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Undifferentiated neoplasms of unknown primary sites are rare. It is difficult to identify their characteristics and determine the appropriate chemotherapy regimen to be used. Undifferentiated/rhabdoid carcinoma is reportedly associated with loss of SWI/SNF chromatin remodeling complexes, such as observed in SMARCA4-deficient tumors. However, little is known about SMARCA2/BRM-deficient tumors. A 48-year-old man presented with low back pain. Computed tomography (CT) revealed intraperitoneal lymph nodes and multiple bone metastases that invaded the thoracic and lumbar spinal canals. The primary tumor was not identified despite the standard diagnostic methods being used. CT-guided needle biopsy of right iliac bone metastasis showed that the tumor had an undifferentiated/rhabdoid morphology. Immunostaining revealed that the tumor was SMARCA2/BRM-deficient despite both SMARCB1/INI1 and SMARCA4/BRG being retained. We found no genomic alterations during domestic next-generation sequencing panel profiling, which can identify 114 genes. Thus, he was diagnosed with SMARCA2/BRM-deficient undifferentiated/rhabdoid carcinoma of an unknown primary site with multiple bone metastases and intraperitoneal lymph node metastasis. We administered radiotherapy to the thoracic and lumbar spine to improve cord compression, and carboplatin (CBDCA) and paclitaxel regimen was chosen as first-line chemotherapy, but this was discontinued due to an anaphylactic shock. We then selected the CBDCA and gemcitabine regimens; however, the patient did not continuously receive the regimen due to myelosuppression. Radiation therapy effectively relieves pain and cord compression. To our knowledge, this is the first reported case of SMARCA2/BRM-deficient undifferentiated/rhabdoid carcinoma of an unknown primary site. Further studies are needed to improve SWI/SNF-deficient tumor identification methods.

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.

Objective: Although emicizumab is a bispecific, monoclonal antibody that has led to a significant improvement of treatment for hemophilia A patients with inhibitors, the routine monitoring of patients treated with emicizumab is difficult. Thrombin time (TT) reflects thrombin burst, which mainly depends on activation of factor V (FV) and FVIII. Methods: We, therefore, developed a method for evaluating clotting activity independent of the presence of emicizumab. Normal plasma (NP) or FVIII-deficient plasma (FVIIIDP) with and without emicizumab was measured using clot waveform analysis (CWA)-activated partial thromboplastin time (APTT) and TT. Results: Emicizumab caused clot formation in FVIIIDP using the CWA-APTT; however, the coagulation peaks of plasma with and without emicizumab measured by the CWA-TT did not differ to a statistically significant extent. Regarding the mixing tests with NP and FVIIIDP, CWA-APTT showed large differences between each mixing test in plasma with and without emicizumab, whereas the CWA-TT showed similar patterns in mixing plasma with and without emicizumab. Regarding the standard curve of FVIII activity, the CWA-APTT showed an FVIII-concentration-dependent increase; however, the values with each concentration of FVIII differed between samples with and without emicizumab, whereas CWA-TT showed FVIII-concentration-dependent fluctuations independent of the presence of emicizumab, and the values with each concentration of FVIII were similar in samples with and without emicizumab. Conclusions: As CWA-TT using a small amount of thrombin (0.5 IU/mL) can reflect thrombin burst and be useful for evaluating FVIII activity, independent of the presence of emicizumab, it is useful for monitoring clotting activity in patients with an anti-FVIII inhibitor treated with emicizumab.

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

Disseminated intravascular coagulation (DIC) is induced by excess activation coagulation, and activated platelets are also involved in pathogenesis. Therefore, plasma levels of soluble C-type lectin-like receptor 2 (sCLEC-2), a new marker for platelet activation, can be expected as a marker of DIC in critically ill patients. Plasma levels of sCLEC-2 and D-dimer were measured using the STACIA system. Plasma sCLEC-2 and D-dimer levels were significantly higher in patients with underlying diseases of DIC than in those with unidentified clinical syndrome (UCS). Plasma sCLEC-2 levels were significantly higher in the patients with DIC and Pre-DIC than in those without DIC or Pre-DIC. Similarly, plasma D-dimer levels were also significantly higher in patients with DIC and Pre-DIC than in those without DIC or Pre-DIC. The plasma sCLEC-2 levels in all patients and those with a DIC score ≤ 4 were significantly higher in non-survivors than survivors. The plasma D-dimer levels in all patients, those with a DIC score ≥ 5 and those with a DIC score ≤ 4, were significantly higher in non-survivors than in survivors. The plasma sCLEC-2 is expected as a marker for DIC/Pre-DIC as well as the prognostic marker in critically ill patients.

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.

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

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.

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.

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.

[Introduction] The triple therapy of pertuzumab, trastuzumab and taxanes (docetaxel or paclitaxel) is coming into widespread use, because of the beneficial effects on HER2 positive breast cancer. However, we don't have enough information about the efficacy and safety of other agents with trastuzumab and pertuzumab (TP). We studied triple therapy of pertuzumab, trastuzumab and eribulin (PTE) for advanced HER2 positive breast cancer to assess the efficacy, safety and QOL prospectively (UMIN000012018). [Patients and methods] Responses were assessed by RECIST criteria v1.1. Adverse events (AEs) were graded according to CTCAE v4.0. Patients with advanced HER2 positive breast cancer were treated with pertuzumab (840 mg loading then 420 mg, day 1), trastuzumab (8 mg/kg loading then 6 mg/kg, day 1), and eribulin (1.4 mg/m2, day 1 and 8) every 3 weeks. Dose reduction was allowed when patients developed febrile neutropenia, grade 3-5 non-hematologic toxicity or skipped day 8 eribulin administration because of neutrophil count [Results] Ten patients were enrolled. Median age of patients was 60 years-old (35-75). Median number of prior chemoregimen for metastatic disease was 3 (0-5). Two patients had a history of docetaxel allergy. Median number of PTE cycle was 6 (3-12). Eight patients reduced eribulin doses 1.4 mg/m2 to 1.1 mg/m2 because of AEs (2 patients), skipped day 8 eribulin (4 patients), or physician's choice (2 patients). One complete response, 1 partial response and 5 stable disease were achieved at 3 months. Two patients (1 CR and 1 SD) stopped eribulin and received TP as maintenance therapy. At 3 months, all 3 patients with progressive disease developed brain metastasis. Two patients had extracranial progressive lesions, but 1 patient had partial response for extracranial disease. The common treatment-related AEs were leukopenia, neutropenia, lymphopenia diarrhea, hypokalemia and stomatitis. Grade 3 AEs were leukopenia (7 patients), neutropenia (8 patients), lymphopenia (2 patients), febrile neutropenia (1 patient), hypokalemia (1 patient) and peripheral neuropathy (1 patient). Grade 4/5 AEs were not observed. Nine patients could be assessed QOL. FACT-B TOI, FACT-G and FACT-B total score had a tendency to be improved at 3 months. [Conclusion] The PTE therapy showed appropriate clinical effect for extracranial lesions and maintained QOL of patients with advanced HER2 positive breast cancer. It may be a choice for patients who have taxane-resistant diseases or a history of taxane allergy. Many patients needed to reduce eribulin dosage. When the PTE therapy is referred to advanced HER2 positive breast cancer patients as a palliative chemotherapy, eribulin (1.1mg/m2) might be a reasonable dosage. Citation Format: Ishihara M, Tamaru S, Oda H, Yamashita Y, Tono Y, Mizuno T, Katayama N. A pilot study of pertuzumab, trastuzumab and eribulin for patients with advanced HER2 positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-21.

Venous thromboembolism (VTE) is a common complication in patients who have undergone major orthopedic surgery, but there are few predictors of VTE after major orthopedic surgery treated with an anticoagulant. We measured levels of fibrin-related markers (FRMs), such as D-dimer, soluble fibrin (SF), and fibrinogen and fibrin degradation products (FDPs) in 66 patients with acute-phase VTE, and 367 patients undergoing major orthopedic surgery. Plasma FDP, D-dimer, and SF levels were significantly higher in patients with acute VTE, but only FDP and D-dimer levels were significantly higher in subclinical VTE. Adequate cut-off levels of D-dimer were 2.2 μg/ml for diagnosing acute VTE and 1.5 μg/ml for diagnosing subclinical VTE. D-dimer of less than 1.9 or 0.7 μg/ml ruled out acute VTE or subclinical VTE. D-dimer of more than 1.3 μg/ml preoperatively showed a moderate risk for postoperative VTE. Measurement of FRMs is useful for evaluating the risk of subclinical or postoperative VTE in patients with major orthopedic surgery. In particular, FDP is the most valuable marker for diagnosing acute VTE, whereas D-dimer is the most valuable for diagnosing subclinical VTE or predicting VTE.

Several studies have reported risk factors for predicting cisplatin-induced acute kidney injury (AKI), including old age, female sex, smoking, hypoalbuminemia, hypokalemia, hypomagnesemia, a high body surface area, advanced cancer and the total dose of cisplatin administered. Recently, some studies have focused on the associations between genetic alterations in the genes coding for renal drug transporters, such as organic cation transporter 2 (OCT2), and the nephrotoxicity of cisplatin. However, genetic variants have not been fully elucidated for clinical use. Patients who had received cisplatin (≥50 mg/m2)-containing chemotherapy as a first-line treatment were considered as eligible for the present study. The occurrence of AKI and its associations with baseline characteristics, conventional biomarkers and single-nucleotide variants (SNV) were assessed. AKI was defined as an increase in the serum creatinine level of >0.3 mg/dl or to 1.5-2 times the baseline level. Genotyping was conducted using the DMET platform (DMET Plus), which characterizes 1,936 genetic variants (1,931 SNV and 5 copy number variations) in 231 genes. Between April 2014 and June 2016, a total of 28 patients (22 men and 6 women) were enrolled. AKI occurred in 8 of the 28 enrolled patients (28.6%). Univariate analyses demonstrated that the urinary β2-microglobulin level and body surface area were significantly higher in the AKI group (P

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.

Gram-negative bacteria import essential nutrients such as iron and vitamin B12 through outer membrane receptors. This process utilizes proton motive force harvested by the Ton system made up of three inner membrane proteins, ExbB, ExbD and TonB. ExbB and ExbD form the proton channel that energizes uptake through TonB. Recently, crystal structures suggest that the ExbB pentamer is the scaffold. Here, we present structures of hexameric complexes of ExbB and ExbD revealed by X-ray crystallography and single particle cryo-EM. Image analysis shows that hexameric and pentameric complexes coexist, with the proportion of hexamer increasing with pH. Channel current measurement and 2D crystallography support the existence and transition of the two oligomeric states in membranes. The hexameric complex consists of six ExbB subunits and three ExbD transmembrane helices enclosed within the central channel. We propose models for activation/inactivation associated with hexamer and pentamer formation and utilization of proton motive force., eLife digest Many biological processes that are essential for life are powered by the flow of ions across the membranes of cells. Similar to how energy is stored in the water behind a dam, energy is also stored when the concentration of ions on one side of a biological membrane is higher than it is on the other. When these ions then flow down this concentration gradient, the energy can be harnessed to power other processes. In many bacteria, the concentration of hydrogen ions, or protons, is higher on the outside of the cell. When the protons flow down the concentration gradient, a protein complex called the Ton system in the bacteria’s inner membrane harnesses the energy to transport various compounds, including essential nutrients, across the outer membrane, which is about 20 nanometres away. Toxins, and viruses that infect bacteria, can also hijack the Ton system to gain entry into these cells. This means that the Ton system could perhaps be targeted via drugs to treat bacterial infections. Though the Ton system is important, structural information on this protein family is limited. The Ton complex is composed of three proteins – ExbB, ExbD and TonB – located in the bacteria’s inner membrane. ExbB and ExbD together form a channel for the protons and the complex made from these two proteins can be thought of as the system’s engine. Maki-Yonekura et al. wanted to understand how the ExbB / ExbD complex works, which was challenging because the complex was not well suited to any single structural biology technique. To get around this issue, a combination of two techniques called X-ray crystallography and single particle cryo-EM were used. This approached revealed that the two proteins form complexes made up of either five or six ExbB subunits with one or three ExbD subunits, respectively. It also showed that the proteins transition between the two forms in a cell’s membrane. More of the larger six-unit complex (also called a “hexamer”) formed at higher pH. This is consistent with the increased flow of protons through the channel when the local conditions inside the cell become less acidic. Based on these results, Maki-Yonekura et al. propose that some subunits in the core of the complex rotate to harness the energy from the flow of protons, and the number of subunits in the complex changes when it switches to become active or inactive. The discoveries may provide a new vision of dynamic membrane biology. Further studies are now needed to see how general this mechanism is in biology, and the new structural information could also be used to help develop more anti-bacterial drugs.

A 64-year-old man visited his physician complaining of bilateral gynecomastia and left shoulder pain. Chest X-ray showed multiple bilateral masses in the lung, and he was referred to our hospital. Radiographical findings, elevation of serum total hCG, and histological findings of the cervical lymph node revealed multiple pulmonary, nodal, and brain metastases of poorly differentiated carcinoma of an unknown primary site with choriocarcinoma components. He was administered a regimen of reduced bleomycin, cisplatin, etoposide combination(reduced BEP regimen)to reduce the risk of acute respiratory failure with intra-alveolar hemorrhage related to post-chemotherapy early tumor necrosis. After chemotherapy, the tumor marker hCG levels were almost restored to normal levels, and radiography showed he had achieved a clinical partial response.

Efficacy of recombinant human soluble thrombomodulin (rhTM), which is frequently used to treat patients with disseminated intravascular coagulation (DIC), was compared with that of gabexate mesilate (GM), which was previously used routinely in the treatment of DIC patients in Japan. Although there was no significant difference in the resolution rates of the patients who were treated with rhTM and GM, the results of our analysis revealed that the mortality rate was significantly higher among infectious disease patients treated with GM than in those treated with rhTM. Levels of fibrinogen and fibrin degradation products (FDP), antithrombin (AT) activity, and thrombin AT complex (TAT) were significantly lower in the DIC patients with infectious diseases, while fibrinogen levels were high. FDP level, D-dimer, platelet count, PT ratio, and DIC score all showed significant improvement following rhTM treatment. There were no significant difference between survivors and non-survivors in terms of DIC score, FDP level, platelet count, AT activity, or in TAT, SF and PPIC levels before rhTM treatment. However, fibrinogen levels were significantly lower in non-survivors than in survivors. These results indicate that rhTM may be superior to GM for the treatment of DIC.

Abstarct The effective atomic number, Z eff , is measured by the ratio of linear attenuation coefficients at two different X-ray energies obtained by monochromatic X-ray computed tomography (CT). However, monochromatic X-rays are available in synchrotron facilities only. By defining narrow energy ranges in energy-resolved CT using a current mode “transXend” detector, Z eff is measured for sugar and K2HPO4 solutions, as well as for water and acrylic. The experimental Z eff values obtained for water and acrylic were in excellent agreement with the theoretical values. The experimental Z eff values obtained for the sugar and K2HPO4 solutions had larger errors.

A novel X-ray Bragg optics is proposed for variable-magnification of an X-ray beam. This X-ray Bragg optics is composed of two magnifiers in a crossed arrangement, and the magnification factor,M, is controlled through the azimuth angle of each magnifier. The basic properties of the X-ray optics such as the magnification factor, image transformation matrix and intrinsic acceptance angle are described based on the dynamical theory of X-ray diffraction. The feasibility of the variable-magnification X-ray Bragg optics was verified at the vertical-wiggler beamline BL-14B of the Photon Factory. For X-ray Bragg magnifiers, Si(220) crystals with an asymmetric angle of 14° were used. The magnification factor was calculated to be tunable between 0.1 and 10.0 at a wavelength of 0.112 nm. At various magnification factors (M≥ 1.0), X-ray images of a nylon mesh were observed with an air-cooled X-ray CCD camera. Image deformation caused by the optics could be corrected by using a 2 × 2 transformation matrix and bilinear interpolation method. Not only absorption-contrast but also edge-contrast due to Fresnel diffraction was observed in the magnified images.

To investigate the effect of moderate to severe endometriosis on mRNA expression of growth differentiation factor-9 (GDF-9) in the granulosa cells of mature follicles. Follicular fluid (FF) was obtained from 13 patients with moderate to severe endometriosis and 11 without endometriosis, as a control group, and GDF-9 protein levels in both were assayed by western blotting. mRNA expression by GDF-9 and LH receptor (LHR) in granulosa cells obtained from all patients in the study were investigated by StepOne Real-Time PCR. Although GDF-9 in FF from patients with endometriosis was no different from that of controls, GDF-9 mRNA expression in granulosa cells of patients with endometriosis was statistically significantly lower than for the control group. The number of oocytes and high-quality embryos was positively correlated with GDF-9 mRNA expression in controls but not in patients with endometriosis Moreover, a negative correlation was identified between GDF-9 mRNA expression and serum estrogen and progesterone levels in the control group, whereas no correlation was observed for the endometriosis group. Moderate to severe endometriosis can significantly reduce GDF-9 mRNA expression in the granulosa cells of patients with the disease compared with those without, thus causing poor oocyte maturation and lower embryo quality.

The “transXend” detector measures X-rays as electric currents and provides the energy distribution of the measured X-rays after analysis. Capabilities of material distinction, effective atomic number measurement, and low-dose exposure computed tomography (CT) with high K-edge contrast agent from the use of the transXend detector in energy-resolved CT have been demonstrated via the first-generation CT measurements. For application of the principle of the transXend detector to the third-generation CT for human subjects in future work, a method for fabrication of a two-dimensional transXend detector is proposed and demonstrated using a commercial two-dimensional detector and two kinds of strip absorbers. The energy-resolved CT is performed by placing a proposed absorber system in front of a two-dimensional detector, which is used for conventional current measurement CT., Published online: 29 Apr 2015

The activated partial thromboplastin time (APTT) waveform includes several parameters that are related to various underlying diseases. The APTT waveform was examined in various diseases. Regarding the pattern of APTT waveform, a biphasic pattern of the first or second derivative curve (DC) was observed in patients with hemophilia and patients positive for antiphospholipid (aPL) antibodies or coagulation factor VIII (FVIII) inhibitors. The time of the first and second DC and fibrin formation at 1/2 height were prolonged in patients with hemophilia, patients with inhibitors, patients positive for aPL, patients treated with anti-Xa agents, and patients with disseminated intravascular coagulation (DIC). These values all tended to decrease in pregnant women (at 28-36 weeks’ gestation). The height of the second derivative peak 1 was significantly lower in patients with hemophilia, patients with FVIII inhibitors, patients positive for aPL, patients treated with anti-Xa agents, and patients with DIC; these values tended to be significantly higher in pregnant women. The height of the first DC was significantly lower in patients who were positive for FVIII inhibitors and was significantly higher in patients treated with anti-Xa agents and pregnant women. The height of the first and second DC was useful for the analysis of hemophilia, FVIII inhibitor, and aPL.

The cutoff values of D-dimer levels for diagnosing or predicting the occurrence of deep vein thrombosis (DVT) were evaluated in preoperative patients and compared to those in non-DVT patients. The levels of 8 different D-dimers were measured using the latex agglutination method or enzyme immunoassay before surgery in 262 orthopedic surgery patients to diagnose subclinical DVT or predict postoperative DVT. There were 15 patients with subclinical DVT and 47 with postoperative DVT, but 200 patients had no DVT at all. All 8 plasma D-dimer values were significantly higher in the patients with subclinical or postoperative DVT than in those without DVT or in healthy volunteers. There were differences in the cutoff values between the assays highly sensitive for low D-dimer levels and wild-range assays of D-dimers. Some D-dimer assays might therefore be more useful than others for diagnosing low levels of D-dimer. Although the measurement of D-dimer levels was useful for diagnosing subclinical DVT and predicting the risk of DVT, the cutoff values for the diagnosis or prediction of DVT varied. The cutoff values for the prediction of postoperative DVT were ≥1.7 µg/mL (D-dimer A-D) and ≥1.0 µg/mL (D-dimer E-H).

OBJECTIVE Oocyte degeneration often occurs after intracytoplasmic sperm injection (ICSI), and the risk factor is low-quality oocytes. The follicular fluid (FF) provides a crucial microenvironment for oocyte development. We investigated the relationships between the FF volume aspirated from individual follicles and oocyte retrieval, oocyte maturity, oolemma stretchability, fertilization, and development. METHODS This retrospective study included data obtained from 229 ICSI cycles. Ovarian stimulation was performed according to a gonadotropin-releasing hormone antagonist protocol. Each follicle was individually aspirated and divided into six groups according to FF volume (

Prevention of deep vein thrombosis (DVT) is important in patients undergoing major orthopedic surgery. Although the detection of an elevated D-dimer level is useful for predicting DVT, it is not efficacious in postoperative patients being treated with anti-Xa agents. The soluble platelet glycoprotein VI (sGPVI) level is a marker of activated platelets, but not bleeding. Therefore, sGPVI levels are usually examined as a predictor of DVT in such patients. In the present study, 83 orthopedic patients were treated with 30 mg of edoxaban for prophylaxis of DVT. Fourteen patients developed DVT and 17 patients discontinued the prophylaxis due to decreased hemoglobin levels. Plasma levels of sGPVI in the patients were significantly higher after surgery than before surgery. On day 1, the sGPVI levels increased, while the platelet counts decreased. There were no significant differences in D-dimer, soluble fibrin, or FDP levels in orthopedic patients with and without DVT before surgery and on days 1, 4, and 8. Plasma sGPVI levels were significantly higher in the patients with DVT than in those without DVT on days 1 and 4. Plasma levels of D-dimer were significantly higher in patients with withdrawal than in those without. However, there were no significant differences in sGPVI levels between those with and without withdrawal. As D-dimer levels are known to increase in patients with withdrawal, this parameter is not useful for evaluating the risk of DVT in these patients. In contrast, the sGPVI level is not increased in those with withdrawal and may therefore be useful for evaluating the risk of DVT in postoperative patients treated with an anticoagulant.

Dienogest, a synthetic progestin, has been shown to be effective against endometriosis, although it is still unclear as to how it affects the ectopic endometrial cells. Decorin has been shown to be a powerful endogenous tumor repressor acting in a paracrine fashion to limit tumor growth. Our objectives were to examine the direct effects of progesterone and dienogest on thein vitroproliferation of the human ectopic endometrial epithelial and stromal cell lines, and evaluate as to how decorin contributes to this effect. We also examinedDCNmRNA expression in 50 endometriosis patients. The growth of both cell lines was inhibited in a dose-dependent manner by both decorin and dienogest. Using a chromatin immunoprecipitation assay, it was noted that progesterone and dienogest directly induced the binding of the decorin promoter in the EMOsis cc/TERT cells (immortalized human ovarian epithelial cells) and CRL-4003 cells (immortalized human endometrial stromal cells). Progesterone and dienogest also led to significant induced cell cycle arrest via decorin by promoting production of p21 in both cell lines in a dose-dependent manner. Decorin also suppressed the expression of MET in both cell lines. We confirmed thatDCNmRNA expression in patients treated with dienogest was higher than that in the control group. In conclusion, decorin induced by dienogest appears to play a crucial role in suppressing endometriosis by exerting anti-proliferative effects and inducing cell cycle arrest via the production of p21 human ectopic endometrial cells and eutopic endometrial stromal cells.