inhibitor than in the patients with LA. Wave changes in the APTT were observed in all 22 patients positive for LA, while a biphasic waveform was observed in patients with hemophilia with FVIII activity

Introduction The aim of this study was to investigate the effect of laparoscopic endometriotic cystectomy and vaporization on ovarian reserve. Methods We prospectively analyzed the serum level of anti-Mullerian hormone (AMH) in 62 patients at four different time points— preoperatively and at 1 month, 6 months, and 1 year postoperatively. Among the 62 cases, a bilateral cystectomy was performed in 10, bilateral vaporization in 16, a unilateral cystectomy in 24, and unilateral vaporization in 12. Results The rate of AMH decline after unilateral cystectomy or bilateral cystectomy was higher than that after unilateral vaporization or bilateral vaporization. Age and bilaterality were associated with an AMH decline at 1 month, and age alone was associated with an AMH decline at 1 year. Moreover, being older than 38 years of age and having a revised American Society for Reproductive Medicine score >80 were independent risk factors for the non-recovery of AMH. Conclusion The rate of AMH decline after laparoscopic endometriotic vaporization is significantly lower than that after cystectomy. Both methods, however, have the potential to lower ovarian reserve, especially in cases of severe endometriosis or in patients older than 38 years of age.

Aim The aim of this study was to investigate whether FOXO1 and FOXO3 mRNA expression in granulosa cells is the cause of unexplained infertility. Methods Thirty-one patients aged 0.5 ng/μL were enrolled in the study. All patients underwent oocyte retrieval under a short protocol from June 2012 to October 2013. Real-time PCR was carried out using mRNA extracted from granulosa cells retrieved from mature follicles. We compared FOXO1 and FOXO3 mRNA expression ratios in granulosa cells between the unexplained infertility group and the male infertility group. The relation between FOXO1 and FOXO3 mRNA expression ratios in granulosa cells and assisted reproduction technology clinical outcome was also examined. Results FOXO3 mRNA expression ratio was significantly lower in the unexplained infertility group than in the male infertility group. Moreover, FOXO3 mRNA expression ratio showed a positive correlation with both the number of retrieved oocytes and serum anti-Mullerian hormone level. A positive correlation was also identified between FOXO1 mRNA expression and total dose of hMG. As well, the number of retrieved oocytes in the unexplained infertility group was statistically lower than that in the male infertility group. Conclusion A lower FOXO3 mRNA expression in granulosa cells leads to poor oocyte development in patients with unexplained infertility undergoing controlled ovarian stimulation for in vitro fertilization–embryo transfer.

Aim To investigate which risk factors contribute to a lower oocyte retrieval ratio in women who are receiving controlled ovarian hyperstimulation. Methods The authors retrospectively analyzed 329 in vitro fertilization (IVF) cycles under controlled ovarian hyperstimulation by using a gonadotropin‐releasing hormone antagonist or agonist at Osaka Medical College, Japan. The patients were classified into five groups: advanced age, male infertility, severe endometriosis, tubal infertility, and unexplained infertility. The primary outcomes were the patients’ age, oocyte retrieval ratio, serum basal follicle‐stimulating hormone, total dose of gonadotropin, and the clinical outcome. A secondary outcome was the stepwise multivariate logistic regression analysis to assess the factors associated with the failure of oocyte retrieval. Results The oocyte retrieval ratio declined significantly with the patient's age. The ratio of endometriosis in unsuccessful cases was significantly higher than that in successful cycles. Advanced age and endometriosis were the factors that were significantly associated with a lowered oocyte retrieval rate. Conclusion Advanced age and endometriosis are high‐risk factors that contribute to oocyte retrieval failure in infertile patients who are receiving IVF treatment.

Objective We evaluated the modified diagnostic criteria for disseminated intravascular coagulation (DIC), which was published by the Japanese Society of Thrombosis and Hemostasis (JSTH), in 274 suspected DIC patients with hematopoietic injury. Materials and methods The diagnoses of the patients were as follows: DIC (n = 125); pre-DIC (n = 42) and non-DIC (n = 107). The efficacy of the diagnostic criteria for DIC was evaluated using a receiver operating characteristic (ROC) analysis. Results The area under the curve (ARC) and odd's ratio for the global coagulation test (GCT) scores in the diagnosis of “DIC” were high, while those for the diagnosis of “DIC and pre-DIC” were low, suggesting that the addition of antithrombin (AT) and soluble fibrin (SF)/thrombin antithrobin complex (TAT) was required to diagnose “DIC and pre-DIC”. Although the addition of the AT and SF/TAT values to the GCT did not increase its ability to predict a poor outcome, the JSTH's modified diagnostic criteria scores were correlated with the odds ratio for death. Discussion and conclusion The JSTH's modified diagnostic criteria for DIC, which included the GCT score, and the AT, and TAT/SF values, were useful for diagnosing DIC and pre-DIC, and predicting a poor outcome.

Background The usefulness of the activated partial thromboplastin time (APTT) waveform has been reported in hemophilia, acquired hemophilia and monitoring for anticoagulants. Material and methods The APTT waveform was examined in patients suspected of having disseminated intravascular coagulation (DIC) to analyze its usefulness for the diagnosis of DIC or the prediction of the outcome or bleeding risk. Results DIC with fibrinogen

Thrombotic microangiopathy (TMA) is caused by activated platelets. The plasma C-type lectin-like receptor 2 (CLEC2) levels in 58 patients with TMA were examined and compared with those in healthy volunteers and other diseases.The plasma levels of soluble platelet surface glycoprotein VI (GPVI) and CLEC2 were measured in patients with TMA.Plasma CLEC2 levels in patients with DIC and TMA were significantly higher (p 0.001) than those in thrombocytopenic patients with other hematological diseases, but no significant differences in the plasma CLEC2 levels were observed among patients with thrombotic thrombocytopenic purpura, hemolytic uremic syndrome (HUS), atypical HUS and other TMA. The plasma CLEC2 levels after the remission were significantly lower than those before treatment (p 0.001). The plasma CLEC2 levels were poorly correlated with the levels of soluble GPVI in the plasma of patients with TMA. The plasma CLEC2 levels were not significantly differ between survivor and non-survivor in TMA patients, but were significantly higher in non-survivor in overall population (p 0.001).The measurement of the plasma CLEC2 level is considered to be important for the diagnosis and evaluation of TMA.

We analyzed the utility for a clot waveform analysis (CWA) of small tissue factor induced FIX activation (sTF/FIXa) assay in patients with major orthopedic surgery (including total hip arthroplasty [THA] and total knee arthroplasty [TKA]) receiving edoxaban for the prevention of venous thromboembolism (VTE). The sTF/FIXa assay using recombinant human TF in platelet-rich plasma (PRP) and platelet-poor plasma (PPP) was performed using a CWA in the above patients to monitor the efficacy of edoxaban administration. Of 147 patients (109 THA and 38 TKA), 21 exhibited deep vein thrombosis (DVT), and 15 had massive bleeding. Increased peak heights of the CWA-sTF/FIX were observed in almost patients after surgery and prolonged peak heights of the CWA-sTF/FIX were observed in almost patients treated with edoxaban. The peak heights and times of the CWA-sTF/FIX were significantly higher and shorter, respectively, in PRP than in PPP. There were no significant differences in parameters of the CWA-sTF/FIXa between the patients with and without DVT or between those with and without massive bleeding. The peak time of CWA-sTF/FIXa were significantly longer in TKA patients than in THA patients on day 1 after surgery. The second derivative peak height of the CWA-sTF/FIXa was significantly lower in TKA patients than in THA patients on day 4. The CWA-sTF/FIX reflected hemostatic abnormalities after surgery and the administration of edoxaban, and the results were better in PRP than PPP. Further studies separately analyzing the THA and TKA subgroups should be conducted.

Objective Although the definitive diagnosis of atypical hemolytic uremic syndrome (aHUS) depends on a genetic analysis for the complement factors, such a genetic analysis is time-consuming and expensive. We examined the usefulness of a diagnostic scoring system for aHUS. Methods The thrombotic microangiopathy (TMA) scoring system consists of hemoglobin, the platelet count, creatinine levels and organ failure, and the aHUS scoring system consists of past history and family history of TMA, age at onset, prodromal symptoms and “red or brownish urine”, and these scoring system were both evaluated in patients with aHUS, thrombotic thrombocytopenic purpura or secondary TMA. Results In a receiver operating characteristics analysis, an adequate cut-off value for diagnosing aHUS, TTP, other TMA or all TMA versus patients without TMA was 7 points for both TMA screening scores. The area under the curve was 0.965 for the TMA screening score and 0.966 for the aHUS score. An adequate cut-off value for diagnosing aHUS was 2 points for a positive aHUS score, - 3 points for an exclusion aHUS score and 0 points for the total aHUS score. Conclusion The TMA screening and aHUS score systems are useful for making a diagnosis of aHUS without performing specific laboratory tests.

Threading dislocations (TDs) in 4H-SiC have been studied by comparing etch pits formed by NaOH vapor etching with results of synchrotron monochromatic-beam X-ray topography (XRT) taken under different g-vectors. Burgers vectors determined based on XRT results were utilized to investigate the etch pit characteristics of edge (TED), screw (TSD) and mixed (Burgers vector b=c+a, TMD) threading dislocations. It has been found that pit formation by NaOH vapor etching was very different to that by conventional molten KOH etching. We discuss the possibility of using NaOH vapor etching to distinguish TMDs from TSDs, and report a variety of characteristic etch pits formed by this method and their correlations to dislocation behavior.