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Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Boston Scientific Japan Background Transcatheter left atrial appendage closure (LAAC) provides an alternative to oral anticoagulation for thromboembolic risk reduction in patients with nonvalvular atrial fibrillation (AF). A meta-analysis of previous two randomized trials reported improved rates of hemorrhagic stroke, cardiovascular/unexplained death, and nonprocedural bleeding compared to warfarin (1). Recently, the next-generation LAAC device, the Watchman FLX system, became available, and showed a low incidence of adverse events and a high incidence of anatomic closure (2). This transcatheter stroke prevention has already been approved in Asian countries. However, there is little data of LAAC in Asian population. Purpose This study sought to assess efficacy and safety of LAAC for patients with nonvalvular AF in Asia. Methods The TERMINATOR (Transcatheter Modification of Left Atrial Appendage by Obliteration with Device) registry is a multicenter nonrandomized study in Japan. This enrolled patients who underwent LAAC in 23 Japanese institutions. The LAAC was indicated for patients with nonvalvular atrial fibrillation in whom oral anticoagulation is required, but who have a risk of bleeding (history of BARC type 3 bleeding or HAS-BLED score ≥3 points). Baseline patient and procedural characteristics and clinical outcomes were evaluated. Results A total of 729 patients were enrolled between September 2019 and November 2021. The mean age was 74.9±8.8 years and the mean CHA2DS2-VASc score was 4.7±1.5. The Watchman generation 2.5 and FLX system were used in 469 (64.3%) and 260 patients (35.7%), respectively. Procedural success was achieved in 722 patients (99.0%). In-hospital adverse events were as follows; 6 tamponades (0.8%), 3 pericardial effusion (0.4%), 2 device embolization (0.3%), no stroke (0%), and no death (0%). During follow-up, device-related thrombus and all-cause death were reported in 16 (2.2%) and 23 patients (3.2%), respectively. Conclusions LAAC with the Watchman system provides compatible efficacy and safety outcomes in Asian population.

Background To compare the observed and individual predicted mortalities according to the SYNTAX score II 2020 (SSII-2020) in the all-comers SYNTAX population, and retrospectively assess the appropriateness of revascularization with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with three vessel disease (3VD) and/or left main disease (LMCAD). Methods Internal and external validation of the SSII-2020 to predict 10-year all-cause death was performed in the respective randomized and registry SYNTAX populations. Differences in individual predicted mortalities following CABG or PCI were ranked and displayed with the observed mortalities. The proportions of screened patients deriving a survival benefit from CABG or PCI were determined retrospectively. Results A total of 2602 participants (as-treated population) were included in the randomized and registry cohorts. In the randomized cohort, all-cause mortality at 10 years, as an average treatment effect, was 23.8% (199/865) with CABG and 28.6% (249/901) with PCI, with a differential survival benefit of 4.6% (95% CI: 0.58% to 8.7%, log-rank p value=0.023). In the CABG and PCI registries, mortalities were 27.8% (167/644) and 55.4% (99/192), respectively. Calibration and discrimination of the SSII-2020 was helpful in CABG and PCI patients in the randomized and registry cohorts. In the PCI registry, the SSII-2020 underestimated mortality since specific comorbidities that entail high mortality are not included in the formula (C-index: 0.72, intercept: 0.38, slope: 0.66), whilst in the CABG registry, it predicted mortality with a helpful calibration and discrimination (C-index: 0.70, intercept: 0.00, slope: 0.76). The proportions of patients with a predicted survival benefit following CABG and PCI were respectively 78.3% (1383/1766) and 21.7% (383/1766) in the randomized cohort, and 82.4% (2143/2602) and 17.7% (459/2602) in the whole SYNTAX trial population. Conclusion In the randomized and registry cohort of this all-comers population with 3VD and/or LMCAD, there was reasonable agreement between the individual predicted and observed mortalities after CABG or PCI, such that the predicted 10-year survival benefit might be helpful in determining the appropriateness of each modality of revascularization. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The SYNTAX Extended Survival study was supported by the German Foundation of Heart Research (Frankfurt am Main, Germany). The SYNTAX trial, during 0-5 years follow-up, was funded by Boston Scientific Corporation (Marlborough, MA, USA). Both sponsors had no role in the study design, data collection, data analyses, and interpretation of the study data, nor were involved in the decision to publish the final manuscript. The principal investigators and authors had complete scientific freedom.

Objectives Elective unilateral neck irradiation in well-lateralized tonsil carcinoma for N2b disease is controversial. Metrics regarding nodal burden beyond the N-stage to define the upper limit of this de-escalation approach remain limited. We investigated the role of nodal number, level, and volume on outcomes in patients with well-lateralized tonsil carcinoma treated with this approach. Methods A total of 37 patients received radiotherapy (RT) with unilateral neck coverage for well-lateralized tonsil cancer. Of patients, 95% had p16+ disease, and 81% were staged with positron emission tomography/computed tomography. The majority of patients received definitive chemoradiation on prospective de-escalation trials. Ten patients had ipsilateral neck dissections and were treated adjuvantly. The median RT dose to the ipsilateral neck (generally II-IV) was 45 Gy. The effects of nodal number, max dimension, volume, and level on recurrence-free survival (RFS) and overall survival (OS) were to be analyzed via Cox proportional hazards (Cox-PH). Results After a median follow-up of 3.9 years, two-year RFS and two-year OS were 100% and 97%, respectively. Given the 0% contralateral recurrence rate, Cox-PH analysis was not performed. Of patients, 70% were American Joint Committee on Cancer (AJCC) 7th edition N2b, with a median number of nodes, number of nodal levels, max dimension, and volume of two, one, 3.4 cm, and 15.6 cc, respectively. There were several patients with low-lying nodes; aggregate nodal volume measured was up to 85.4 cc. Conclusion Unilateral neck irradiation in well-lateralized tonsil carcinoma resulted in no contralateral recurrence. Nodal volume, level, and number do not seem to have a significant impact on outcomes.

Antibody-mediated rejection is a major cause of graft injury and contributes to failure of pig xenografts in nonhuman primates (NHPs). Most 'natural' or elicited antibodies found in humans and NHPs are directed against pig glycan antigens, but antibodies binding to swine leukocyte antigens (SLA) have also been detected. Of clinical importance is (i) whether the presence of high levels of antibodies directed towards human leukocyte antigens (HLA) (i.e., high panel-reactive antibodies) would be detrimental to the outcome of a pig organ xenograft; and (ii) whether, in the event of sensitization to pig antigens, a subsequent allotransplant would be at increased risk of graft failure due to elicited anti-pig antibodies that cross-react with human HLA or other antigens.A literature review of pig-to-primate studies indicates that relatively few highly-HLA-sensitized humans have antibodies that cross-react with pigs, predicting that most would not be at increased risk of rejecting an organ xenograft. Furthermore, the existing evidence indicates that sensitization to pig antigens will probably not elicit increased alloantibody titers; if so, 'bridging' with a pig organ could be carried out without increased risk of subsequent antibody-mediated allograft failure.These issues have important implications for the design and conduct of clinical xenotransplantation trials.

Burrowing nematode (Radopholus similis) causes severe stunting and yield reduction in anthurium (Anthurium andraeanum) cut flower production. Two field trials were conducted at commercial grower farms to test the efficacy of fluopyram or fluopyram + trifloxystrobin for managing burrowing nematodes. Nematode population densities in roots and cinder media were evaluated during the trial in addition to cut flower yield and canopy cover. In the first trial, the nematode population in roots was reduced by 57% after two applications of fluopyram 3 months apart. As plant health improved, the increasing anthurium root weight supported higher nematode populations. After 14 months, fluopyram-treated plots had 43% more green canopy cover and a 53% increase in flower production compared with the untreated control plots. At a second location, population densities of burrowing nematode were reduced in roots after one application of fluopyram + trifloxystrobin and remained low with quarterly applications. Nematode populations were initially reduced in fluopyram-treated plots followed by a resurgence as demonstrated in the other trial. Ten months after the initial treatment, flower yield was greater in fluopyram + trifloxystrobin-treated plots with more large and extra-large flowers produced. Canopy cover was 45% and 22% greater with fluopyram + trifloxystrobin and fluopyram applications, respectively. Fluopyram shows potential for management of burrowing nematodes in anthurium by improving plant vigor and cut flower production.

The CLASP2 (Chromospheric LAyer SpectroPolarimeter 2) sounding rocket mission was launched on 2019 April 11. CLASP2 measured the four Stokes parameters of the Mg II h & k spectral region around 2800 Angstroms along a 200 arcsecond slit at three locations on the solar disk, achieving the first spatially and spectrally resolved observations of the solar polarization in this near ultraviolet region. The focus of the work presented here is the center-to-limb variation of the linear polarization across these resonance lines, which is produced by the scattering of anisotropic radiation in the solar atmosphere. The linear polarization signals of the Mg II h & k lines are sensitive to the magnetic field from the low to the upper chromosphere through the Hanle and magneto-optical effects. We compare the observations to theoretical predictions from radiative transfer calculations in unmagnetized semi-empirical models, arguing that magnetic fields and horizontal inhomogeneities are needed to explain the observed polarization signals and spatial variations. This comparison is an important step in both validating and refining our understanding of the physical origin of these polarization signatures, and also in paving the way toward future space telescopes for probing the magnetic fields of the solar upper atmosphere via ultraviolet spectropolarimetry., 14 pages, 5 figures, to be published in the Astrophysical Journal (ApJ), initially submitted May 2022, revised submission July 2022

Citrus is a globally cultivated fruit crop that has been heavily industrialised to manufacture food products. It is commonly sought out for its nutritional benefits. However, parallel to rapid industrialisation, parts of the crop’s physical composition (inner and outer peel, seeds etc.) are often discarded to the environment as waste. Recent advancement in technology has led researchers to look for alternatives to recover potential therapeutic compounds from citrus fruit waste, directly extending the life of the waste and indirectly solving waste management concerns. Citrus fruit peels are especially rich in flavonoid compounds, a subclass of the many phytochemicals largely present in the body of the fruit. Flavonoid compounds have the capacity to be act as antioxidants, leaving room for the potential of the flavonoids present in fruit waste to be commercialized as a natural bioresource. This study aims to extract and recover the flavonoid compounds present in the peels of citrus fruits calamansi (Citrus microcarpa), kaffir lime (Citrus hystrix), and key lime (Citrus aurantiifolia) via ethanolic extraction and test the presence of recovered flavonoid compounds via alkaline reagent test. In addition, this study also aims to measure the antioxidant activities of all three citrus fruit peel samples via the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay. This study hopes to shed light on the therapeutic potential of citrus fruit peel waste as a bioresource which could benefit communities in the future.

The coconut tree, Cocos nucifera L., is planted for a variety of purposes. According to the Malaysian Agricultural Research and Development Institute (MARDI), rising coconut production has resulted in an increase in agricultural waste (coconut husk) in Malaysia (536,606 million coconuts in 2018 compared to 22,167 million coconuts in 2016). More than 60% of solid waste degradation in the environment is caused by the manufacture of coconut husks each year. Recycling coconut waste, particularly coconut husk, as a source of natural compounds offers environmental and economic benefits. The objectives of this study are to extract the flavonoid compounds from coconut husk from three different types of coconut fruit (Pandan Coconut, MAWA Coconut and Yellow Coconut) by using ethanolic solvent and compare them. Secondly, the antioxidant activity of coconut husk was determined by using the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. Thirdly, the alkaline reagent test was used to determine the presence of flavonoid compounds. The flavonoid compounds are existed in the coconut husk ethanolic extract and it have the antioxidant activity. IC50 of the standard compounds, ascorbic acid was 9.2 μg/ml. The most powerful radical scavenging effect was seen in Yellow Coconut husk extract, which had an IC50 value of 8.4 μg/ml. Flavonoids found in the husk of coconuts are known to have antioxidant properties. This shows that coconut husk extract has enormous potential as a natural preservative and a good bioresource of antioxidants.

Background: The standard of care for T4 laryngeal cancer patients (pts) includes surgical resection followed by adjuvant radiation (RT) with or without chemotherapy (CRT). Our institution has experience with organ preservation (OP) for this population. This study assessed racial differences in survival outcomes of T4 larynx cancer pts pursuing OP.Method: T4 larynx pts at our institution who received definitive CRT were identified from January 1990 to December 2019. Race was self-reported. CRT consisted of 4-6 alternating weekly cycles of paclitaxel (100mg/m2 on d1), infusion 5-fluorouracil (600mg/m2/d on d1-5), hydroxyurea (500mg PO BID), and either 2 Gy daily or 1.5 Gy twice-daily RT (TFHX). Clinicodemographic characteristics: age at diagnosis, sex, diagnosis period (10-year), nodal stage, tracheostomy or g-tube use, chemotherapy, RT dose or fractionation, and clinical trial enrollment were compared using Student’s t, X2, or Fisher’s exact tests. The Kaplan-Meier method was used to estimate 2- and 5-year distant metastasis-free survival (DMFS), overall survival (OS), and laryngectomy free-survival (LFFS), overall and by race. Multivariable Cox proportional hazards were modeled for survival outcomes between Black and White pts to report adjusted hazard ratios (aHR) and 95% confidence intervals (CI).Results: Of 104 pts, 45% were Black, 55% were White, mean age at diagnosis was 60 (SD 10) years, 66% were male, and median follow-up time was 52 (IQR: 24-99) months. The rate of Black pts decreased from 71% (1990-1999), 54% (2000-2009) to 28% (2010-2019). 64% of Black pts enrolled in a clinical trial compared to 51% of White pts. A higher rate of Black pts required tracheostomy before treatment than White pts (87% vs. 47%, p Citation Format: Jared H. Hara, Jason Q. Freeman, Sara E. Kochanny, Naomi S. Ecanow, Ari J. Rosenberg, Alexander T. Pearson, Zhen Gooi, Brandon J. Baird, Elizabeth A. Blair, Nishant Agrawal, Everett E. Vokes, Daniel J. Haraf, Aditya Juloori. Racial differences in organ preservation with definitive chemoradiotherapy among patients with T4 laryngeal squamous cell carcinoma [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A085.

The purpose of this prospective study was to assess the ability of plasma vascular endothelial growth factor-A short isoforms (pVEGF-Asi) to predict bevacizumab (BV) efficacy and to explore other circulating biomarkers in metastatic colorectal cancer (mCRC) patients treated with modified FOLFOX6/XELOX plus BV (mFOLFOX6/XELOX + BV).Pre-treatment plasma samples were collected from 100 mCRC patients receiving first-line chemotherapy with mFOLFOX6/XELOX + BV. The plasma levels of 11 angiogenesis-associated molecules, including pVEGF-Asi and 22 cancer-associated gene mutations in circulating tumor DNA, were analyzed. For the primary endpoint, we assumed that the hazard ratio (HR) for progression-free survival (PFS) calculated using a Cox proportional hazards model was1.15, comparing patients with a high versus those with a low pVEGF-Asi level divided according to the median pVEGF-Asi value.The median value of pVEGF-Asi was 37 (range 6.5-262) pg/ml. The HR for PFS between the high and low pVEGF-Asi patient groups was 1.3 [95% confidence interval (CI) 0.8-2.1; log rank, P = 0.25], which was larger than the predefined threshold of 1.15. The multivariate analysis demonstrated that PFS was significantly associated with plasma intercellular adhesion molecule-1 (pICAM-1) (≥190.0 versus190.0 ng/ml; HR 2.1; 95% CI 1.3-3.5), RAS (mutant versus wild; HR 2.5; 95% CI 1.5-4.3), and FBXW7 (mutant versus wild; HR 2.8; 95% CI 1.2-6.8), whereas overall survival was significantly associated with pICAM-1 (HR 2.0; 95% CI 1.1-3.7) and RAS (HR 2.6; 95% CI 1.5-4.6).The addition of BV was unable to compensate for the poor PFS associated with a high pVEGF-Asi level, suggesting that pVEGF-Asi is unlikely to be a good predictive biomarker of the efficacy of mFOLFOX6/XELOX + BV therapy. The clinical significance of circulating ICAM-1, mutant RAS, and mutant FBXW7 levels should be studied further.

[Background] JBCRG-16 (NeoLath) study is a five-arm study to evaluate the efficacy and safety of lapatinib and trastuzumab (6 weeks) followed by lapatinib and trastuzumab plus weekly paclitaxel (12 weeks) with/without prolongation of anti-HER2 therapy prior to chemotherapy (18 vs. 6 weeks), and with/without endocrine therapy in patients with HER2+ and/or estrogen receptor (ER)+ disease. The primary endpoint was pathological complete response (pCR) rate and pCR rate was 47.9% (Masuda N, et al. Breast Cancer, 2018). It is recently reported that microRNAs (miRNAs) are stably present in serum and potentially useful in the diagnosis and evaluation of treatment of cancer. We performed exploratory analysis of detecting pCR by comprehensive analysis of serum miRNAs. [Materials and Methods] Serum samples were obtained from study participants who received neoadjuvant systemic therapy with trastuzumab, lapatinib and paclitaxel. Before profiling of miRNAs, the overall serum samples were randomly devided in two sets, namely the training set and the testing set with pCR or non-pCR. Pathological complete response (pCR) was defined as the absence of residual invasive cancer of the resected breast specimen and all sampled regional lymph nodes. Total RNA was extracted from a 300 ul serum sample using 3D-Gene® RNA extraction reagent from a liquid sample kit. A comprehensive quantitative expression analysis of miRNA was performed using the by DNA chip 3D-Gene®, which was designed to detect 2565 miRNA sequences registered in miRBase release 21 (http://www.mirbase.org/). The expression level of miRNAs were normalized by internal control (miR-2861, miR-149-3p and miR-4463). Clinicopathological data was retrieved from trial data. [Results] A total of 112 samples were obtained. Seventy were used in the training set and others were used in the testing set. Median age was 54 years (range 26-70). Sixty-five (58%) patients were pre-menopausal. ER was positive in 59 patients (52.7%). Fourteen (12.5%) were T1c, 78 (69.6%) were T2 and 20 (17.9%) were T3. Fifty-seven (50.9%) patients were node-positive. Fifty-nine (52.7%) patients achieved pCR. The formula with the combination of three miRNAs (miR-A, miR-B, miR-C) was found to be able to predict pCR. This set had a sensitivity of 62.5%, specificity of 86.7% and accuracy of 71.8% in the testing cohort. Area under curve of receiver operationg characteristic curve was 0.753. [Conclusion] The combination of three miRNAs has potential to predict pCR in patients who received neoadjuvant combination therapy of trastuzumab, lapatinib and paclitaxel in HER2-positive primary breast cancer. The further analysis of changing expression of miRNAs during neoadjuvant therapy is underway and further results will be presented in the symposium. Citation Format: Shimomura A, Masuda N, Kawauchi J, Takizawa S, Ichikawa M, Matasuzaki J, Kuroi K, Hara H, Yamamoto N, Inoue K, Suganuma N, Aogi K, Ohno S, Tamura K, Ochiya T, Toi M. Predicting pathological complete response by the combination of microRNAs in patients with HER2-positive primary breast cancer who received neoadjuvant combination therapy of trastuzumab, lapatinib and paclitaxel: Results from JBCRG-16 (NeoLath) study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-16.

Total marrow radiation is an emerging treatment modality used in patients undergoing stem cell transplantation. We present a rare case of a patient undergoing total marrow irradiation with concurrent ablative stem cell transplantation with local failures in two out-of-field areas that were not included in the clinical target volume A 31-year-old female patient initially presented with abdominal pain secondary to chronic myelogenous leukemia. She underwent dasatinib treatment for years, but subsequently developed recurrence and underwent consolidation systemic chemotherapy followed by allogeneic stem cell transplantation with adjuvant total marrow irradiation. Several months later, she noticed increased left jaw swelling and dysphagia with associated right ankle swelling. Biopsy of the right ankle and left mandible were consistent with recurrent myeloid sarcoma. This case report suggests that inclusion of the mandible and lower extremities may be necessary when performing total marrow radiation.

Summary The purpose of this paper is to report on the relationship between lymphoscintigraphic findings and the operative results of lymphaticovenous anastomosis (LVA) as well as the resection of genital acquired lymphangiectasia (GAL). Seventeen patients with GAL who underwent lymphoscintigraphy between April 2012 and June 2016 were included in this retrospective study. LVA and GAL resections were performed for 14 patients. The GALs were resected in a spindle shape to the full thickness of the genital skin, and the wounds were closed primarily. Following the procedure, we investigated the recurrence rate and compared the results with the lymphoscintigraphic findings. The average follow-up period was 19.2 months. Six patients were without recurrence, and eight patients experienced a small recurrence of GAL. The average period from operation to recurrence was 16.8 months (range: 1–41 months). Of the six patients who had genital accumulation in lymphoscintigraphy, two patients experienced recurrence (33.3%), whereas six of the eight patients without genital accumulation experienced recurrence (75.0%). The frequency of cellulitis was observed to be reduced postoperatively in all patients, and recurrence was observed in one patient at 11 months postoperatively. In conclusion, lower limb LVA combined with genital skin tumor resection was effective for preventing the recurrence of GAL in patients who demonstrated communication between the lymphatic vessels in the lower limb and genitals. This procedure also had the benefit of reducing the frequency of cellulitis for an average of 19.2 months of follow-up.

Analysis of sound pressure data obtained from audio recordings of night-time Eleutherodactylus coqui chorusing was used to estimate population density of calling male coqui frogs in the major Hawaiian island populations. Study plots 400 m2 in size (20 by 20 m; n = 32) were established on the islands of Hawaii and Maui to provide venues for field counting calling male frogs to investigate the ground truth relationship with the recorded sound pressure data. Male coqui frogs emit a two-note ‘co-qui’ advertisement call at regular intervals. Exploiting the temperature-related and relatively consistent male coqui call repetition rate and the average emitted ‘co’ call sound pressure level (70.4 dB at 1 m), cue counts obtained from a correlation process available in the program Raven were also used to estimate the density of calling male coqui. The study methodology included comparing linear regression results between the field-counted frogs and the number of frogs obtained from the cue count method. Both...

The dry micro-blasting effects on the fracture resistance of PVD-AlTiN coated cemented carbide cutting tools were studied. The AlTiN coatings with the composition of (Al0.60Ti0.40)N were deposited using cathodic arc evaporation method. The two types of coatings, which had a compressive residual stress of 0.1 GPa (Low-σ) and 2.6 GPa (High-σ), were prepared. The coated samples were subjected to the dry micro-blasting treatment by Al2O3 grains at pressures of 0.11 MPa, 0.14 MPa, and 0.17 MPa. A milling test using AISI 4140 (42CrMo4) steel as the workpiece material was carried out for evaluating the fracture resistance of the prepared samples. The tool life cutting distance of Low-σ sample micro-blasted at 0.14 MPa and 0.17 MPa was 2.9 m and 7.2 m, respectively, largely extended as compared to that of as-deposited Low-σ sample, 1.0 m. On the other hand, the tool life of High-σ sample micro-blasted at 0.14 MPa was 8.6 m, almost same with that of as-deposited High-σ one, 8.8 m. Those results indicate that the dry micro-blasting effect on the fracture resistance is larger for the Low-σ coating than for the High-σ one.

For those with total hearing loss, there are no direct remedies except for electronic (i.e. cochlear) implants. They are invasive and do not always function in a satisfactory manner. Although sign language opens the window to a rich culture but communication with the hearing world is hindered. Lip reading can bridge that gap but communication is not without some stress. Inability to detect possible life threatening situations outside the visual field also affects the quality of life for those without the ability to hear. If the hearing process is viewed from the point of system engineering, there is a sound source and air is the transmission medium to the ear. The hearing structure of the ear converts mechanical vibrations to electrical signals that are then transmitted through nerve paths to the section of the brain where sound signals are processed. In most cases of total hearing loss, the hearing structure of the ear is non-functional. A cochlear implant bypasses this hearing structure. It electronically converts sounds from the air into their frequency components and feeds them into transmission nerve paths to the brain as electrical signals. This system-engineering point of view suggests that other pathways to the brain might be explored. The following section considers the visual pathway.

Energies, E1, M1, E2, M2 transition rates, oscillator strengths, and lifetimes from relativistic configuration interaction calculations are reported for the states of the 2p 6 , 2p 5 3s, 2p 5 3p, and 2p 5 3d, configurations in all Ne-like ions between Mg III and Kr XXVII. Core-valence and core-core correlation effects are accounted for through SD-expansions to increasing sets of active orbitals. The Breit interaction and leading QED effects are included as perturbations. The results are compared with experiments and other recent benchmark calculations. In Mg III, Al IV, Si V, P VI, S VII, and Ar IX, for which experimental energies are known to high accuracy, the mean error in the calculated energies is only 0.011%.

Background TAS-117 is a novel highly potent and selective oral allosteric AKT inhibitor. This study investigated the safety, efficacy, pharmacokinetics, pharmacodynamics, and pharmacogenomics profiles of TAS-117 in patients (pts) with advanced solid tumors, for whom no standard treatment remains. Methods The primary objective was to evaluate the safety profile of TAS-117, including the identification of the maximum tolerated dose (MTD) and the recommended dose (RD) with regimen (RR) in a 21-day cycle. Dose escalation was assessed in a once-daily repeated dosing regimen (QD), starting at 4 mg/day, with an accelerated titration design. Dose-limiting toxicity (DLT) was evaluated in a first cycle. After RD and RR were determined, pts with endometrial cancer (EC) harboring PIK3CA or AKT gene alterations or ovarian clear cell carcinoma (OCC) were enrolled for further safety evaluation. Results TAS-117 was administered QD (n = 12) and in a 4 days on/3 days off regimen (4d/3d) (n = 10). The dose was escalated to 24 mg/day in QD dosing and 32 mg/day in 4d/3d; the MTD was not reached. The DLT was a grade 3 rash maculo-papular at 32 mg/day in 4d/3d dosing. The RD and RR were determined as TAS-117 24 mg/day and 4d/3d. As of 24 Apr 2019, 42 pts (15 with PIK3CA-mutated (mt) EC, 7 with AKT-altered EC, and 20 with OCC) were enrolled, and safety profiles were investigated. The common (≥30%) treatment-related adverse events (TRAEs) were rash maculo-papular (grade 3, observed in 42.5% of pts), stomatitis, hyperglycemia, white blood cell decrease, and neutrophil count decreased. Common TRAEs, especially rash maculo-papular, were manageable with dose reduction, dose interruption, or symptomatic therapy. TAS-117 exposure tended to increase in a dose-dependent matter. In efficacy-evaluable pts, objective responses were observed in 1 pt with PIK3CA-mt EC and 5 pts with OCC. The disease control rate was 61.5% in 13 pts with PIK3CA-mt EC, 80.0% in 5 pts with AKT-altered EC, and 37.5% in 16 pts with OCC. Conclusions TAS-117 had a manageable safety profile with clinical antitumor activity in pts with advanced solid tumors. Further investigation of the drug in a combination therapy is in preparation. Clinical trial identification JapicCTI-152780. Legal entity responsible for the study Taiho Pharmaceutical Co., Ltd. Funding Has not received any funding. Disclosure S. Takahashi: Honoraria (self), Research grant / Funding (self): Eisai; Honoraria (self): Bristol-Myers-Squibb; Honoraria (self), Research grant / Funding (self): Taiho; Honoraria (self): Bayer; Research grant / Funding (self): MSD; Research grant / Funding (self): Astrazeneka; Research grant / Funding (self): Quintiles; Research grant / Funding (self): IQVIA; Research grant / Funding (self): Daiichi-Sankyo; Research grant / Funding (self): Ono pharmaceutical. D. Aoki: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical Co., Ltd.; Honoraria (self), Advisory / Consultancy: AstraZeneca K.K.; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd.; Honoraria (self), Advisory / Consultancy: MSD K.K.. K. Yonemori: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self), Research grant / Funding (institution): Taiho; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Ono; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): ICON Japan; Research grant / Funding (institution): Kissei; Research grant / Funding (institution): Kyowa Hakko Kirin; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Nippon Kayaku; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): 3D MATRIX. H. Hara: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Honoraria (self): Yakult Honsha; Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Takeda; Honoraria (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): MSD; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Incyte. K. Hasegawa: Honoraria (self), Research grant / Funding (self): Daiichi-Sankyo; Honoraria (self): Chugai; Honoraria (self): Nippon Kayaku; Honoraria (self): Bayer; Honoraria (self): AstraZeneca; Advisory / Consultancy: MSD; Research grant / Funding (self): OncoTherapy Science; Research grant / Funding (self): Yakult Honsha. K. Takehara: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Kyowa Kirin; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Nippon Kayaku; Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Treumo; Speaker Bureau / Expert testimony: Ono; Speaker Bureau / Expert testimony: Daiichi Sankyo; Speaker Bureau / Expert testimony: Chugai Pharma; Speaker Bureau / Expert testimony: Eisai. K. Harano: Honoraria (self): Eisai; Honoraria (self), Advisory / Consultancy: Taiho; Honoraria (self): AstraZeneca; Honoraria (self), Non-remunerated activity/ies: Chugai; Advisory / Consultancy: Takeda. E. Noguchi: Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Nippon Kayaku; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Chugai; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): ICON Japan; Research grant / Funding (institution): Kissei; Research grant / Funding (institution): Kyowa Hakko Kirin; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): 3D MATRIX. T. Doi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy: Otsuka; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Kyowa Hakko Kirin; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: AstraZeneka; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Daiichisankyo; Advisory / Consultancy, Research grant / Funding (institution): Dainippon Sumitomo; Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Taiho, Zenyaku Kogyo, Astellas; Research grant / Funding (institution): Janssen, Eisai, Sanofi; Research grant / Funding (institution): NanoCarrier, Quintiles, Pfizer; Research grant / Funding (institution): Bristol-myers; Research grant / Funding (institution): Bristol-Myers-Squibb. All other authors have declared no conflicts of interest.

This study was designed to determine whether oral streptococci modulate the growth and functions of regulatory T cells. Heat-killed cells of wild-type strains of Streptococcus gordonii and Streptococcus mutans induced the Toll-like receptor 2 (TLR2) -mediated nuclear factor-κB (NF-κB) activation, but their lipoprotein-deficient strains did not. Stimulation with these streptococci resulted in a significant increase in the frequency of CD4(+) CD25(+) Foxp3(+) regulatory T cells in splenocytes derived from both TLR2(+/+) and TLR2(-/-) mice, but the level of increase in TLR2(+/+) splenocytes was stronger than that in TLR2(-/-) splenocytes. Both strains of S. gordonii enhanced the proliferation of CD4(+) CD25(+) Foxp3(+) regulatory T cells isolated from TLR2(+/+) mice at the same level as those from TLR2(-/-) mice in an interleukin-2-independent manner. However, wild-type and lipoprotein-deficient strains of both streptococci did not enhance the suppressive activity of the isolated regulatory T cells in vitro, but rather inhibited it. TLR ligands also inhibited the suppressive activity of the regulatory T cells. Inhibition of the suppressive activity was recovered by the addition of anti-IL-6 antibody. Pretreatment of antigen-presenting cells with the NF-κB inhibitor BAY11-7082 enhanced the suppressive activity of the regulatory T cells. These results suggested that interleukin-6 produced by antigen-presenting cells inhibits the suppressive activity of the regulatory T cells. Wild-type strain, but not lipoprotein-deficient strain, of S. gordonii reduced the frequency of CD4(+) CD25(+) Foxp3(+) regulatory T cells in the acute infection model, whereas both strains of S. gordonii increased it in the chronic infection model mice. Hence, this study suggests that oral streptococci are capable of modulating the growth and functions of regulatory T cells in vitro and in vivo.

Background: Studies have suggested that HOXB9 expression in breast cancer cells promotes cellular invasiveness, metastatic ability, and tumor neovascularization in the surrounding tissue in in vitro and in vivo assays. These findings imply that HOXB9 overexpression may alter tumor-specific cell fates and the tumor stromal microenvironment, contributing to breast cancer progression (Hayashida et al., PNAS 2010). We previously reported that clinical outcomes were significantly decreased in HOXB9-positive patients (Seki et al., Ann Surg Oncol. 2012). In this study, it was demonstrated that HER2 type and basal-like breast cancers were more associated with HOXB9 positivity than the luminal type. Therefore, it is required to identify more detail clinicopathological features most likely to be associated with HOXB9 overexpression. We investigated the correlation between HOXB9 overexpression and clinicopathological variables, and clinical outcomes in estrogen receptor (ER)-positive breast cancer patients. Patients and methods: A consecutive series of 118 ER-positive breast cancer patients who underwent surgical treatment were examined. HOXB9 expression was analyzed immunohistochemically using the anti-human HOXB9 polyclonal antibody. Immunostaining of Ki-67 and CD31 were also performed to evaluate tumor proliferation and angiogenesis. Results: The median age was 59 years and median observation period was 62 months. Of 118 tumor specimens immunostained for HOXB9, 49 specimens (41.5%) were positive staining. Univariate logistic regression revealed high nuclear grade (p < 0.001), lymph node metastasis (p = 0.019), the number of micro vessel density (p < 0.001) and the Ki-67 ratio (p = 0.019) as significant variables associated with HOXB9 positive. The disease-free survival (DFS) was significantly decreased in HOXB9-positive patients (HR = 4.262, 95% CI = 1.531 — 11.869, p = 0.006) A Multivariate analysis indicated that HOXB9 expression was the only independent prognostic factor for DFS (HR = 3.380 95% CI=1.160 — 9.849, p = 0.026). Conclusions: Our results suggest that HOXB9 expression promoting the cellular proliferation and the angiogenesis in tumor microenvironment is a significant prognostic factor for clinical outcomes in ER-positive breast cancer patients. Further study might help to determine the application of anti-angiogenic therapy for metastatic ER-positive breast cancer patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-09-08.

Cast aluminium alloy has sometimes been utilised for various products after applying plastic working combining with heat treatment. The thermomechanical treatment will bring not only positive effects (workhardening and grain refinement) but also negative effects (damage on particles and increase of porosity) on the mechanical properties in the cast aluminium alloy. In this study, the relation between microstructures and fatigue properties has been investigated in hot forged and heat treated Al–Si–Mg casting alloys with different Si contents. An ex situ observation of fatigue crack propagation showed different crack behaviours depending on the microstructures arising from the different Si contents. The crack in the α phase propagated quickly in comparison with the crack located in the eutectic and grain boundaries in the Al–3·1Si–0·4Mg alloy. The crack propagation rate was not constant in the Al–7·7Si–0·4Mg alloy due to the agglomerated Si particles in the eutectic region.

Mg germanide nanorods were successfully fabricated by interdiffusion of the Mg into Ge nanorods on Si substrates at 425 oC for 0.5 h. It was observed that the Mg2Ge nanorod structures were formed by an interdiffusion process between the deposited Mg atoms and the Ge nanorods. Moreover, Mg2Si nanorods were formed by additional interdiffusion between the Mg2Ge nanorods and the Si substrates at 425 oC for 4 h. The structural properties of the Mg2Ge and Mg2Si nanorods were characterized, and the growth evolution of the structural and morphological properties of the nanorods was discussed.