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Background: Thromboxane is a key clinical risk endpoint of smoking-induced inflammation which has been associated in the pathogenesis of cardiovascular disease. The goal of this review is to quantify the effect of smoking and smoking cessation on one of its urinary metabolites, 11-dehydrothromboxaneB2. Methods: PubMed and SCOPUS were searched to identify publications which report urinary 11-dehydrothromboxaneB2 levels in smokers and non-smokers, as well as articles reporting the effect of smoking cessation on urinary 11-dehydrothromboxaneB2 excretion. Results: We found ten studies assessing urinary 11-dehydrothroboxaneB2 levels in smokers and non-smokers. Four papers reported the amount of urinary 11-dehydrothromboxaneB2 excreted in 24 h while six reported the amount excreted adjusted for creatinine. The meta-analyses comparing the excretion of urinary 11-dehydrothromboxane in current smokers to non-smokers report increased levels in current smokers (mean difference = 0.31 μg/24-h [95%CI: 0.27–0.34] and 166.45 pg/mg creatinine [95%CI: 120.51–212.40]). There were not enough publications to perform meta-analyses on the effects of smoking cessation on urinary 11-dehydrothromboxaneB2 excretion. Conclusions: Urinary 11-dehydrothromboxaneB2 levels are increased in cigarette smokers, however, more data are needed to elucidate the effects of smoking cessation on urinary 11-dehydrothromboxaneB2 excretion. Keywords: Smoking, Inflammation, Thromboxane, Meta-analysis

Introduction: Abemaciclib is being developed for the treatment of cancer, including advanced and metastatic breast cancer. Tablet formulations, which are smaller than the capsules used in the pivotal MONARCH 1, 2 and 3 breast cancer studies, have recently been developed. This study evaluated the bioequivalence of abemaciclib capsule and tablet formulations following single 150-mg doses, and the effect of food on the pharmacokinetics (PK) of abemaciclib following dosing with a 150-mg tablet. Methods: This was an open-label, randomized, 3-part study conducted in 127 healthy male (13%) and female (87%) subjects. Plasma concentrations of abemaciclib and its major metabolites were assessed up to 192 hours postdose using validated LC-MS/MS methods. Part A was a 2-period, crossover pilot study to compare abemaciclib capsules (3 x 50-mg) and tablets (1 x 150-mg) formulations in the fasted state. Results from Part A were used to ensure adequate PK sampling and estimate intra-individual variability to confirm the sample size required for Part B of the study. Part B was a 3-period, crossover, bioequivalence study of a 50-mg capsule (3 x 50-mg) compared to a 150-mg tablet (1 x 150-mg) and a 50mg tablet (3 x 50-mg) in the fasted state. Part C was a 2-period crossover food effect study to determine the effect of a high-fat, high-calorie meal on the PK of abemaciclib when administered as a single 150-mg tablet compared to the fasted state. Abemaciclib Cmax and AUC determined using noncompartmental methods were log-transformed and analyzed using a linear mixed-effects model. Geometric least squares (LS) mean for each treatment, the ratio of the geometric LS means, and their 90% CIs were calculated. Results: In Part A, the abemaciclib intra-subject variability for Cmax was 26.7%, requiring a sample size of 76 subjects for Part B to ensure approximately 90% probability that the 90% CIs of the geometric means would be contained within the 0.80 to 1.25 limits, assuming that the true ratio was 1.09. In Part B, both the 3 x 50-mg and 1 x 150-mg tablets were bioequivalent to the 3 x 50-mg capsules; the 90% CIs of the ratios of geometric LS means for Cmax and AUC were contained within the bioequivalence interval of 0.80 to 1.25. Ratio of geometric LS mean (90% CI) compared to 3x50 mg capsule 1x150 mg tablet3x50 mg tabletAUC(0-tlast)1.02 (0.979,1.06)1.03 (0.987,1.07)AUC(0-∞)1.02 (0.982,1.06)1.02 (0.986,1.06)Cmax1.00 (0.955,1.05)1.03 (0.986,1.08) In Part C, consumption of a high-fat, high-calorie meal before abemaciclib dosing resulted in an increase of 13% (90% CI 1.05,1.22) in AUC(0-∞) and 30% (90% CI 1.20,1.40) in Cmax, which was not considered clinically relevant given the magnitude of the effect relative to the inter-subject variability for Cmax (36.5%). Also, the magnitude of the change was within the therapeutic window for abemaciclib. There was no difference in median tmax in the fed state compared to the fasted state for abemaciclib. Single 150-mg doses of abemaciclib were generally well tolerated when administered with or without food. The majority of the AEs reported during the study were gastrointestinal and mild in severity. Conclusions: Abemaciclib 150-mg and 50-mg tablets are bioequivalent to the 50-mg capsule formulation, based on a single dose in the fasted state, and could be administered with or without food. Citation Format: Turner PK, Chappell JC, Aburub A, Ng WT, Zhang W, Royalty J, Kulanthaivel P. Abemaciclib tablet formulation is bioequivalent to capsules [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-14.

The objective of this study was to identify factors associated with stroke, myocardial infarction (MI), all-cause mortality, or a diagnosis of ischemic heart disease (IHD) or unstable angina (UA), among patients newly-diagnosed with type 2 diabetes (T2DM) with no recent history of cardiovascular (CV) events who rapidly achieve and maintain HbAData were obtained from the Clinical Practice Research Datalink (CPRD) from January 1990 to December 2012. A nested case-control design was used with Cox proportional hazards analysis. Cases were identified by the first occurrence of stroke, MI, IHD, UA, or death within 5 years after HbAA total of 11,426 T2DM patients met the inclusion criteria for cases. Of these, 5,261 experienced a CV event. Stroke was the most frequent CV event (40%), followed by IHD (29%), MI (22%), and UA (9%). Mean HbA1c ≥7.0% over the length of exposure (vs 6.5 to7.0%) was associated with an increased risk of stroke, MI, and IHD. The use of anti-platelet medications at baseline was also associated with increased risk of stroke (HR = 1.82 [CI = 1.60-2.06]), MI (HR = 1.67 [CI = 1.38-2.03]), and IHD (HR = 1.85 [CI = 1.57-2.17]). Mean HbA1c 6.0% was associated with increased risk of stroke (HR = 1.29 [CI = 1.02-1.63]) and IHD (HR = 1.65 [CI = 1.25-2.19]). Use of nitrate medications at baseline was associated with increased risk of MI (HR = 2.83 [CI = 2.24-3.57]), IHD (HR = 4.32 [CI = 3.57-5.22]), and UA (HR = 10.38 [CI = 7.67-14.03]).Early and sustained HbA

One of the main problems of high data rate transmission over wireless channel is the delay spread. Orthogonal Frequency Division Multiplexing (OFDM) system, which is robust against multipath propagation, is often employed for such hostile wireless environments. However, due to fast time varying (Doppler spread) channels, the performance of OFDM system degrades considerably. It is found that by using directional antenna or beamforming, the amount of Doppler spread can be reduced. To investigate the effect, Doppler Power Spectral Density (PSD) equations are derived where directional antennas are employed at the mobile or/and the base station. The Doppler PSDs are derived for two different Doppler spread channel models, the two dimensional (2-D) and three dimensional (3-D) models. The 2-D model considers only the azimuthal plane, whereas the 3-D model takes into account the effect of both azimuthal and elevation planes. The 2-D model is derived from the popular classical Clake/Jakes' model, whereas the 3-D model is extended from the uniform Doppler spread model. DOCTOR OF PHILOSOPHY (EEE)

BACKGROUND Smoking is a significant risk factor for periodontal disease and tooth loss, as shown in several clinical studies comparing smokers and nonsmokers. Although only a few longitudinal studies have assessed the outcome of periodontal disease after smoking cessation, they indicated that recovery after nonsurgical treatment was more successful in those who had quit smoking. As part of tobacco harm reduction strategies, substituting cigarettes with alternative, less harmful tobacco products is an approach complementary to cessation for smokers who would otherwise continue to smoke. The Tobacco Heating System (THS), developed by Philip Morris International (commercialized as IQOS), is part of the heat-not-burn product category. The IQOS device electrically heats tobacco instead of burning it, at much lower temperatures than cigarettes, thereby producing substantially lower levels of harmful and potentially harmful constituents, while providing the nicotine, taste, ritual, and a sensory experience that closely parallel those of cigarettes. Phillip Morris International has published the results from a broad clinical assessment program, which was established to scientifically substantiate the harm reduction potential of the THS among adult healthy smokers switching to the THS. The program is now progressing toward including adult smokers with smoking-related diseases. OBJECTIVE The goal of this study is to demonstrate favorable changes of periodontal endpoints in response to mechanical periodontal therapy in patients with generalized chronic periodontitis who completely switched to THS use compared with continued cigarette smoking. METHODS This is a randomized controlled two-arm parallel-group multicenter Japanese study conducted in patients with chronic generalized periodontitis who switch from cigarettes to THS compared with smokers continuing to smoke cigarettes for 6 months. The patients were treated with mechanical periodontal therapy as per standard of care in Japan. The primary objective of the study is to demonstrate the beneficial effect of switching to THS use compared with continued cigarette smoking on pocket depth (PD) reduction in all sites with an initial PD≥4 mm. The secondary objectives include evaluation of other periodontal parameters (eg, clinical attachment level or gingival inflammation) and overall oral health status upon switching to THS. Safety was monitored throughout the study. RESULTS In total, 172 subjects were randomized to the cigarette (n=86) or THS (n=86) groups, and all 172 completed the study. The conduct phase of the study is completed, while data cleaning and analyses are ongoing. CONCLUSIONS This study is the first to test a heat-not-burn tobacco product in smokers with an already established disease. The results should further strengthen the evidence that switching to THS can significantly reduce the risk of smoking-related diseases if favorable changes in the evolution of chronic generalized periodontitis after mechanical therapy are found when compared with continued cigarette smoking. CLINICALTRIAL ClinicalTrials.gov NCT03364751; https://clinicaltrials.gov/ct2/show/NCT03364751 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/15350

In data communication and digital storage applications, interleaver, which rearranges the encoded data stream, follows the channel encoder to prevent burst errors. In general, forward error correction (FEC) codes provide protection against randomly distributed errors, whereas interleaver provides protection against error bursts. To de-interleave the interleaved data, accurate information about the interleaver parameters is required at the receiver. However, in non-cooperative context, the parameters are either not known or only partially known at the receiver. Therefore, blind/semi-blind estimation of interleaver parameters is mandatory at the receiver in order to successfully de-interleave the interleaved data. In this context, this paper proposes innovative algorithms for the estimation of interleaver parameters such as interleaver period (or size of the interleaver matrix), number of rows and columns of the interleaver matrix, and helical array step size in the presence of bit errors provided the knowledge of type of interleaver is known at the receiver. In addition, it has been assumed that the block and helical scan interleavers follow a convolutional encoder. Accepted version

Background Smoking is a significant risk factor for periodontal disease and tooth loss, as shown in several clinical studies comparing smokers and nonsmokers. Although only a few longitudinal studies have assessed the outcome of periodontal disease after smoking cessation, they indicated that recovery after nonsurgical treatment was more successful in those who had quit smoking. As part of tobacco harm reduction strategies, substituting cigarettes with alternative, less harmful tobacco products is an approach complementary to cessation for smokers who would otherwise continue to smoke. The Tobacco Heating System (THS), developed by Philip Morris International (commercialized as IQOS), is part of the heat-not-burn product category. The IQOS device electrically heats tobacco instead of burning it, at much lower temperatures than cigarettes, thereby producing substantially lower levels of harmful and potentially harmful constituents, while providing the nicotine, taste, ritual, and a sensory experience that closely parallel those of cigarettes. Phillip Morris International has published the results from a broad clinical assessment program, which was established to scientifically substantiate the harm reduction potential of the THS among adult healthy smokers switching to the THS. The program is now progressing toward including adult smokers with smoking-related diseases. Objective The goal of this study is to demonstrate favorable changes of periodontal endpoints in response to mechanical periodontal therapy in patients with generalized chronic periodontitis who completely switched to THS use compared with continued cigarette smoking. Methods This is a randomized controlled two-arm parallel-group multicenter Japanese study conducted in patients with chronic generalized periodontitis who switch from cigarettes to THS compared with smokers continuing to smoke cigarettes for 6 months. The patients were treated with mechanical periodontal therapy as per standard of care in Japan. The primary objective of the study is to demonstrate the beneficial effect of switching to THS use compared with continued cigarette smoking on pocket depth (PD) reduction in all sites with an initial PD≥4 mm. The secondary objectives include evaluation of other periodontal parameters (eg, clinical attachment level or gingival inflammation) and overall oral health status upon switching to THS. Safety was monitored throughout the study. Results In total, 172 subjects were randomized to the cigarette (n=86) or THS (n=86) groups, and all 172 completed the study. The conduct phase of the study is completed, while data cleaning and analyses are ongoing. Conclusions This study is the first to test a heat-not-burn tobacco product in smokers with an already established disease. The results should further strengthen the evidence that switching to THS can significantly reduce the risk of smoking-related diseases if favorable changes in the evolution of chronic generalized periodontitis after mechanical therapy are found when compared with continued cigarette smoking. Trial Registration ClinicalTrials.gov NCT03364751; https://clinicaltrials.gov/ct2/show/NCT03364751 International Registered Report Identifier (IRRID) DERR1-10.2196/15350

Background and Objectives: Cytochrome P450 2C9 (CYP2C9) is involved in the biotransformation of many commonly used drugs, and significant drug interactions have been reported for CYP2C9 substrates. Previously published physiologically based pharmacokinetic (PBPK) models of tolbutamide are based on an assumption that its metabolic clearance is exclusively through CYP2C9; however, many studies indicate that CYP2C9 metabolism is only responsible for 80–90% of the total clearance. Therefore, these models are not useful for predicting the magnitude of CYP2C9 drug–drug interactions (DDIs). This paper describes the development and verification of SimCYP-based PBPK models that accurately describe the human pharmacokinetics of tolbutamide when dosed alone or in combination with the CYP2C9 inhibitors sulfaphenazole and tasisulam. Methods: A PBPK model was optimized in SimCYP for tolbutamide as a CYP2C9 substrate, based on published in vitro and clinical data. This model was verified to replicate the magnitude of DDI reported with sulfaphenazole and was further applied to simulate the DDI with tasisulam, a small molecule investigated for the treatment of cancer. A clinical study (CT registration # NCT01185548) was conducted in patients with cancer to assess the pharmacokinetic interaction of tasisulum with tolbutamide. A PBPK model was built for tasisulam, and the clinical study design was replicated using the optimized tolbutamide model. Results: The optimized tolbutamide model accurately predicted the magnitude of tolbutamide AUC increase (5.3–6.2-fold) reported for sulfaphenazole. Furthermore, the PBPK simulations in a healthy volunteer population adequately predicted the increase in plasma exposure of tolbutamide in patients with cancer (predicted AUC ratio = 4.7–5.4; measured mean AUC ratio = 5.7). Conclusions: This optimized tolbutamide PBPK model was verified with two strong CYP2C9 inhibitors and can be applied to the prediction of CYP2C9 interactions for novel inhibitors. Furthermore, this work highlights the utility of mechanistic models in navigating the challenges in conducting clinical pharmacology studies in cancer patients.

Preclinical and interim results from a clinical pharmacology study in patients with cancer indicated that enzastaurin might have the potential to prolong the QT. Rather than undertake a formal thorough QT study, the effect of enzastaurin on the QT was assessed by combining the QT corrected for heart rate (QTc) intervals from 3 clinical pharmacology studies totaling 85 patients with cancer receiving multiple therapeutic or supratherapeutic doses of enzastaurin. Neither a placebo nor an active control was used. Serial, replicate, time-matched electrocardiograms were collected during a no-drug baseline day and when enzastaurin and its major active metabolite, LSN326020, had achieved steady state. Plasma concentrations of enzastaurin and LSN326020 were determined at each electrocardiogram point to enable concentration-QT analyses. The cross-study analysis showed that enzastaurin resulted in a statistically significant prolongation of the QTc at therapeutic and supratherapeutic doses. At an enzastaurin maximum plasma concentration (Cmax ) of 3660 nmol/L, the predicted QTc using Fridericia's formula (QTcF) interval and its 90% confidence interval was 17.72 milliseconds (16.52-18.92 milliseconds). Likewise, at an LSN326020 Cmax value of 1718 nmol/L, the predicted QTcF interval was 20.23 milliseconds (18.72-21.74 milliseconds). The concentration-QTcF slopes for enzastaurin and LSN326020 were positive and statistically significantly different from zero (all P < .05).

To achieve better mitigation of both cochannel interference (CCI) and intersymbol interference, a new structure using generalized estimation of multipath signals in conjunction with maximal-ratio combining diversity for wireless communications over multipath channels is introduced. In this structure, the signal replicas received from multiple paths are first independently produced by a bank of blind spatial filters and then constructively combined by a diversity combining receiver for final signal estimate. The new scheme can be applied on single antenna array or between multiple antenna subarrays. It will be shown, from both theoretical analysis and numerical experiments, that the new scheme provides both space diversity gains and path diversity gains while suppressing the CCIs.

Necitumumab is a second-generation, recombinant, human immunoglobulin G1 monoclonal antibody that blocks the ligand binding site of the epidermal growth factor receptor. The primary objective of this phase 2 study, conducted in accordance with International Conference on Harmonisation E14 guidance, was to determine the effect of necitumumab treatment on QT/QTc interval in patients with advanced solid tumors. Patients received necitumumab monotherapy at an absolute dose of 800 mg, once per week for each 6-week cycle. Triplicate electrocardiogram readings were taken at pretreatment (baseline) and then weekly at multiple timepoints that were time-matched with blood samples to determine necitumumab concentrations. Seventy-five patients received treatment. Overall, the upper bound of the two-sided 90 % confidence interval for mean change from baseline in QTc in cycle 1 did not exceed 10 ms. No patients had a mean QTcF interval >500 ms, and no patients had an increase of >60 ms. Necitumumab concentration–QTc analysis also showed that necitumumab is unlikely to cause QTc prolongation. The results demonstrate lack of effect of necitumumab on the QTc interval in heavily pretreated patients with advanced solid tumors, suggesting that QT prolongation is not a major safety concern for necitumumab at the recommended therapeutic dose. The safety profile was consistent with the known safety profile of necitumumab.

This paper proposes a filter for joint detection and tracking of a single target using measurements from multiple sensors under the presence of detection uncertainty and clutter. To capture the target presence/absence in the surveillance region as well as its kinematic state, we represent the target state as a set that can take on either the empty set or a singleton. The uncertainty in such a set is modeled by a Bernoulli random finite set (RFS), and Bayes optimal estimators for joint detection and tracking are presented. A closed-form solution for the linear-Gaussian model is derived and an analytic implementation is proposed for nonlinear models based on the unscented transform. We apply the technique to tracking targets constrained to move on roads with time difference of arrival/frequency difference of arrival (TDOA/FDOA) measurements.

Preclinical and interim results from a clinical pharmacology study in patients with cancer indicated that enzastaurin might have the potential to prolong the QT. Rather than undertake a formal thorough QT study, the effect of enzastaurin on the QT was assessed by combining the QT corrected for heart rate (QTc) intervals from 3 clinical pharmacology studies totaling 85 patients with cancer receiving multiple therapeutic or supratherapeutic doses of enzastaurin. Neither a placebo nor an active control was used. Serial, replicate, time-matched electrocardiograms were collected during a no-drug baseline day and when enzastaurin and its major active metabolite, LSN326020, had achieved steady state. Plasma concentrations of enzastaurin and LSN326020 were determined at each electrocardiogram point to enable concentration-QT analyses. The cross-study analysis showed that enzastaurin resulted in a statistically significant prolongation of the QTc at therapeutic and supratherapeutic doses. At an enzastaurin maximum plasma concentration (Cmax ) of 3660 nmol/L, the predicted QTc using Fridericia's formula (QTcF) interval and its 90% confidence interval was 17.72 milliseconds (16.52-18.92 milliseconds). Likewise, at an LSN326020 Cmax value of 1718 nmol/L, the predicted QTcF interval was 20.23 milliseconds (18.72-21.74 milliseconds). The concentration-QTcF slopes for enzastaurin and LSN326020 were positive and statistically significantly different from zero (all P.05).

Olaratumab (Olara), a fully human monoclonal antibody that selectively binds human platelet-derived growth factor receptor alpha and blocks ligand binding, shows encouraging efficacy in combination with Dox in STS. Patients with metastatic or locally advanced STS not amenable to treatment with surgery or curative radiotherapy, aged ?18 years with an ECOG PS of 0-2 and documented LVE fraction ?50% were included. The primary objective was to assess the effect of Olara on the PK of Dox. Secondary objectives were to further characterize the PK and safety profiles of Olara alone and in combination with Dox. Drug-drug interaction (DDI) was assessed in 21-day cycles, where patients received each drug alone (Cycle 1) then in combination (Cycle 2). In Cycles 3-8, patients with clinical benefit could continue treatment with Olara+Dox. 15-mg/kg Olara was given IV over ∼60 min; 75-mg/m2 Dox was given IV over ∼15 min. Overall, 25 patients (10 male and 15 female, aged 27-83 years) received at least one dose of study drug; as planned, 15 patients were evaluable for PK and DDI assessment. The AUC and Cmax for Dox were similar with or without Olara; the 90% CIs for the ratios of geometric LS means for AUC were within the standard no-effect boundary (0.8, 1.25); the 90% CI for Cmax was only slightly out of the boundary but with a Cmax ratio close to unity (0.984). After the first infusion of Olara alone (Cycle 1, Day 10), a mean Olara Cmax of 293μg/mL was achieved at ∼2h post start of infusion, with a mean t1/2 of ∼157h. The mean Olara CL was 0.0259L/h. After the second infusion (Cycle 2, Day 1, Olara+Dox), Olara serum concentration had a median tmax of ∼2.8h post start of infusion, and the mean Cmax was higher (393μg/mL), due to the residual Olara serum concentrations from cycle 1. The mean t1/2 (∼131h) and CL (0.0218L/h) were, however, similar to those obtained after the first infusion. These Olara PK results are consistent with those previously reported. No deaths occurred. The most common treatment-emergent AE reported during the study were nausea (48%) and fatigue (44%). One Grade 4 IRR was observed; there was no evidence of QT prolongation. IV infusion of Olara did not have a clinically relevant effect on systemic exposure to Dox when both agents were given in combination. The PK of Olara alone and with Dox was consistent with previously reported data. Olara+Dox had an acceptable safety profile Citation Format: Victor Villalobos, Mark Agulnik, Seth M. Pollack, Daniel A. Rushing, Arun Singh, Brian A. Van Tine, Chukwuemeka Okereke, Wee Teck Ng, Damien M. Cronier. A phase I open-label study to evaluate the effect of olaratumab on the pharmacokinetics (PK) of doxorubicin (Dox) in patients with advanced soft tissue sarcoma (STS). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT145.

Abemaciclib is an oral, selective, and potent small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) being investigated for the treatment of patients with refractory hormone-receptor positive (HR+) advanced or metastatic breast cancer. The absolute bioavailability and effect of food on pharmacokinetics (PK) following a single 200-mg oral dose of abemaciclib in healthy subjects were evaluated in three studies (Table 1). Abemaciclib plasma concentrations were measured serially pre-dose through 192 hours post-dose. Non-compartmental analysis was used to calculate PK parameters, and a mixed-effects model was used for statistical inference. In Study 1 the absolute bioavailability of a 200-mg dose of abemaciclib was 45% (90% CI: 40%, 51%). In Study 2 the ratios of AUC0-? after a high-fat or standard meal compared to fasting showed no effect (90% CIs within 0.80, 1.25). However, Cmax increased by 24% and 25% following high-fat and standard meals, respectively, compared to fasting (upper 90% CIs >1.25). No differences were found in the AUC0-? and Cmax of abemaciclib following a high-fat meal compared to a standard meal (90% CI within 0.80, 1.25). The median tmax was delayed by 2 hours following a high-fat meal compared to fasting (p = 0006). However, there was no difference in median tmax between the standard meal and fasting (p = .7197). Abemaciclib terminal half-life was similar across fed and fasted conditions. The late-breaking Study-3 results will be presented. In conclusion, abemaciclib oral bioavailability is sufficient to achieve therapeutic exposure. Food with abemaciclib does not reduce or increase the inter-individual PK variability and does not have a clinically-relevant impact on the PK of abemaciclib. Therefore, abemaciclib may be administered without regard to food. Table 1Designs for three open-label clinical studies of abemaciclib as a single 200-mg oral dose administered to healthy subjectsStudy ParametersNCT02327143a (Study 1)I3Y-MC-JPBSNCT02059148a (Study 2)I3Y-MC-JPBGNCT02482935a (Study 3)I3Y-MC-JPBUCompleted subjects (N)82329Overall designs and formulationsAbsolute bioavailability, 4 x 50-mg (25% w/w) capsules and tracer IVbPilot food effect, randomized crossover 3 period, 6 sequence 4 x 50-mg (50% w/w) capsulesPivotal food effect, randomized crossover 2 period, 2 sequence 2 x 100-mg (25% w/w) capsulesMeal conditionFastedFastedStandard mealHigh-fat, high-calorie mealFastedHigh-fat, high-calorie meal Citation Format: Kellie Turner, Jill Chappell, Palaniappan Kulanthaivel, Wee Teck Ng, Jane Royalty. Food effect on the pharmacokinetics of 200-mg abemaciclib in healthy subject. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT152.

Abemaciclib is a selective and potent small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) being investigated for treatment of refractory hormone-receptor positive (HR+) advanced or metastatic breast cancer. In vitro, CYP3A is responsible for >99% of the CYP-mediated microsomal metabolism of abemaciclib and its active metabolites. Three clinical studies evaluated the disposition and metabolism and drug interaction potential of abemaciclib in the presence of a strong CYP3A-inducer, rifampin, or a strong CYP3A-inhibitor, clarithromycin. Abemaciclib disposition and metabolism were determined following a single oral 150 mg dose of [14C]-abemaciclib in healthy subjects (N = 6). In the rifampin interaction study, abemaciclib was administered as a single oral 200 mg dose in healthy subjects (N = 24) on 2 occasions: alone on Day 1 of Period 1 and in combination with 600 mg rifampin on Day 7 of Period 2, after 6 days of rifampin once daily (QD) dosing; rifampin continued QD for 7 days after abemaciclib. In the clarithromycin interaction study, abemaciclib was administered as a single oral 50 mg dose in patients with advanced cancer (N = 26) on 2 occasions: alone in Period 1 and on Day 5 of clarithromycin dosing (500 mg BID) in Period 2 followed by an additional 7 days of clarithromycin. Abemaciclib was extensively metabolized, with less than 10% of parent drug recovered unchanged in feces. Parent drug and 3 active metabolites; (LSN2839567 [M2], LSN3106729 [M18], and LSN3106726 [M20]) were detected in plasma. The mean t1/2 in healthy subjects was 29.0, 104.0, 55.9, and 43.1 hours for abemaciclib, M2, M18, and M20, respectively. Coadministration with rifampin compared to abemaciclib alone decreased abemaciclib AUC(0-?) and Cmax by 95% and 92%, respectively, and decreased AUC(0-?) and Cmax of total active species (abemaciclib + M2 + M18+ M20) by 77% and 45%, respectively. Coadministration with clarithromycin compared to abemaciclib alone increased abemaciclib AUC(0-?) and Cmax by 237% and 30%, respectively; and increased the total active species AUC(0-?) by 119% and decreased Cmax by 7%. The mean abemaciclib t1/2 was prolonged from 28.8 to 63.6 hours. No clinically significant safety concerns were observed following single doses of abemaciclib in healthy subjects or in patients with advanced cancer based on vital signs, clinical laboratory evaluations, and electrocardiogram data. The human absorption, distribution, metabolism and excretion study indicated that abemaciclib was cleared primarily by hepatic metabolism, and the clinical drug-drug interaction studies with strong CYP3A inducer and inhibitor substantiated the major role of CYP3A in the metabolism of abemaciclib. Due to significant changes in abemaciclib and active-metabolite exposure in the presence of strong CYP3A inducers and inhibitors, concomitant use with abemaciclib should be avoided, or abemaciclib dose may require adjustment. Citation Format: Palaniappan Kulanthaivel, Daruka Mahadevan, P. Kellie Turner, Jane Royalty, Wee Teck Ng, Ping Yi, Jessica Rehmel, Kenneth Cassidy, Jill Chappell. Pharmacokinetic drug interactions between abemaciclib and CYP3A inducers and inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT153.

In this letter, we analyze the inter-carrier-interference (ICI) caused by Doppler spreading in an orthogonal frequency-division multiplexing system when the angle-of-arrival (AOA) of the received signal is not uniformly distributed. An expression of the ICI power is derived by taking into account the probability density function of the AOA. We also present examples using directional antennas at the base station, at the mobile or at both mobile and base station. The ICI power changes marginally when a directional antenna is placed at the base station. Finally, we show that the ICI power can be reduced substantially when a directional antenna, along with frequency tracking, is employed at the mobile.

In the letter by Xu et al. (see ibid., vol.5, p.13-15, Jan. 2001), the Doppler PSD when using directional antenna at the mobile station was derived. However, the ranges in some equations in this letter were not correctly stated. In this letter, we point out the discrepancies and give correct range of values.

Large SONET/SDH networks typically have 20-30% "stranded" resources, both in wasted bandwidth and in untracked hardware. We present a novel approach that uses localized heuristics to uncover stranded resources and configuration errors based on field data alone. Unlike traditional solution which requires complex reconciliations between field data and various inventory databases, our approach synthesizes higher-level models from field data and analyzes the models to identify stranded resources and configuration errors. Field trial results indicate that our approach is very effective. For example, we found that 33% of 1 + 1 protection circuits have incorrect configurations impacting service reliability, and 10% of the circuits in a large carrier network have stranded bandwidth that can be "recovered".

Orthogonal frequency division multiplexing (OFDM) can be successfully used in mitigating the effect of multipath in a wireless channel. However, its' performance degrade in the presence of Doppler spreading. In this paper, multiple beamforming using uniform linear arrays (ULA) is used for OFDM systems to reduce Doppler spread and exploit the advantage of diversity. Each of the beams receiver signal which equal Doppler spread, which are combined using equal gain combining (EGC). We also present a method of determining the frequency compensating parameters, for beams pointing in different directions. Finally, our simulation results show that angular diversity in OFDM systems can provide significant improvement as compared to using only single beamforming.

We analyze the inter-carrier-interference (ICI) caused by multiple Rician path and Doppler spreading in orthogonal frequency division multiplexing (OFDM) systems. The general form for the ICI power is derived by taking into consideration the correlation equation of the Rician channel. We have derived a equation for estimating the frequency tracking parameter. We also present examples by using ideal beamforming at the mobile. For a multiple Rician channel, it shows that the reduction in ICI power is not as much as in the case of Rayleigh channel. However, in the presence of only one Rician path, the reduction in ICI power is marginally better than the Rayleigh channel.

Fault injection is typically used to characterize failures and to validate and compare fault-tolerant mechanisms. However fault injection is rarely used for all these purposes to guide the design and implementation of a fault tolerant system. We present a systematic and quantitative approach for using software-implemented fault injection to guide the design and implementation of a fault-tolerant system. Our system design goal is to build a write-back file cache on Intel PCs that is as reliable as a write-through file cache. We follow an iterative approach to improve robustness in the presence of operating system errors. In each iteration, we measure the reliability of the system, analyze the fault symptoms that lead to data con option, and apply fault-tolerant mechanisms that address the fault symptoms. Our initial system is 13 times less reliable than a write-through file cache. The result of several iterations is a design that is both more reliable (1.9% vs. 3.1% corruption rate) and 5-9 times as fast as a write-through file cache.

Memory is commonly viewed as an unreliable place to store permanent data (files) because it is perceived to be vulnerable to system crashes. Yet despite all the negative implications of memory's unreliability, no data exists that quantifies how vulnerable memory actually is to system crashes. This paper quantitatively compares the vulnerability of disk and memory to operating system crashes. We use software fault injection to induce a wide variety of operating system crashes in DEC Alpha workstations running Digital Unix, ranging from bit errors in the kernel stack to deleting branch instructions to C-level allocation management errors. We find that files on disk are rarely corrupted (1.1% corruption rate), which agrees with our intuition. We also find that, surprisingly files in memory are nearly as safe as files on disk. Only 10 of the 650 crashes we observed (1.5%) corrupt any files in memory. Our data contradicts the common assumption that operating system crashes often corrupt files in memory and suggests that memory can be used to store permanent data rather than needing to write it back to disk.

One of the fundamental limits to high-performance, high-reliability file systems is memory's vulnerability to system crashes. Because memory is viewed as unsafe, systems periodically write data back to disk. The extra disk traffic lowers performance, and the delay period before data is safe lowers reliability. The goal of the Rio (RAM I/O) file cache is to make ordinary main memory safe for persistent storage by enabling memory to survive operating system crashes. Reliable memory enables a system to achieve the best of both worlds: reliability equivalent to a write-through file cache, where every write is instantly safe, and performance equivalent to a pure write-back cache, with no reliability-induced writes to disk. To achieve reliability, we protect memory during a crash and restore it during a reboot (a "warm" reboot). Extensive crash tests show that even without protection, warm reboot enables memory to achieve reliability close to that of a write-through file system. Adding protection makes memory even safer than a write-through file system while adding essentially no overhead. By eliminating reliability-induced disk writes, Rio performs 4-22 times as fast as a write-through file system, 2-14 times as fast as a standard Unix file system, and 1-3 times as fast as an optimized system that risks losing 30 seconds of data and metadata.