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A blended tutorial is a single learning event which gives students the opportunity of attending face-to-face or online. This article reports the findings of a scholarship of teaching and learning project conducted at The Open University, and considers the barriers and opportunities to using blended tutorials to support distance learning. Two pilot blended tutorials were carried out on the honours mathematics module M337 Complex Analysis, and the results of the evaluation are presented. Using qualitative data from practitioner reflections, lesson observations and semi-structured student interviews, this project uses thematic analysis to identify barriers and opportunities to using blended tutorials. Particular emphasis is given to the unique challenges in learning mathematics, and in the distance learning context of The Open University. The report concludes with recommendations for the design of blended tutorials, and recommendations for future research.

Supplementary Figure 2 - PDF file 64K, Effect of modulation of CYP1A1 activity on the growth of breast. cancer cells

Supplementary Figure 1 - PDF file 103K, Effect of AhRsiRNA on the growth of breast cancer cells

Supplementary Figure Legends- PDF file 57K, Legends for Supplementary Figures 1 and 2

Cytochrome P450-1A1 (CYP1A1) is an extrahepatic phase I metabolizing enzyme whose expression is suppressed under physiologic conditions but can be induced by substrates via the aryl hydrocarbon receptor (AhR). Recent studies have shown that the majority of breast cancer tumors constitutively express CYP1A1. These findings led us to test the hypothesis that CYP1A1 promotes breast cancer progression by evaluating the effects of CYP1A1 knockdown on the proliferation and survival of the MCF7 and MDA-MB-231 lines. Independently of estrogen receptor status, CYP1A1 knockdown decreased colony formation, decreased cell proliferation, blocked the cell cycle at G0-G1 associated with reduction of cyclin D1, and increased apoptosis associated with reduction of survivin. CYP1A1 knockdown markedly increased phosphorylation of AMP-activated protein kinase (AMPK) and decreased phosphorylation of AKT, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and 70-kDa ribosomal protein S6 kinase (P70S6K). AMPK inhibition by compound C partially abrogated the proapoptotic effects of CYP1A1 knockdown, suggesting that effects of CYP1A1 knockdown are mediated in part through AMPK signaling. Consistent with CYP1A1 knockdown, pharmacologic reduction of CYP1A1 levels by the phytopolyphenol carnosol also correlated with impaired proliferation and induced AMPK phosphorylation. These results indicate that reduction of basal CYP1A1 expression is critical for inhibition of proliferation, which is not affected by α-naphthoflavone-mediated inhibition of CYP1A1 activity nor modulated by AhR silencing. This study supports the notion that CYP1A1 promotes breast cancer proliferation and survival, at least in part, through suppression of AMPK signaling and that reduction of CYP1A1 levels is a potential strategy for breast cancer therapeutics. Mol Cancer Res; 11(7); 780–92. ©2013 AACR.

Background Aromatase inhibitors (AIs) are recommended as adjuvant treatment for estrogen-receptor positive breast carcinoma in postmenopausal women. Studies demonstrate mixed results as to the impact of AIs on cardiovascular (CV) events and overall survival. With the increasing number of pre- and postmenopausal women on AIs for five to ten years, understanding the long-term impact of AIs on blood vessels and CV risk in cancer survivors is vital. Methods A single arm longitudinal study of 14 postmenopausal women with ER+ breast cancer prescribed adjuvant AIs at the University of Minnesota. Subjects with a history of tobacco use, hypertension, or hyperlipidemia were excluded. Participants underwent routine labs, blood pressure assessments, and vascular testing at baseline (prior to starting AIs) and at six months. Vascular assessment was performed using the EndoPAT 2000 and HDI/PulseWave CR-2000 Cardiovascular Profiling System and pulse contour analysis on two occasions as previously described. Vascular measurements were conducted by one trained vascular technician. Assessments were performed in triplicate, and the mean indices were used for analyses. All subjects were on an AI at the follow-up visit. The protocol was approved by the UMN Institutional Review Board and all participants were provided written informed consent. Baseline and follow-up characteristics were compared using Wilcoxon signed-rank tests. Analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria). Results After six months of AI treatment, EndoPAT® ratio declined to a median 1.12 (Q1: 0.85, Q3: 1.86; p=0.045) and median estradiol levels decreased to 2 pg/mL (Q1: 2, Q3: 3; p=0.052). There was no evidence of association between change in EndoPAT® and change in estradiol level (p=0.91). There were no statistically significant changes in small or large arterial elasticity. Conclusion Endovascular dysfunction is an early sign for atherosclerosis and vascular impairment. This study suggests that postmenopausal breast cancer survivors on aromatase inhibitor therapy develop endothelial dysfunction as early as six months which is a predictor of adverse CV disease. We hypothesize that long-term use of AIs can lead to persistent endothelial dysfunction. It is unclear if these changes are reversible once AI use is discontinued and further investigation is necessary.

Supplementary Figure S1; Supplementary Tables S1-S3.

Purpose: This study was performed to discover prognostic genomic markers associated with postoperative outcome of stage I to III non–small cell lung cancer (NSCLC) that are reproducible between geographically distant and demographically distinct patient populations.Experimental Design: American patients (n = 27) were stratified on the basis of recurrence and microarray profiling of their tumors was performed to derive a training set of 44 genes. A larger Korean patient validation cohort (n = 138) was also stratified by recurrence and screened for these genes. Four reproducible genes were identified and used to construct genomic and clinicogenomic Cox models for both cohorts.Results: Four genomic markers, DBN1 (drebrin 1), CACNB3 (calcium channel beta 3), FLAD1 (PP591; flavin adenine dinucleotide synthetase), and CCND2 (cyclin D2), exhibited highly significant differential expression in recurrent tumors in the training set (P < 0.001). In the validation set, DBN1, FLAD1 (PP591), and CACNB3 were significant by Cox univariate analysis (P ≤ 0.035), whereas only DBN1 was significant by multivariate analysis. Genomic and clinicogenomic models for recurrence-free survival (RFS) were equally effective for risk stratification of stage I to II or I to III patients (all models P < 0.0001). For stage I to II or I to III patients, 5-year RFS of the low- and high-risk patients was approximately 70% versus 30% for both models. The genomic model for overall survival of stage I to III patients was improved by addition of pT and pN stage (P < 0.0013 vs. 0.010).Conclusion: A 4-gene prognostic model incorporating the multivariate marker DBN1 exhibits potential clinical utility for risk stratification of stage I to III NSCLC patients. Clin Cancer Res; 17(9); 2934–46. ©2011 AACR.

Purpose:This open-label, multicenter, phase IB/II study evaluated sapanisertib, a dual inhibitor of mTOR kinase complexes 1/2, plus exemestane or fulvestrant in postmenopausal women with hormone receptor–positive (HR+)/HER2-negative (HER2−) advanced/metastatic breast cancer.Patients and Methods:Eligible patients had previously progressed on everolimus with exemestane/fulvestrant and received ≤3 (phase IB) or ≤1 (phase II) prior chemotherapy regimens. Patients received sapanisertib 3 to 5 mg every day (phase IB), or 4 mg every day (phase II) with exemestane 25 mg every day or fulvestrant 500 mg monthly in 28-day cycles. Phase II enrolled parallel cohorts based on prior response to everolimus. The primary objective of phase II was to evaluate antitumor activity by clinical benefit rate at 16 weeks (CBR-16).Results:Overall, 118 patients enrolled in phase IB (n = 24) and II (n = 94). Five patients in phase IB experienced dose-limiting toxicities, at sapanisertib doses of 5 mg every day (n = 4) and 4 mg every day (n = 1); sapanisertib 4 mg every day was the MTD in combination with exemestane or fulvestrant. In phase II, in everolimus-sensitive versus everolimus-resistant cohorts, CBR-16 was 45% versus 23%, and overall response rate was 8% versus 2%, respectively. The most common adverse events were nausea (52%), fatigue (47%), diarrhea (37%), and hyperglycemia (33%); rash occurred in 17% of patients. Molecular analysis suggested positive association between AKT1 mutation status and best treatment response (complete + partial response; P = 0.0262).Conclusions:Sapanisertib plus exemestane or fulvestrant was well tolerated and exhibited clinical benefit in postmenopausal women with pretreated everolimus-sensitive or everolimus-resistant breast cancer.

Supplementary Material containing Supplementary Methods, 5 Supplementary Figures, and 8 Supplementary Tables

The characterization of hydraulic fractures is crucial for fracturing evaluation and strategy optimization. Low-frequency electromagnetic triaxial induction measurement is a promising candidate in hydraulic fracture characterization. However, it is difficult to accurately monitor fracture shape, orientation, and the multistage fracture network distribution. A novel method that combines triaxial induction measurement with sector-shaped coils axial rotation measurement (TIM-SCARM) is proposed to characterize hydraulic fractures. It is implemented by using the finite element method with transition boundary conditions (FEM-TBCs), which approximates the thin fracture as a surface to enhance the computational efficiency. The study focuses on quantitative analysis of conductivity, cross-sectional shape, half-length, and orientation of hydraulic fractures to assess their effects on specific configurations of the TIM-SCARM. Furthermore, the correlations between multicomponent signals and fracture characteristics are investigated. Numerical results indicate that the coaxial component signal in SCARM can distinguish the cross-sectional shape and orientation. The cross-polarized component signals provide important features of tilted fractures, and the 3-D signal obtained by instrument rotation could determine the spatial distribution of fracture networks. Therefore, measurements that integrate the multicomponent signals and axial information improve fracture geometry evaluation.

Over the past decades, the development of fibre optic cables, which pass light waves carrying data guided by total internal reflection, has led to advances in high-speed and long-distance communication, large data transmission, optical imaging, and sensing applications. Thus far, fibre optic sensors (FOSs) have primarily been employed in engineering, biomedicine, and basic sciences, with few reports of their usage in geophysics as point and distributed sensors. This work aimed at reviewing the studies on the use of FOSs in geophysical applications with their fundamental principles and technological improvements. FOSs based on Rayleigh, Brillouin, and Raman scatterings and fibre Bragg grating sensors are reviewed based on their sensing performance comprising sensing range, spatial resolution, and measurement parameters. The recent progress in applying distributed FOSs to detect acoustic, temperature, pressure, and strain changes, as either single or multiple parameters simultaneously on surface and borehole survey environments with their cable deployment techniques, has been systematically reviewed. Despite the development of fibre optic sensor technology and corresponding experimental reports of applications in geophysics, there have not been attempts to summarise and synthesise fibre optic methods for prospecting as a comprehensive and modern branch of geophysics. Therefore, this paper outlines the fibre optic prospecting methods, with an emphasis on their advantages, as a guide for the geophysical community. The potential of the new outlined fibre optic prospecting methods to revolutionise conventional geophysical approaches is discussed. Finally, the future challenges and limitations of the new prospecting methods for geophysical applications are elucidated.

Neutrophil and macrophage (Mϕ) migration underpin the inflammatory response. However, the fast velocity, multidirectional instantaneous movement, and plastic, ever-changing shape of phagocytes confound high-resolution intravital imaging. Lattice lightsheet microscopy (LLSM) captures highly dynamic cell morphology at exceptional spatiotemporal resolution. We demonstrate the first extensive application of LLSM to leukocytes in vivo, utilizing optically transparent zebrafish, leukocyte-specific reporter lines that highlighted subcellular structure, and a wounding assay for leukocyte migration. LLSM revealed details of migrating leukocyte morphology, and permitted intricate, volumetric interrogation of highly dynamic activities within their native physiological setting. Very thin, recurrent uropod extensions must now be considered a characteristic feature of migrating neutrophils. LLSM resolved trailing uropod extensions, demonstrating their surprising length, and permitting quantitative assessment of cytoskeletal contributions to their evanescent form. Imaging leukocytes in blood vessel microenvironments at LLSM’s spatiotemporal resolution displayed blood-flow-induced neutrophil dynamics and demonstrated unexpected leukocyte-endothelial interactions such as leukocyte-induced endothelial deformation against the intravascular pressure. LLSM of phagocytosis and cell death provided subcellular insights and uncovered novel behaviors. Collectively, we provide high-resolution LLSM examples of leukocyte structures (filopodia lamellipodia, uropod extensions, vesicles), and activities (interstitial and intravascular migration, leukocyte rolling, phagocytosis, cell death, and cytoplasmic ballooning). Application of LLSM to intravital leukocyte imaging sets the stage for transformative studies into the cellular and subcellular complexities of phagocyte biology.

Introduction: Immune checkpoint blockade (ICB) has clinical activity in triple negative breast cancer (TNBC) but is less effective in the ER+HER2- signature, where there is a cold immune microenvironment (IM) and regulatory T cells (Tregs) may suppress effector T cells. Agents that activate the IM by turning cold tumors hot may support ICB. The biguanides hexyl-benzyl-biguanide (HBB) and its bioisostere hexyl-(cuban-1-yl-methyl)-biguanide (HCB) are candidate agents to activate the IM because they potently inhibit biosynthesis of immunosuppressive epoxyeicosatrienoic acids (EETs) and EET-driven oxidative phosphorylation (OXPHOS), while blocking N-glycosylation of immune checkpoint (IC) proteins. We hypothesized that reversal of hypoxia by biguanides in the ovarian dependent ER+HER2- STAT1 KO SSM2ucd mouse mammary carcinoma (MC) model would suppress Tregs and promote effector T cells in the tumor IM. While the SSM2ucd model did not express immune checkpoint protein PD-L1 (B7-H1), it did express related IC proteins B7-H3 and B7-H4. We hypothesized that by inhibiting OXPHOS and reducing N-glycosylation of immune checkpoint proteins, HBB and HCB may promote efficacy of ICB. We chose the SSM2ucd model to test impact of HCB on the ER+ MC IM. Results: SSM2ucd cells exhibited longer tumor latency (60 days) than the basal 4T1 (10 days) and 67NR (20 days) mouse MC models. SSM2ucd tumor reimplantation shortened latency by more than half, to 20 days. Immunohistochemistry showed that B7-H3 and B7-H4 protein levels were 1.2 (P=0.001) and 1.3-fold (P=0.04) higher in reimplanted tumors vs. control. In SSM2ucd cells, HCB inhibited N-glycosylation of B7-H3 (P=0.01) by 35% and B7-H4 (P=0.02) by 45% and suppressed TGFβ induction of B7-H3 by 21% (P=0.02) and B7-H4 by 79% (P=0.001) at 24 hours, while 14,15-EET promoted N-glycosylation of B7-H3 (1.2-fold; P=0.03) and B7-H4 (1.3-fold; P=0.04) at 4 hours. Effects of HBB and HCB on anti-CD3 and anti-CD28 stimulated mouse splenocytes were assayed. The proliferative effects of HBB on CD4+ and CD8+ cells peaked at 12 uM (p Conclusion: B7-H3 and B7-H4 expression inversely correlated with latency of ER+ MC and may represent targets for immune checkpoint antibodies and their drug conjugates. HCB, an inhibitor of OXPHOS and EET biosynthesis, reduced intratumoral hypoxia, increased CD8+ TIL and reduced the Treg:CD8+ ratio, potentially supporting ICB therapy of ER+ MC by turning cold tumors hot. Supported by CDMRP BCRP Grant BC180596, Award Number W81XWH-19-1-0099 Citation Format: Zhijun Guo, Jianxun Lei, Hrishi Venkatesh, David Owen, Adam Bass, Christine Cannon, Joshua McCarra, Brenda Koniar, Craig Flory, Beverly Norris, Robert J. Schumacher, Swaathi Jayaraman, John Hawse, Emmanuel S. Antonarakis, Emanuel F. Petricoin, Julia Wulfkuhle, Robert D. Cardiff, Elizabeth A. Ambrose, Gunda I. Georg, Kaylee L. Schwertfeger, Michael A. Farrar, Brad St. Croix, Matthew P. Goetz, David A. Potter. Hexyl-(cuban-1-yl-methyl)-biguanide (HCB) suppresses N-glycosylation of immune checkpoint proteins B7-H3 and B7-H4, reverses tumor hypoxia, decreases intratumoral regulatory T cells, and increases intratumoral CD8+ T cells in the ovarian dependent ER+HER2- SSM2ucd mammary cancer allograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB102.

Sperm swim through the female reproductive tract by propagating a 3D flagellar wave that is self-regulatory in nature and driven by dynein motors. Traditional microscopy methods fail to capture the full dynamics of sperm flagellar activity as they only image and analyze sperm motility in 2D. Here, an automated platform to analyze sperm swimming behavior in 3D by using thin-lens approximation and high-speed dark field microscopy to reconstruct the flagellar waveform in 3D is presented. It is found that head-tethered mouse sperm exhibit a rolling beating behavior in 3D with the beating frequency of 6.2 Hz using spectral analysis. The flagellar waveform bends in 3D, particularly in the distal regions, but is only weakly nonplanar and ambidextrous in nature, with the local helicity along the flagellum fluctuating between clockwise and counterclockwise handedness. These findings suggest a nonpersistent flagellar helicity. This method provides new opportunities for the accurate measurement of the full motion of eukaryotic flagella and cilia which is essential for a biophysical understanding of their activation by dynein motors.

Reactions of fuel derived radicals, R, and oxygen, are of interest for low temperature combustion and autoignition. A method for measuring R + O2 rate coefficients based on the real time regeneration of OH radicals following initiation of the reaction via OH + RH is presented; values for kR+O2 can be extracted from the resulting biexponential OH profiles. The rate coefficient for the reaction of CH3OCH2, with O2, at 291–483 K, in 4.1–32.6 Torr of nitrogen are reported. At room temperature, kCH3OCH2+O2 = (0.94 ± 0.04) × 10−11 cm3 molecule−1 s−1, where the error represents statistical uncertainty at the 2σ level.

Marketed (bosentan, ambrisentan) and discontinued (sitaxsentan, CI-1034) endothelin receptor antagonists were examined in the human micropatterned hepatocyte co-culture (MPCC) model HepatoPac® . Differences across hepatocellular health (cellular adenosine triphosphate/glutathione content), function (urea production/albumin secretion) and taurocholic acid transport (biliary clearance/excretion index) were compared using amiodarone and ciclosporin A as positive controls. Ambrisentan had the weakest potency in all six endpoints, while sitaxsentan, bosentan and CI-1034 had more potent effects on hepatobiliary transport than health/function endpoints. Normalization to clinical Cmax gave the following relative rank order of safety based on margins for each endpoint: ambrisentan ≥ CI-1034 ~ bosentan > sitaxsentan. These data suggested impaired hepatobiliary disposition might contribute to a more prominent role in liver injury associated within sensitive human populations exposed to these compounds than direct hepatocellular toxicity. Rat, dog and monkey MPCCs also showed greater sensitivity potential to disrupted hepatobiliary disposition compared with hepatocellular health/functional endpoints. Drug metabolism competency was exhibited across all species. In vivo, rats and dogs appear more resistant to transaminase elevations and/or histological evidence of liver injury caused by these mechanisms even at exceedingly high systemic exposures relative to sensitive humans. Rats and dogs are resistant to hepatobiliary toxicants due to physiological differences in bile composition/handling. Although traditional animal testing provides adequate safety coverage for advancement of novel pharmaceuticals into clinical trials, supplemental assays employing human MPCCs may strengthen weight-of-evidence predictions for sensitive human populations. Proving the predictive value of this single impact assessment model in advance of clinical trial information for human liver injury risk is needed across more pharmaceuticals.

Fertilization requires sperm to travel long distances through the complex environment of the female reproductive tract. Despite the strong association between poor motility and infertility, the kinetics of sperm tail movement and the role individual proteins play in this process is poorly understood. Here, we use a high spatiotemporal sperm imaging system and an analysis protocol to define the role of CRISPs in the mechanobiology of sperm function. Each of CRISP1, CRISP2, and CRISP4 is required to optimize sperm flagellum waveform. Each plays an autonomous role in defining beat frequency, flexibility, and power dissipation. We thus posit that the expansion of the CRISP family from one member in basal vertebrates, to three in most mammals, and four in numerous rodents, represents an example of neofunctionalization wherein proteins with a common core function, boosting power output, have evolved to optimize different aspects of sperm tail performance.

While much is known about the microstructure of sperm flagella, the mechanisms behind the generation of flagellar beating patterns by the axoneme are still not fully understood. We demonstrate a technique for investigating the energetics of flagella or cilia. We record the planar beating of tethered wildtype andCrisp2-knockout mouse sperm at high-speed and high-resolution and extract centerlines using digital image processing techniques. We accurately reconstruct beating waveforms using a Chebyshev-polynomial based Proper Orthogonal Decomposition of the centerline tangent-angle profiles. External hydrodynamic forces and the internal resistance from the passive flagellar material are calculated from the observed kinematics of the beating patterns using a Soft, Internally-Driven Kirchhoff-Rod (SIDKR) model. Energy conservation is employed to further compute the flagellar energetics. We thus obtain the distribution of mechanical power exerted by the dynein motors without any further assumptions about mechanisms regulating axonemal function. We find that, in both the mouse genotypes studied, a large proportion of the mechanical power exerted by the dynein motors is dissipated internally, within the passive structures of the flagellum and by the motors themselves. This internal dissipation is considerably greater than the hydrodynamic dissipation in the aqueous medium outside. The net power input from the dynein motors in sperm fromCrisp2-knockout mice is significantly smaller than in corresponding wildtype samples. The reduced power is correlated with slower beating and smaller amplitudes. These measurements of flagellar energetics indicate that the ion-channel regulating cysteine-rich secretory proteins (CRISPs) may also be involved in regulating mammalian sperm motility.

The orientation of stable single domain (SSD) ferrimagnetic particles in an igneous rock sample was determined by a sensitive technique utilizing gyroremanent magnetization (GRM). Components of GRM were measured in the sample upon exposure to an alternating field (AF) at various orientations in 3 orthogonal planes. The major components of GRM exhibited a sin(2θ) dependence on AF orientation in the respective perpendicular planes. This was in accordance with theory [1] and contrary to some previously reported experimental results on magnetic recording tape, which produced a distorted sin(2θ) dependence of the GRM [1]. The explanation is likely due to the SSD ferrimagnetic particles in the rock sample being more dispersed (less interacting) compared to the highly interacting SSD particles in the magnetic tape sample of the previous study. The GRM results were consistent with another remanence anisotropy method, anisotropy of isothermal remanent magnetization (AIRM). This method again measures the anisotropy of the remanence carrying ferrimagnetic particles, but the IRM is also acquired by larger multidomain (MD) particles as well as by the SSD particles. The results were also consistent with the visible rock anisotropy (petrofabric), the anisotropy of magnetic susceptibility (AMS), and the shear wave velocity anisotropy. A comparison of all the methods demonstrated that the fine SSD particles, which make up only a small proportion of the rock, were aligned in quite a similar orientation to that of the main rock forming minerals that constituted the bulk of the sample.

Owls play crucial roles in the environment and provide ecosystem services making them important to monitor and study. However, standardized methods for most species do not exist, and we lack understanding of the effects of many environmental variables and call-broadcast on detection of owls during surveys. We performed a multispecies occupancy analysis of owl monitoring data collected from 2004 to 2013 across the state of Maine to examine the effects of environmental variables, conspecific and heterospecific call-broadcast, and general survey protocols on detection of 3 forest owls: Northern Saw-whet Owl (Aegolius acadicus), Barred Owl (Strix varia), and Great Horned Owl (Bubo virginianus). We found that environmental variables such as cloud cover, precipitation, temperature, time of night, and wind had species-specific effects on detection probability, and ambient noise decreased detection probability for all species. Snow cover did not affect detection of any species. We also found that conspecific call-broadcast increased detection of each species, while heterospecific call-broadcast had variable effects. Specifically, we found that Long-eared and Barred owl broadcast increased the detection of Northern Saw-whet Owl, and our results suggest additional heterospecific effects may exist. Our study showed that, compared to the protocol of the Maine Owl Monitoring Program, surveys simultaneously examining all 3 of our focal species can increase efficiency and lower disturbance by only broadcasting Long-eared and Barred owl calls during a 10-min survey. We recommend that future owl surveys take into account species-specific effects of conspecific and heterospecific call-broadcast, and use our results when designing survey protocols that include one or more of our focal species.

Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. Tucatinib is a potent HER2 (ErbB2) tyrosine kinase inhibitor, selective for HER2 vs. epidermal growth factor receptor (EGFR) and is active vs. brain metastases. Safety and efficacy of tucatinib combined with paclitaxel, pertuzumab, and trastuzumab are unknown and were tested in a planned 10 patient (pt) safety run-in of the I-SPY 2 trial. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only pts with tumors that were HER2+ by FISH were eligible for this treatment. Treatment included tucatinib (max dose 300 mg) BID for 12 weeks with weekly paclitaxel 80 mg/m2 and trastuzumab (2 mg/kg weekly following loading), and pertuzumab (420 mg every 3 weeks following loading), followed by doxorubicin/cyclophosphamide (AC) every 2 weeks x 4. The control arm was weekly paclitaxel and trastuzumab with pertuzumab for 12 weeks followed by AC every 2 weeks x 4. All pts undergo serial MR imaging and response at 3 & 12 weeks is combined with real time pCR data to estimate, and continuously update, the predicted pCR rate for each trial arm. The goal of the trial is to identify/graduate regimens with ≥85.% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 neoadjuvant trial with a pCR endpoint. This run-in arm was conducted to determine safety of combining tucatinib with paclitaxel/trastuzumab/pertuzumab, monitoring special adverse events of interest including LFT elevations and gastrointestinal toxicities.Methods: The I-SPY 2 methods have been previously published. Results: 20 pts were evaluable in tucatinib treatment arm. The control arm included 329 historical controls enrolled since April 2010. The initial tucatinib dose was 300 mg BID. After enrollment of the first 8 pts, there were 3 pts with grade 3 LFT elevations, 2 pts with grade 2/3 diarrhea, 1 pt with grade 2 neutropenia, and 1 pt with grade 3 nausea. After this safety review, the tucatinib dose was lowered to 250 mg BID. Among 5 additional pts enrolled, 3 developed grade 2/3 LFT abnormalities. The protocol was then modified to tucatinib 150 mg BID days 1-28 and then 250 mg BID days 29-84; 7 pts were treated. Safety data were reviewed after 20 pts were enrolled; the arm was then suspended due to similar LFT elevations regardless of tucatinib dose reduction or schedule. 7 of 20 pts (35%) had reversible Grade 3 or higher ALT/AST elevation (Table). No pt met criteria for Hy’s Law. In terms of efficacy, 12 of 14 evaluable pts had > 80% reduction of tumor volume by 12 weeks, measured by MRI assessment of functional tumor volume (FTV). Conclusion: The goal of the run-in arm was to determine the safety of adding tucatinib to the combination of paclitaxel/trastuzumab/pertuzumab. The addition of tucatinib resulted in unacceptable but reversible LFT elevations despite tucatinib dose reduction. Tucatinib containing therapy resulted in >80% decline in tumor volume at 12 weeks in 86% of pts. Tucatinib showed a high level of activity when combined with paclitaxel/trastuzumab/pertuzumab, but the combination is not feasible. Table: Number of pts with grade 2, 3, and 4 LFT elevations by treatment schedule (highest grade per patient per event, ALT or Treatment scheduleGrade 2 LFT elevationGrade 3 LFT elevationGrade 4 LFT elevationTucatinib 300 mg BID030Tucatinib 250 mg BID210Tucatinib 150 mg BID days 1-28 followed by 250 mg BID days 29 to 84112 Citation Format: David A Potter, Erin Roesch, Christina Yau, Ruixiao Lu, Denise Wolf, Susan Samson, Debra Stafford, Kathy S Albain, Claudine Isaacs, Meghana Trivedi, Douglas Yee, Judy Boughey, Alexandra Thomas, A. Jo Chien, Nola Hylton, Wen Li, Angela DeMichele, Jane Perlmutter, W. Fraser Symmans, Dawn L Hershman, Michelle Melisko, Laura J van 't Veer, Amy Wilson, Smita M Asare, Donald A Berry, Richard Schwab, Hope S Rugo, Laura J Esserman. Evaluation of Tucatinib + (Paclitaxel + Pertuzumab + Trastuzumab) followed by AC in high-risk HER2 positive (HER2+) stage II/III breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD8-07.

The mass susceptibility (χmass) and mass magnetization (Mmass) were determined for a series of ternary manganese and zinc ferrite nanoparticles (Mn–Zn ferrite NPs, MnxZn1−xFe2O4) with different Mn:Zn ratios (0.08 ≤ x ≤ 4.67), prepared by the thermal decomposition reaction of the appropriate metal acetylacetonate complexes, and for the binary homologs (MxFe3−xO4, where M = Mn or Zn). Alteration of the Mn:Zn ratio in Mn–Zn ferrite NPs does not significantly affect the particle size. At room temperature and low applied field strength the mass susceptibility increases sharply as the Mn:Zn ratio increases, but above a ratio of 0.4 further increase in the amount of manganese results in the mass susceptibility decreasing slightly, reaching a plateau above Mn:Zn ≈ 2. The compositional dependence of the mass magnetization shows less of a variation at room temperature and high applied fields. The temperature dependence of the mass magnetization of Mn–Zn ferrite NPs is significantly less for Mn-rich compositions making them more suitable for downhole imaging at higher temperatures (>100 °C). For non-shale reservoirs, replacement of nMag by Mn-rich Mn–Zn ferrites will allow for significant signal-to-noise enhancement of 6.5× over NP magnetite.

Introduction Cardiac sodium channel antagonists have historically been used to treat cardiac arrhythmias by preventing the reentry of the electrical impulse that could occur following myocardial damage. However, clinical studies have highlighted a significant increase in mortality associated with such treatment. Cardiac sodium channel antagonist activity is now seen as an off-target pharmacology that should be mitigated during the drug development process. The aim of this study was to examine the correlation between in vitro/ex vivo assays that are routinely used to measure Nav1.5 activity and determine the translatability of the individual assays to QRS prolongation in the clinic. Methods A set of clinical compounds with known Nav1.5 activity was profiled in several in vitro/ex vivo assays (binding, membrane potential, patch clamp and the Langendorff isolated heart). Clinical data comprising compound exposure levels and changes in QRS interval were obtained from the literature. Sensitivity/specificity analysis was performed with respect to the clinical outcome. Results The in vitro assays showed utility in predicting QRS prolongation in the clinic. Optimal thresholds were defined for each assay (binding: IC20; membrane potential: IC10; patch clamp: IC20) and sensitivity (69–88%) and specificity (53–84%) values were shown to be similar between assay formats. Discussion The data provide clear statistical insight into the translatability of Nav1.5 antagonism data generated in vitro to potential clinical outcomes. These results improve our ability to understand the liability posed by such activity in novel development compounds at an early stage.

Courses: This activity is designed specifically for public-speaking courses, but it could be used in the general introductory communication course. It also holds potential for use in persuasion, argumentation, or strategic communication courses.Objectives: This activity helps students understand audience as a more complicated concept—one that recognizes the power of a speaker in creating and challenging communities and interrogating power through their performative speeches in the courses named above.

High quality paleomagnetic poles (a.k.a. paleopoles) are essential for quantitative lithospheric plate reconstruction. However, the current paleomagnetic database of the major Chinese blocks, including the North China Block (NCB), the South China Block (SCB), and the Tarim Block (TB), since the Late Paleozoic Era contain outdated and low quality data. Here, we update the database by adding recently published high quality paleopoles and rejecting low quality outdated ones. The database includes 288 paleopoles published 1980–2014, 90 of them published after 2000. Following the Van der Voo selection criteria, 75 paleopoles, each with a quality factor Q smaller than 4, were rejected in the first round of selection. We then removed another 59 paleopoles that have been locally rotated or shallowed since the acquisition of stable remanence. Eventually, 154 paleopoles were selected and adopted to calculate the new apparent polar wander paths (APWPs) for the major Chinese blocks. We found comparable clastic and igneous paleopoles at intervals when a quantitative comparison was available. As such comparison was not possible during most periods/epochs, our conclusions reflect an unclear extent of inclination errors in Chinese clastic paleopoles. New models of the Chinese APWPs, with and without inclination error corrections, were computed from carefully selected paleopoles: version 1 running mean (V1RM) paths were calculated at the period/epoch level; version 2 running mean (V2RM) paths were computed in a set sliding time window of 20 or 30 Myr; spline paths were calculated with the same time windows along with a smoothing parameter of 50. Using a recent global reconstruction model and up-to-date geological observations, new models of the Chinese APWPs allowed us to re-evaluate the coalescence history of East Eurasia since the Late Paleozoic Era. Four major tectonic events were confirmed: (1) the TB accreted with the Kazakhstan orocline during amalgamation of the West Altaids during the Middle–Late Permian Period (ca. 265–250 Ma); (2) the suturing of the NCB and the SCB likely occurred in a scissor-like pattern and had been accomplished no later than the Middle Jurassic Period (ca. 180–160 Ma); (3) the amalgamation between the NCB and the TB along with the microblocks between the two might have been achieved during the Late Jurassic–Early Cretaceous Periods (ca. 160–140 Ma); (4) the Mongol-Okhotsk Ocean should have been closed no later than the Early Cretaceous Period (ca. 140–120 Ma).

Understanding the present-day fast seismic velocity anomalies in the mantle requires an accurate kinematic reconstruction of past convergent tectonics. Using the paleomagnetism-based absolute reconstruction method from Wu and Kravchinsky [2014], we present here the restoration of the closing of the Mongol-Okhotsk Ocean (MOO) that existed between Siberia and North China-Amuria (NCA) during the Mesozoic. Three stages, i.e., 250-200 Ma, 200-150 Ma and 150-120 Ma, are identified from the time-varying convergence rates of Siberia and NCA. The spherical distance between the suture margins was reduced by ca. 66.7% at an average convergence rate of 8.8±0.6 cm/yr during the first stage at 250-200 Ma, when ca. 62.5-76.1% of the slabs associated with the MOO lithosphere were formed primarily through intra-oceanic convergence. In the second stage at 200-150 Ma, the spherical distance was reduced by another 21.1% with a convergence rate of 3.6±0.3 cm/yr. During this stage, ca. 14.2-30.9% of the MOO slabs were formed and continental-oceanic convergence outpaced intra-oceanic subduction. In the last stage at 150-120 Ma, the convergence rate dropped to ca. 0.4-0.6 cm/yr with the formation of ca. 4.6-9.8% slabs associated with the MOO lithosphere. The final closure of the MOO remnant basin could have been accomplished by 130-120 Ma, which explains the origin of the fast-velocity anomalies inside the restored continents at 120 Ma near the suture margins.

Mood disorders can be triggered by stress and are characterized by deficits in reward processing, including disrupted reward learning (the ability to modulate behavior according to past rewards). Reward learning is regulated by the anterior cingulate cortex (ACC) and striatal circuits, both of which are implicated in the pathophysiology of mood disorders. Here, we assessed in rats the effects of a potent stressor (social defeat) on reward learning and gene expression in the ACC, ventral tegmental area (VTA), and striatum. Adult male Wistar rats were trained on an operant probabilistic reward task (PRT) and then exposed to 3 days of social defeat before assessment of reward learning. After testing, the ACC, VTA, and striatum were dissected, and expression of genes previously implicated in stress was assessed. Social defeat blunted reward learning (manifested as reduced response bias toward a more frequently rewarded stimulus) and was associated with increased nociceptin/orphanin FQ (N/OFQ) peptide mRNA levels in the striatum and decreased Fos mRNA levels in the VTA. Moreover, N/OFQ peptide and nociceptin receptor mRNA levels in the ACC, VTA and striatum were inversely related to reward learning. The behavioral findings parallel previous data in humans, suggesting that stress similarly disrupts reward learning in both species. Increased striatal N/OFQ mRNA in stressed rats characterized by impaired reward learning is consistent with accumulating evidence that antagonism of nociceptin receptors, which bind N/OFQ, has antidepressant-like effects. These results raise the possibility that nociceptin systems represent a molecular substrate through which stress produces reward learning deficits in mood disorders.

Japan is developing a grand strategy for “international cooperation,” a mix of official development assistance policy and other policy tools, most notably security policy, that is currently a feature of the Abe administration’s “proactive contribution to peace.” The research asks how this new aid is strategic and how it understands the concept of security. Finally, what does Japanese aid to Southeast Asia tell us about these two points? This chapter addresses these questions in two ways. First, it clarifies what is meant by “strategic aid” by analysing the concept through three lenses: strategic thinking, organization, and allocation of aid. Second, it provides an analytical framework for measuring strategic aid, through which Japan’s aid to Southeast Asia, in particular Myanmar, is analysed.