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Plant physiology can offer invaluable insights to accelerate genetic gain. However, translating physiological understanding into breeding decisions has been an ongoing and complex endeavor. Here we demonstrate an approach to leverage physiology and genomics to hasten crop improvement. A half-diallel maize (Zea mays) experiment resulting from crossing 9 elite inbreds was conducted at 17 locations in the USA corn belt and 6 locations at managed stress environments between 2017 and 2019 covering a range of water environments from 377 to 760 mm of evapotranspiration and family mean yields from 542 to 1,874 g m−2. Results from analyses of 35 families and 2,367 hybrids using crop growth models linked to whole-genome prediction (CGM–WGP) demonstrated that CGM–WGP offered a predictive accuracy advantage compared to BayesA for untested genotypes evaluated in untested environments (r = 0.43 versus r = 0.27). In contrast to WGP, CGMs can deal effectively with time-dependent interactions between a physiological process and the environment. To facilitate the selection/identification of traits for modeling yield, an algorithmic approach was introduced. The method was able to identify 4 out of 12 candidate traits known to explain yield variation in maize. The estimation of allelic and physiological values for each genotype using the CGM created in silico phenotypes (e.g. root elongation) and physiological hypotheses that could be tested within the breeding program in an iterative manner. Overall, the approach and results suggest a promising future to fully harness digital technologies, gap analysis, and physiological knowledge to hasten genetic gain by improving predictive skill and definition of breeding goals.

A major focus for genomic prediction has been on improving trait prediction accuracy using combinations of algorithms and the training data sets available from plant breeding multi-environment trials (METs). Any improvements in prediction accuracy are viewed as pathways to improve traits in the reference population of genotypes and product performance in the target population of environments (TPE). To realize these breeding outcomes there must be a positive MET-TPE relationship that provides consistency between the trait variation expressed within the MET data sets that are used to train the genome-to-phenome (G2P) model for applications of genomic prediction and the realized trait and performance differences in the TPE for the genotypes that are the prediction targets. The strength of this MET-TPE relationship is usually assumed to be high, however it is rarely quantified. To date investigations of genomic prediction methods have focused on improving prediction accuracy within MET training data sets, with less attention to quantifying the structure of the TPE and the MET-TPE relationship and their potential impact on training the G2P model for applications of genomic prediction to accelerate breeding outcomes for the on-farm TPE. We extend the breeder’s equation and use an example to demonstrate the importance of the MET-TPE relationship as a key component for the design of genomic prediction methods to realize improved rates of genetic gain for the target yield, quality, stress tolerance and yield stability traits in the on-farm TPE.

Transgenes that improve quantitative traits have traditionally been evaluated in one or a few genetic backgrounds across multiple environments. However, testing across multiple genetic backgrounds can be equally important to accurately quantify the value of a transgene for breeding objectives. Creating near-isogenic lines across a wide germplasm space is costly and time consuming, which renders it impractical during early stages of testing. In this experiment, we evaluate three approaches to sample the genetic space while concurrently testing across environments. We created both transgenic and non-transgenic doubled haploid lines, F2:3lines, and bulk F3families to determine if all methods resulted in similar estimation of transgene value and to identify the number of yield trial plots from each method necessary to obtain a stable estimate of the transgene value. With one exception, the three methods consistently estimated a similar effect of the transgene. We suggest that bulked F3lines topcrossed to a tester inbred is the most effective method to estimate the value of a transgene across both genetic space and environments.

Transgenes have been successfully commercialized for qualitatively inherited insect and herbicide resistance traits that show similar effects across genetic backgrounds. However, for quantitative traits like yield, genetic background may affect the measured transgene value. In this paper, we evaluated whether different genetic backgrounds impact the estimated value of a transgene for grain yield, ear height, and anthesis-silking interval for maize by developing isogenic pairs of lines with and without a transgene and testing them in hybrid combination with non-transgenic lines from a complementary heterotic group across eleven environments in the USA. Over all hybrid combinations, the transgene increased yield by 0.2 Mg ha−1. Across multiple non-transgenic lines of the opposing heterotic group, the transgene effect within a line pair ranged from an increase of 0.8 Mg ha−1for the NSS4 and SS7 transgenic lines to a reduction of 0.3 Mg ha−1for the NSS5 transgenic line when compared to their non-transgenic isoline. Transgenic hybrids were often taller than non-transgenic hybrids (P

Because plants capture water and nutrients through roots, it was proposed that changes in root systems architecture (RSA) might underpin the 3-fold increase in maize (Zea mays L.) grain yield over the last century. Here we show that both RSA and yield have changed with decades of maize breeding, but not the crop water uptake. Results from X-ray phenotyping in controlled environments showed that single cross (SX) hybrids have smaller root systems than double cross (DX) hybrids for root diameters between 2465 µm and 181µm (P, Emerging opportunity to continue long-term genetic gain in maize yield in the US corn belt by improving the balance between canopy, root, and reproductive growth and development.

Water floods are typically conducted using the least expensive, easily available, non-damaging brine. Very little attention is given to the possibility of changing brine composition to improve oil recovery. Over the last 20 years, there has been laboratory and field trial evidence that shows changing brine chemistry, especially to low salinity, can sometimes increase the recovery. The various mechanisms of additional oil recovery from changing brine chemistry are not entirely clear. We report here on the effect of using low salinity and divalent altered brines on oil recovery through a variety of laboratory methods and materials. More than twenty corefloods were conducted to evaluate the effect of brine chemistry and initial wettability on incremental oil recovery. We also performed phase behavior tests, contact angle measurements, and wettability index measurements to evaluate recovery mechanisms. Initial wettability of the core was altered by ageing it with different crude oil containing wide range of asphaltene content. The core flood with lowest wettability index (least water-wet) produced about 12% incremental recovery while the most water-wet core only produced ∼ 4% during the secondary low salinity waterflood.

FD-180 and FD-600 are two next-generation sequencing panels developed by First Dimension Biosciences Co. for detecting mutations in cancer tissues and providing therapeutics guidance in precision medicine applications. FD-180 includes the coding exons of about 180 genes, including all the known drug target genes and some important driver genes; whereas FD-600 includes the coding exons of 578 cancer driver genes in the COSMIC database as of year 2016 when the panels are developed. Additional noncoding regions in the selected genes are included if they are reported as clinically meaningful in ClinVar. Tumor mutation burden (TMB) is a statistical index calculated from genomic sequencing for immunotherapeutic treatments, especially for PD1/PD-L1 antibodies. We used our computational algorithm on 81 patients and provided their classifications. TMB can be estimated quite accurately for the FD-180 and FD-600 panels, both for The Cancer Genome Atlas data and in clinical practice.

BACKGROUND AND AIMS Interleukin-22 has beneficial effects on inflammation and impaired hepatic regeneration that characterize alcohol-associated hepatitis (AH). F-652 is a recombinant fusion protein of human interleukin-22 and immunoglobulin G2 fragment crystallizable. This study aims to assess the safety and efficacy signals of F-652 in patients with moderate and severe AH. APPROACH AND RESULTS A phase-2 dose-escalating study was carried out. F-652 (10 μg/kg, 30 μg/kg, or 45 μg/kg) administered on days 1 and 7 was tested in 3 patients each with moderate (Model for End-Stage Liver Disease [MELD] scores: 11-20) and severe AH (MELD scores: 21-28). Safety was defined by absence of serious adverse events and efficacy was assessed by Lille score, changes in MELD score, and serum bilirubin and aminotransferases at days 28 and 42. Three independent propensity-matched comparator patient cohorts were used. Plasma extracellular vesicles and multiplex serum cytokines were measured to assess inflammation and hepatic regeneration. Eighteen patients (9 moderate and 9 severe AH) were enrolled, 66% were male, and the mean age was 48 years. The half-life of F-652 following the first dose was 61-85 hours. There were no serious adverse events leading to discontinuation. The MELD score and serum aminotransferases decreased significantly at days 28 and 42 from baseline (P

Serious games provide a way for stakeholders to become engaged in and understand the issues and constraints on a real-world system. An application of a serious game is explored, as a way to improve engagement and learning of participants in a water management planning process. Bow River Sim is a single-player game that helps the user to understand the Water Resources Management Model (WRMM) and to visualize the implications and impacts around system interactions in the basin. The Bow River Sim simulates water management decision-making based on maximizing social, economic, and environmental benefits while managing limited water supply. The game incorporates the principles of ‘meaningful play’ and provides a user-friendly interface, a fun game, and visual elements. The paper aims to (a) provide an overview of Bow River Sim, (b) illustrate how innovations such as serious games enhance learning processes for the user, and (c) illustrate the application of Bow River Sim and key learnings.

A Crop Growth Model (CGM) is used to demonstrate a biophysical framework for predicting grain yield outcomes for Genotype by Environment by Management (G×E×M) scenarios. This required development of a CGM to encode contributions of genetic and environmental determinants of biophysical processes that influence key resource (radiation, water, nutrients) use and yield‐productivity within the context of the target agricultural system. Prediction of water‐driven yield‐productivity of maize for a wide range of G×E×M scenarios in the U.S. corn‐belt is used as a case study to demonstrate applications of the framework. Three experimental evaluations are conducted to test predictions of G×E×M yield expectations derived from the framework: (1) A maize hybrid genetic gain study, (2) A maize yield potential study, and (3) A maize drought study. Examples of convergence between key G×E×M predictions from the CGM and the results of the empirical studies are demonstrated. Potential applications of the prediction framework for design of integrated crop improvement strategies are discussed. The prediction framework opens new opportunities for rapid design and testing of novel crop improvement strategies based on an integrated understanding of G×E×M interactions. Importantly the CGM ensures that the yield predictions for the G×E×M scenarios are grounded in the biophysical properties and limits of predictability for the crop system. The identification and delivery of novel pathways to improved crop productivity can be accelerated through use of the proposed framework to design crop improvement strategies that integrate genetic gains from breeding and crop management strategies that reduce yield gaps.

Key messageWe evaluate self-organizing maps (SOM) to identify adaptation zones and visualize multi-environment genotypic responses. We apply SOM to multiple traits and crop growth model output of large-scale European sunflower data.AbstractGenotype-by-environment interactions (G × E) complicate the selection of well-adapted varieties. A possible solution is to group trial locations into adaptation zones with G × E occurring mainly between zones. By selecting for good performance inside those zones, response to selection is increased. In this paper, we present a two-step procedure to identify adaptation zones that starts from a self-organizing map (SOM). In the SOM, trials across locations and years are assigned to groups, called units, that are organized on a two-dimensional grid. Units that are further apart contain more distinct trials. In an iterative process of reweighting trial contributions to units, the grid configuration is learnt simultaneously with the trial assignment to units. An aggregation of the units in the SOM by hierarchical clustering then produces environment types, i.e. trials with similar growing conditions. Adaptation zones can subsequently be identified by grouping trial locations with similar distributions of environment types across years. For the construction of SOMs, multiple data types can be combined. We compared environment types and adaptation zones obtained for European sunflower from quantitative traits like yield, oil content, phenology and disease scores with those obtained from environmental indices calculated with the crop growth model Sunflo. We also show how results are affected by input data organization and user-defined weights for genotypes and traits. Adaptation zones for European sunflower as identified by our SOM-based strategy captured substantial genotype-by-location interaction and pointed to trials in Spain, Turkey and South Bulgaria as inducing different genotypic responses.

Recently Solid-State Battery has received increased attention as the next generation energy storage device due to its high energy density, improved safety, and thermal stability. Among various types of solid electrolytes (SE), lithium (Li)-stuffed garnet-type Li6.75La3Zr1.75Ta0.25O12 (LLZT) delivered high ionic conductivity (~10-4 S/cm) and wide electrochemical stability window. Despite such promising properties, there are few technical challenges that prevent the implementation of LLZT in practical battery cells. First, LLZT suffers from a high interfacial resistance due to its poor wettability in contact with Li metal anode. Second, LLZT suffers from Li-dendrite penetration through grain boundaries during cycling. The grain boundaries have high electrical and low ionic conductivities which attracts Li-ions and electrons and nucleates metallic Li. Additionally, poor wetting between Li-anode and LLZT causes their limited contact at the Li/SE interface. Electrical current will be concentrated on those limited interfacial areas and accelerate the Li nucleation and subsequent dendritic growth. To address these issues, various strategies have been proposed including elemental doping, in-situ solid-electrolyte interface (SEI) formation, and interlayer engineering. Among these strategies, amorphous glass layer between Li-anode and LLZT has advantages of simple processing and manufacturing friendliness, which involves heating to melt a glass followed by a fast cooling. Therefore, moderate melting temperature (e.g., T < 800 oC) is an important selection criteria for suitable glass material candidate. In addition, the coating layer should have reasonably good ionic conductivity . In this study, we selected and investigated Li3BO3 (LBO) as the glass interlayer based on its low melting temperature (~700 oC), good stability between Li metal and LLZT, and moderate ionic conductivity (~ 10-6 S/cm). A systematic design of experiments was performed to understanding the synthesis parameter – microstructure – performance relationship. First, we examined the effect of temperature programs (e.g., heating/cooling rate, temperature, time) and slurry composition on the microstructure of the LBO glass layer coated onto LLZT pellet. Scanning electron microscopy (SEM) revealed that homogeneous LBO layer without cracks or pinhole could be obtained by optimizing the parameters. Secondly, we investigated the effect of LBO glass interlayer on the electrochemical properties of the solid-state battery cells. Introducing LBO interlayer to a Li/SE/Li symmetrical cell (i) increased cell interfacial conductivity from 1.32*10-4 to 1.06*10-3 S/cm as evidenced by electrochemical impedance spectroscopy (EIS) and (ii) increased critical current densities (CCD) from 0.1 mA/cm2 (baseline) to 0.4 mAh/cm2. Finally, we performed extended plating/stripping cycling test from the symmetric cells at a specific current of 0.1 mA/cm2. Although the bare LLZT cell failed after 10 cycles, the cell with LBO interlayer operated without short-circuit for 93 cycles. The electrochemical characterization test clearly demonstrated that the LBO layer stabilize the Li/SE interface by improving a tolerance against the Li-dendrite penetration. Our promising results will offer a useful guideline for the future researchers on the design and optimization of the solid-state battery interfaces.

Genetic gain in breeding programs depends on the predictive skill of genotype-to-phenotype algorithms and precision of phenotyping, both integrated with well-defined breeding objectives for a target population of environments (TPE). The integration of physiology and genomics could improve predictive skill by capturing additive and non-additive interaction effects of genotype (G), environment (E), and management (M). Precision phenotyping at managed stress environments (MSEs) can elicit physiological expression of processes that differentiate germplasm for performance in target environments, thus enabling algorithm training. Gap analysis methodology enables design of GxM technologies for target environments by assessing the difference between current and attainable yields within physiological limits. Harnessing digital technologies such as crop growth model-whole genome prediction (CGM-WGP) and gap analysis, and MSEs, can hasten genetic gain by improving predictive skill and definition of breeding goals in the U.S. maize production TPE. A half-diallel maize experiment resulting from crossing 9 elite maize inbreds was conducted at 17 locations in the TPE and 6 locations at MSEs between 2017 and 2019. Analyses over 35 families represented by 2367 hybrids demonstrated that CGM-WGP offered a predictive advantage (y) compared to WGP that increased with occurrence of drought as measured by decreasing whole-season evapotranspiration (ET; log(y) = 0.80(±0.6) − 0.006(±0.001) ×ET;r2= 0.59;df= 21). Predictions of unobserved physiological traits using the CGM, akin to digital phenotyping, were stable. This understanding of germplasm response to ET enables predictive design of opportunities to close productivity gaps. We conclude that enabling physiology through digital methods can hasten genetic gain by improving predictive skill and defining breeding objectives bounded by physiological realities.

Over the last decade, society witnessed the largest expansion of agricultural land planted with drought tolerant (DT) maize (Zea maysL.) Dedicated efforts to drought breeding led to development of DT maize. Here we show that after two decades of sustained breeding efforts the rate of crop improvement under drought is in the range 1.0-1.6% yr−1, which is higher than rates (0.7% yr−1) reported prior to drought breeding. Prediction technologies that leverage biological understanding and statistical learning to improve upon the quantitative genetics framework will further accelerate genetic gain. A review of published and unpublished analyses conducted on data including 138 breeding populations and 93 environments between 2009 and 2019 demonstrated an average prediction skill (r) improvement around 0.2. These methods applied to pre-commercial stages showed accuracies higher that current statistical approaches (0.85 vs. 0.70). Improvement in hybrid and management choice can increase water productivity. Digital gap analyses are applicable at field scale suggesting the possibility of transition from evaluating hybrids to designing genotype x management (GxM) technologies for target cropping systems in drought prone areas. Due to the biocomplexity of drought, research and development efforts should be sustained to advance knowledge and iteratively improve models.HighlightCrop improvement rate in maize increased after implementation of drought breeding efforts. Harnessing crop, quantitative genetics and gap models will enable the transition from genetic evaluation to crop design.

Plants capture soil resources to produce the grains required to feed a growing population. Because plants capture water and nutrients through roots, it was proposed that changes in root systems architecture (RSA) underpin the three-fold increase in maize grain yield over the last century1,2,3,4. Within this framework, improvements in reproductive resilience due to selection are caused by increased water capture1. Here we show that both root architecture and yield have changed with decades of maize breeding, but not the water capture. Consistent with Darwinian agriculture5 theory, improved reproductive resilience6,7 enabled farmers increase the number of plants per unit land8,9,10, capture soil resources, and produced more dry matter and grain. Throughout the last century, selection operated to adapt roots to crowding, enabling reallocation of C from large root systems to the growing ear and the small roots of plants cultivated in high plant populations in modern agriculture.

A successful strategy for prediction of crop yield that accounts for the effects of genotype, environment and their interactions with management will create many opportunities for enhancing the productivity of agricultural systems. Crop growth models (CGMs) have a history of application for crop management decision support. Recently, whole genome prediction (WGP) methodologies have been developed and applied in breeding to enable prediction of crop traits for new genotypes, and thus increased the size of plant breeding programs without expanding expensive field testing. The integration of a CGM into the algorithm for WGP, referred to as CGM-WGP, has opened up the potential for prediction of G × E × M interactions for breeding and product placement applications. The main objectives of this study were to extend CGM-WGP methodology to train models using data from multiple environments, and to evaluate, using both synthetic and experimental data from a maize drought breeding program, whether CGM-WGP methodology can enable improved phenotypic prediction when G × E interactions are an important determinant of performance. The CGM-WGP methodology was improved by 1) reformulating the model as a Bayesian generalized linear hierarchical model, and 2) by sampling the posterior distribution using a Metropolis-within-Gibbs sampling algorithm. The increased efficiency of the algorithm enabled the use of multiple environments and larger populations than those used in previous studies. Synthetic datasets included three environments and an empirical dataset included two environments contrasting for drought stress pattern and intensity. The empirical dataset included four double haploid populations expressing different levels of G × E interaction. Collectively, the prediction accuracy results for the empirical study indicate there were realized advantages in prediction accuracy for yield, in both the water limited and the not water limited environments, from the modeling of the G × E interactions by the CGM-WGP methodology relative to the reference method BayesA. Similarly, the difference in CGM-WGP accuracy relative to BayesA increased with decreasing similarity between the environment types utilized for training and evaluating the predictions. The synthesis provided in this work that encompasses crop physiology and modeling, quantitative genetics, genomic prediction and breeding, should stimulate a cross disciplinary dialogue towards building the next generation of prediction methodologies.

Background: Identifying bladder cancer-specific miRNA expression signatures by large scale miRNA profiling Methods：30 bladder cancer (BC) tissue samples and matched adjacent normal bladder tissue samples from patients with BC were collected and were divided into two groups； a training group and a blind testing group. Expressions of 1900 miRNAs and controls were detected in a BC miRNA pool and in a normal miRNAs pool, respectively. 380 differential expressed miRNAs between the BC miRNA pool and the normal miRNA pool were selected. The primers for detecting the 380 selected miRNAs and controls were used to generate one 384-well panel. This panel was used to profile miRNA expression of each individual sample in the training group and in the blind testing group. Data analysis was performed using a machine learning approach of a support vector machine classifier with a Student's t-test feature selection procedure. Results： We identified signatures consisting of three or four miRNAs that could distinguish BC from normal controls with an accuracy of 100% in the training model and an accuracy of over 95% in the blind test. All identified signatures contain hsa-miR-133a. We also revealed that the miRNA183-96 cluster and the miR200 cluster are both significantly up-regulated in BC. Conclusions：The identified signatures containing hsa-miR-133a could be used as biomarkers in the diagnosis and prognosis of BC.

Abstract: Background：to explore several miRNA expression signatures correlated with bladder cancer diagnosis according to a large scale miRNA expression profiling. Methods：30 patients’ tissue samples contain BC and adjacent normal tissue samples were divided into two groups, training group and double-blind test group. Expressions of miRNAs in BC tissue samples pool and adjacent normal tissue samples pool were detected by primers for 1900 miRNAs and controls in five 384-well plates. Differential expressed miRNAs between BC tissue samples pool and adjacent normal tissue samples pool were selected and generated one 384-well panel to detect 380 selected miRNAs. This panel will be used to profile miRNA expression of each individual sample in training group and in double blind test group. Data analysis was performed using a machine learning approach of a Support Vector Machine classifier with a Student's t-test feature selection procedure. Results： We identified signatures consisting of three or four miRNAs with optimum classification performance; all identified signatures containing hsa-miR-133a could distinguish BC cases from normal controls with an accuracy of 100% in training model and accuracy over 95% in double blinding test. We also revealed two miRNA clusters of miR183-96-and miR200 are significantly up-regulated in bladder cancer tissue samples compared with those in normal tissue samples.suggesting theses miRNAs. Conclusions：miRNA signatures containing hsa-miR-133a may be involved in bladder cancer development and may be used as bio-markers in BC diagnosis and serves as a complement to cystoscopy.

Recently, the electronics industry is moving maturely on the mobile/tablet market. With the aggressive demand on self-driving car, the next fast growing market will be Automotive in the near future. Advance technology/packages are needed to provide ideal solutions for reliablitly and high electrical performance. Multi-function integration is also one of the critical requirements. To approach these requirements, innovative packages including Flip Chip Chip Scale Pakcage (FCCSP) and Flip Chip Ball Grid Array (FCBGA) are the potential solutions. A key components of self-driving car are radar systems that basically detects the distance and the relative speed of the vehicles. In this paper, a FCCSP device was demostrated for the 77-GHz automotive radar application. To achieve low signal loss on the high frequency (77-GHz), coreless substrate and low dielectric tangent material were implemented, the impact of substrate trace routing and laser via design were also simulated and discussed. FCCSP could provide a cost-effective, reliable package solution for 77-GHz automotive radar systems. Advance FCCSP and FCBGA also are the solutions to meet the increasing preformance requirements for the infotainment and Advanced Driver Assistance Systems (ADAS) applications in car. 2.5D IC is a platform for monoor multi-functional integration. CPU, GPU, DRAM and main-broad might be all shrunken into one chip package. 2.5D IC is also a solution of high bandwidth, small form factor and multi-function integration. In this paper, another FCCSP device was demostrated for the power managerment system in car. Another FCBGA device with copper pillar bump also was developed, it not only provides the high computing performance but also passed the Automotive related qualification and is under production. Finally, this paper will sum up the progress of advanced Flip Chip packages-FCCSP and FCBGA for the Automotive applications

Biometric features, such as fingerprint, facial recognition, etc, are convenient personal identification methods in mobile electronics. Fingerprint recognition is one of mature technologies and is embedded in an increasing number of mobile devices. For fingerprint sensor packaging, wire bonding and over-molding Land Grid Array (LGA) is one of major package types. Inside the wire bond LGA package, the dielectric constant (Dk) of over-molding compounds is one dominant factor for the sensitivity of capacitive fingerprint sensors. Normal molding compounds contain epoxy base polymers and silica base fillers. Their Dk value is relative low (3~5 at 1 MHz). Those compounds are suitable for the general encapsulation purpose. But they have shielding effects on the sensing signal transmission in capacitive fingerprint sensor packages. This shielding effect needs to be reduced as much as possible, especially when thick glass is used on fingerprint module for the mechanical protection. Therefore, high Dk (7~40 at 1 MHz) molding compounds were developed for the sensor performance enhancement. High Dk property of molding compound can be achieved by using new type polymers and metal oxide fillers. With new type polymers and fillers, the major challenges of high Dk molding compounds come from the warpage and stress during the package assembly process. In order to diminish the warpage and stress, lots of experiments were conducted which including molding compound composition adjustment, post-mold cure process optimization and so on. In this paper, several types of high dielectric constant molding compounds were evaluated and compared. Stress simulations were performed to determine the package construction. Screen and corner DoEs of molding process parameters were conducted to come out the process window. Functional test and reliability test have been preformed as well. Two types of high Dk molding compounds have proven to be feasible and reliable materials for enhancing the performance of fingerprint sensors.

Gastrointestinal cancer is one of the most common types of cancer with high mortality rates. Mutations in several genes are reportedly involved in the progression of gastrointestinal cancer, including tumor protein 53 (TP53), APC regulator of WNT signaling pathway (APC), KRAS proto-oncogene GTPase (KRAS) and erb-b2 receptor tyrosine kinase 2 (ERBB2). Most notably, there are numerous mutations in DNA repair genes, including mismatch repair (MMR) and homologous recombination (HR) genes. The focus of the present study was to investigate the effects of MMR and HR gene mutations on genomic instability in gastrointestinal cancer. Using targeted capture and massively parallel genomic sequencing, 137 gastrointestinal cancer patients were analyzed for somatic single-nucleotide variants (SNVs) and insertion-deletion (indel) mutations in the exon regions of 183 cancer driver genes, including 4 MMR genes [MutL homolog MLH1, MLH2, MLH6 and PMS1 homolog 2, mismatch repair system component (PMS2)] and 15 HR genes [BRCA1 DNA repair associated (BRCA1), BRCA2 DNA repair associated (BRCA2), ATM serine/threonine kinase (ATM), phosphatase and tensin homolog, BLM RecQ like helicase, FA complementation group A, FA complementation group C, FA complementation group D2, FA complementation group E, FA complementation group F, FA complementation group G, nibrin, partner and localizer of BRCA2 and Werner syndrome RecQ like helicase]. A number of frequently mutated genes, including but not limited to, mechanistic target of rapamycin kinase, neurofibromin 1, APC and, in particular, DNA repair genes, including PMS2, ATM and BRCA2, were identified. Frequency analysis was performed based on the SNVs and indels in the 183 genes to indirectly indicate the relative status of genomic instability in each patient. Correlation analysis suggested that MMR and HR gene mutations directly affected the count of SNVs and indels. Overall, 56 of the gastrointestinal cancer patients (40%) were found to have an inactivation mutation (stopgain/frameshift/splicing) in one or more of the four MMR genes, whereas 112 patients (82%) harbored at least one HR gene inactivation mutation. In addition, patients with MMR or HR inactivation variants had more SNVs and indels compared with patients with no such mutations. No other clinical characteristics (including sex and age) appeared to have a statistically significant impact. Further analysis indicated that different MMR or HR genes exerted distinct effects on genomic instability. The results obtained in the current study may lay a foundation for investigations into the tumorigenic process and for the development of novel therapeutic strategies for the treatment of gastrointestinal cancer.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. A number of targeted therapies have been approved for clinical use or are in clinical trials. Next generation sequencing (NGS) is widely applied in the identification of actionable genomic alterations and enables personalized cancer therapy for patients. Several multiple-gene panels are available in China for the practice of precision medicine-based cancer therapy. However, the efficiency of these panels requires evaluation. The current study investigated 23 NSCLC samples using a custom designed panel of complete coding regions of ~180 cancer driver genes (FD-180) and whole exome sequencing for control samples, obtained from white blood cell samples. The results obtained suggested that actionable mutations with available targeted therapeutic options were identified in 69.6% of cases, including 60.9% of therapeutic targets recommended by the National Comprehensive Cancer Network guidelines. Furthermore, 8.7% of patients had a gene mutation that potentially qualified them for clinical trials or associated off-label therapies. As such, the results obtained in the current study demonstrated the reliability of the targeted NGS panel and its potential use for identifying actionable gene alterations and designing personalized therapies for patients with NSCLC.

While the applications of consumer electronics are trending to with slim and stylish outlook, the space is extremely constraint within the electronic devices. WLCSP enables low profile, small form factor and relatively easy assembly process, it is perfect to meet those space constrains. However, for ultra-thin WLCSP, reduced wafer thickness would increase the risk of warpage and crack during the processing. When the silicon of WLCSP is ultra-thin (less than 200um), its mechanical strength is low, its handling post wafer lapping process is one of the major challenges. The crack risk is even higher when the wafer is big (12”) and with brittle ELK layer. The other challenge is wafer warpage, which is from the CTE miss-match between silicon and passivation polymer. Therefore, in order to diminish the wafer warpage and crack risk, experiments are performed to conduct for the risk mitigation, including laser grooving process optimization, dicing tooling selection and recipe optimization study. In this study, a test vehicle with 170um Silicon thickness was evaluated. Screen and corner DOEs which includes laser grooving conditions and dicing conditions were performed to come out the tooling selection and process windows. Finally, functional test and reliability test are all passed. This ultra-thin WLCSP has been proved to apply to the consumer electrics products.

Currently, the methods available for preimplantation genetic diagnosis (PGD) of in vitro fertilized (IVF) embryos do not detect de novo single-nucleotide and short indel mutations, which have been shown to cause a large fraction of genetic diseases. Detection of all these types of mutations requires whole-genome sequencing (WGS). In this study, advanced massively parallel WGS was performed on three 5- to 10-cell biopsies from two blastocyst-stage embryos. Both parents and paternal grandparents were also analyzed to allow for accurate measurements of false-positive and false-negative error rates. Overall, >95% of each genome was called. In the embryos, experimentally derived haplotypes and barcoded read data were used to detect and phase up to 82% of de novo single base mutations with a false-positive rate of about one error per Gb, resulting in fewer than 10 such errors per embryo. This represents a ∼100-fold lower error rate than previously published from 10 cells, and it is the first demonstration that advanced WGS can be used to accurately identify these de novo mutations in spite of the thousands of false-positive errors introduced by the extensive DNA amplification required for deep sequencing. Using haplotype information, we also demonstrate how small de novo deletions could be detected. These results suggest that phased WGS using barcoded DNA could be used in the future as part of the PGD process to maximize comprehensiveness in detecting disease-causing mutations and to reduce the incidence of genetic diseases.

Background Gastric cancer (GC) ranks the second in mortality rate among all cancers. Metastases account for most of the deaths in GC patients. Yet our understanding of GC and its metastasis mechanism is still very limited. Methods We performed 20 whole-exome sequencing (WES) on 5 typical metastatic gastric adenocarcinoma (GAC) patients with lymph node metastasis. We compared both the primary tumors to their metastatic lymph nodes, and a specific analysis pipeline was used to detect single nucleotide variants (SNVs), small insertions/deletions (indels) and copy number variants (CNVs). Results (1) We confirmed 30 candidate mutations in both primary and lymph nodes tissues, and other 7 only in primary tumors. (2) Copy number gains were observed in a large section of 17q12–21, as well as copy number losses in regions containing CDKN2A and CDKN2B in both primary and lymph nodes tissues. Conclusions Our results provide preliminary insights in the molecular mechanisms of GC initiation, development, and metastatic progression. These results need to be validated through large-scale studies. Electronic supplementary material The online version of this article (10.1186/s12885-018-5097-8) contains supplementary material, which is available to authorized users.

Background: Little prior research has been conducted regarding resident physicians’ opinions on the subject of Physician Assisted Death (PAD), despite past surveys ascertaining the attitudes of practicing physicians towards PAD in Canada. We solicited British Columbia residents’ opinions on the amount of education they receive about palliative care and physician assisted death, and their attitudes towards the implementation of PAD.Methods: We conducted a cross sectional, anonymous online survey with the resident physicians of British Columbia, Canada. Questions included: close-ended questions, graded Likert scale questions, and comments. Results: Among the respondents (n=299, response rate 24%), 44% received ≥5 hours of education in palliative care, 40% received between zero and four hours of education, and 16% reported zero hours. Of all respondents, 75% had received no education about PAD and the majority agreed that there should be more education about palliative care (74%) and PAD (85%). Only 35% of residents felt their program provided them with enough education to make an informed decision about PAD, yet 59% would provide a consenting patient with PAD. Half of the respondents believed PAD would ultimately be provided by palliative care physicians.Interpretation: Residents desire further education about palliative care and PAD. Training programs should consider conducting a thorough needs assessment and implementing structured education to meet this need.

Germplasm, genetics, phenotyping, and selection, combined with a clear definition of product targets, are the foundation of successful hybrid maize breeding. Breeding maize hybrids with superior yield for the drought-prone regions of the US corn-belt involves integration of multiple drought-specific technologies together with all of the other technology components that comprise a successful maize hybrid breeding programme. Managed-environment technologies are used to enable scaling of precision phenotyping in appropriate drought environmental conditions to breeding programme level. Genomics and other molecular technologies are used to study trait genetic architecture. Genetic prediction methodology was used to breed for improved yield performance for drought-prone environments. This was enabled by combining precision phenotyping for drought performance with genetic understanding of the traits contributing to successful hybrids in the target drought-prone environments and the availability of molecular markers distributed across the maize genome. Advances in crop growth modelling methodology are being used to evaluate the integrated effects of multiple traits for their combined effects and evaluate drought hybrid product concepts and guide their development and evaluation. Results to date, lessons learned, and future opportunities for further improving the drought tolerance of maize for the US corn-belt are discussed.

OBJECTIVES: Andrographis paniculata has in vitro inhibitory activity against TNF-α, IL-1β and NF-κB. A pilot study of A. paniculata extract (HMPL-004) suggested similar efficacy to mesalamine for ulcerative colitis. METHODS: A randomized, double-blind, placebo-controlled trial evaluated the efficacy of A. paniculata extract (HMPL-004) in 224 adults with mild-to-moderate ulcerative colitis. Patients were randomized to A. paniculata extract (HMPL-004) 1,200 mg or 1,800 mg daily or placebo for 8 weeks. RESULTS: In total, 45 and 60% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical response at week 8, compared with 40% of those who received placebo (P=0.5924 for 1,200 mg vs. placebo and P=0.0183 for 1,800 mg vs. placebo). In all, 34 and 38% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical remission at week 8, compared with 25% of those who received placebo (P=0.2582 for 1,200 mg vs. placebo and P=0.1011 for 1,800 mg vs. placebo). Adverse events developed in 60 and 53% of patients in the A. paniculata 1,200 mg and 1,800 mg daily groups, respectively, and 60% in the placebo group. CONCLUSIONS: Patients with mildly to moderately active ulcerative colitis treated with A. paniculata extract (HMPL-004) at a dose of 1,800 mg daily were more likely to achieve clinical response than those receiving placebo.

As mobile electronics are continuously driven for compact, slim and lightweight, miniaturization of IC packaging has been a must. There are increasing Wafer Level Chip Scale and fan-in Package (WLCSP) employed in electronics to achieve the miniaturization. Since WLCSP just is the Die with solder balls attached, WLCSP has the smallest footprint and the lightest weight compare to substrate base and lead-frame base package. However, WLCSP side wall with pure silicon is brittle, it is easily damaged and cracked during transportation and SMT processes. How to protect the WLCSP sidewall and to prevent the cracks is a rising issue for WLCSP applications. Therefore, as a molded WLCSP has aroused lots of attention in IC semiconductor industry. It not only provides side wall protection but also enhances package board level reliability by additional molding fixture around solder balls. By using a wafer form molding technology, it solves side wall crack issue and has no concern for high cost. Without rigid support and with unsymmetrical structure, the major challenges of this molded WLCSP come from the wafer warpage post backside grinding process. In order to diminish the warpage during backend processes, lots of experiments were conducted extensively to reduce the wafer warpage, including molding compound selection (which focus on its CTE and Tg adjustments), post-mold cure optimization, die thickness decision, and so on. In this paper, a test vehicle with ultra-low profile was evaluated. Stress simulation was conducted to determine the package construction and work out the bill of material. Screen and corner DOEs which includes molding compound selection and post-mold cure parameters were performed to come out the optimal material and process window. Functional test and Board reliability test have been passed as well. Additional collision test also shows good side wall protections. Hence five sides molded WLCSP has been proven to be a feasible and reliable way for the miniaturization in assembly industry.

Alkali flooding in heavy oil reservoirs is known to stabilize emulsion in-situ and improve the recovery beyond that of conventional waterflood under certain boundary and initial conditions. The overarching goal of this study is to develop a systematic approach to optimize this process and capture underlying recovery mechanisms. Therefore, we experimentally evaluated the performance of alkali flood as a function of emulsion type and viscosity. Phase behavior and viscosity of the microemulsion are modified by introducing seven different surfactants. Microscope imaging techniques are employed to measure the droplet size distribution for type I and II emulsions. Viscosities of generated emulsions are measured with a rotational rheometer at low temperatures and with an electromagnetic viscometer at reservoir conditions. Finally, corefloods are conducted at different conditions to evaluate the performance of displacement as a function of emulsion type and viscosity. Enhanced alkali floods showed an incremental recovery of 8 – 50% beyond that of waterflood. Formation of higher viscosity emulsion has a large contribution on the sweep efficiency and therefore improved oil recovery during alkali flood; however, other mechanisms (e.g. entrainment and entrapment) also have contribute to the incremental recovery. Results of our experiments indicated that the incremental recovery is a strong function of emulsion type, emulsion viscosity, and the droplet size distribution.

As mobile electronics are continuously driven for compact, slim and lightweight, miniaturization of IC packaging has been a must. Coreless substrate with fine-trace embedded technology is a key to achieve package miniaturization. Compare to conventional substrate, coreless substrate technology eliminates the substrate core, and utilize build-up layers to interconnect the chip and the PCB board. It brings about not only low z-height, lightweight, but also short interconnection and good power integrity. Coreless technology is a promising solution for the next generation substrate.

We have discovered a family of small secreted proteins in Homo sapiens and Mus musculus. The IGF-like (IGFL) genes encode proteins of approximately 100 amino acids that contain 11 conserved cysteine residues at fixed positions, including two CC motifs. In H. sapiens, the family is composed of four genes and two pseudogenes that are referred as IGFL1 to IGFL4 and IGFL1P1 and IGFL1P2, respectively. Human IGFL genes are clustered together on chromosome 19 within a 35-kb interval. M. musculus has a single IGFL family member that is located on chromosome 7. Further, evolutionary analysis shows a lack of direct orthology between any of the four human members and the mouse gene. This relationship between the mouse and the human family members suggests that the multiple members in the human complement have arisen from recent duplication events that appear limited to the primate lineage. Structural considerations and sequence comparisons would suggest that IGFL proteins are distantly related to the IGF superfamily of growth factors. IGFL mRNAs display specific expression patterns; they are expressed in fetal tissues, breast, and prostate, and in many cancers as well, and this pattern is consistent with that of the IGF family members.

In the recent years, compact, slim and lightweight mobile electronics are requested from customers. Miniaturization of IC packaging has been a must. Coreless substrate technology is the key to achieve it. Compare to conventional substrate, coreless substrate technology eliminates the substrate core, and utilize build-up layer to interconnect chip and the motherboard. It brings about not only low z-height, lightweight, but also short interconnection and good power integrity. Coreless technology is a promising solution for the next generation substrate. Therefore, as a NEW innovative coreless structure, a substrate with the features of lead-frame and pre-molding compound techniques has aroused lots of attention in IC semiconductor industry. Its trace is plated on the metal carrier and is embedded by molding compound. By using this unique embedded trace technology, it makes the fine-line of having 20um/20um or 15um/15um line width/space and having no concern for high cost. However, without rigid substrate core material supporting, the major challenges of this coreless substrate come from the warpage throughout substrate manufacturing and assembly process. In order to diminish the warpage, lots of experiments were conducted and discussed in this paper. Thermal performance and mechanical stress simulations also were employed to establish the package structure and also to narrow down the row material selections, including die thickness decision, pre-molding and molding compound selection (which focus on its CTE and Tg adjustments). Screen and corner DOEs which includes molding compounds, die-bond reflow profile and post-mold cure parameters were performed to come out the optimal material and process window. Reliability and functional tests have been passed as well. Hence, this pre-molded coreless substrate has been proven to be a feasible and reliable way for the miniaturization in assembly industry.

An emerging series of papers has identified new receptor proteins that predict seven-transmembrane pass topologies. We have consolidated this family to 11 human genes and have named the family PAQR, after two of the initially described ligands (progestin and adipoQ receptors). This protein family has ancient evolutionary roots, with identified homologs found in eubacteria. To date, published data indicate that the prokaryotic members of this family appear to encode hemolysin-type proteins, while in eukaryotes, PAQR proteins encode functional receptors with a broad range of apparent ligand specificities. We provide the complete human and mouse complement of this family, suggest a conserved structure/topology with invariant intracellular amino acid residues, and have measured mRNA expression levels for these genes across a range of human tissues.

We have discovered a family of small secreted proteins in Homo sapiens and Mus musculus using a novel database searching strategy. The family is composed of five highly homologous genes referred to as TAFA-1 to -5. The TAFA genes encode proteins of approximately 100 amino acids that contain conserved cysteine residues at fixed positions. TAFA-1 to -4 are more closely related to each other than to TAFA-5, in which a conserved motif including CC in TAFA-1 to -4 is not present. In H. sapiens, TAFA-3 has two isoforms formed by alternative splicing. Sequence homology analyses reveal that TAFA proteins appear distantly related to MIP-1α, a member of the CC-chemokine family. TAFA mRNAs are highly expressed in specific brain regions, with little expression seen in other tissues.

Background: Linezolid is a novel oxazolidinone antibiotic that is effective for the treatment of gram-positive bacterial infections. The oral formulation has the potential to reduce length of stay (LOS) when used as a substitute for parenteral glycopeptide antibiotics. In a recent multinational trial comparing linezolid (IV followed by oral administration) with teicoplanin (IV alone or switched to IM administration), linezolid was found to have better efficacy ( P = 0.005) and similar safety for treating serious gram-positive infections. Objective: The purpose of this study was to compare hospital resource use (primarily LOS) and cost of treatment between linezolid and teicoplanin for hospitalized patients with serious gram-positive infections in South America and Mexico using data from the multinational trial. Methods: In a multinational, Phase IIIb, open-label, comparator-controlled trial, data were collected from hospitalized patients in centers in 6 South America can countries and Mexico with suspected or confirmed serious gram-positive infections. Patients were randomly assigned to receive IV linezolid 600 mg BID (for the entire treatment period [7–28 days] or switched to oral linezolid 600 mg BID) or IV teicoplanin (for the entire treatment period or switched to IM teicoplanin) dosed per approved prescription information. Data on direct medical resource utilization were collected for each patient, including duration and doses of study medication, location of hospitalization and LOS, comedications, tests and procedures, and outpatient service usage. Unit costs for the medical resources were obtained from secondary sources. Results: A total of 203 patients (97 treated with linezolid and 106 treated with teicoplanin) were enrolled from these 7 countries. The unadjusted results showed that compared with teicoplanin, patients treated with linezolid had a 3.1-day shorter mean IV antibiotic treatment duration ( P P = 0.03), and a $311 lower mean total cost of treatment ( P = NS). After controlling for age, race, sex, site of infection, inpatient location when the antibiotic treatment started, number of historical and current comorbidities, and whether the patient had a diagnosis of systemic inflammatory response syndrome or sepsis, the multivariate adjusted results were similar to the unadjusted results. The linezolid group had a 1.6-day shorter adjusted LOS or 66% greater odds of early discharge ( P = 0.049) and a $335 lower adjusted mean total cost of treatment ( P = NS). Conclusion: Linezolid was associated with shorter LOS and duration of IV antibiotic treatment than teicoplanin for serious gram-positive infections in the population studied. Linezolid therapy has the potential to reduce the total cost of treatment.

e23123 Background: Pleural carcinosis caused by tumors of the chest (e.g., lung and breast cancer) or elsewhere in the body (e.g., ovarian carcinoma) that metastasize to the visceral and/or parietal pleura. Recurrent malignant pleural effusion due to pleural carcinosis is one of the most common findings in oncology. The aim of the study was to identify a miRNA signature associated with clinicians’ prescription of patients with MPE. Methods: We used qRT-PCR assay to evaluate a wide range miRNAs (1920 miRNAs) signature measured from pleural effusion between patients with cancer and healthy controls. From the data of our previous studies we selected a panel of 96 miRNAs related to malignant pleural effusion. Data were compared by three classification methods software for statistics and modeling. We used a first set of 77 pleural effusion samples as training group, including 27 patients affected by Lung Adenocarcinomas (LAC), 9 with other lung cancer, 17 with other tumors and 24 inflammatory patients as negative controls. Moreover, we used more 64 pleural effusion samples for double-blind predictive study. Data analysis was performed using a machine learning approach of a Support Vector Machine classifier with a Student's t-test feature selection procedure. Results: We identified a panel of ten miRNAs with optimum classification performance. The combination of these 10-miRNAs alone could discriminate MPE cases from negative controls with an AUC of 0.969 (accuracy = 93.5%; specificity = 91.7%). The selected panel of another 10-miRNAs could separate lung cancer cases from negative controls with an AUC of 0.973 (accuracy = 94.8%; specificity = 95.8%), and a small panel of 4-miRNAs could good discriminate LAC cases from negative controls with an AUC of 0.946 (accuracy 88.9%; specificity = 100%). The accuracy rate of the double-blind predictive sensitivity value was 90.9% and specificity value was 95.8% for MPE patients with lung cancer of miRNA signature. Conclusions: Our miRNAs profile may serve as a new biomarker for MPE diagnosis. Otherwise, we identified a 10-miRNAs signature for MPE patients with lung cancer and a 4-miRNAs for MPE patients with lung adenocarcinoma.

Because the new Proton platform from Life Technologies produced markedly different data from those of the Illumina platform, the conventional Illumina data analysis pipeline could not be used directly. We developed an optimized SNP calling method using TMAP and GATK (OTG-snpcaller). This method combined our own optimized processes, Remove Duplicates According to AS Tag (RDAST) and Alignment Optimize Structure (AOS), together with TMAP and GATK, to call SNPs from Proton data. We sequenced four sets of exomes captured by Agilent SureSelect and NimbleGen SeqCap EZ Kit, using Life Technology's Ion Proton sequencer. Then we applied OTG-snpcaller and compared our results with the results from Torrent Variants Caller. The results indicated that OTG-snpcaller can reduce both false positive and false negative rates. Moreover, we compared our results with Illumina results generated by GATK best practices, and we found that the results of these two platforms were comparable. The good performance in variant calling using GATK best practices can be primarily attributed to the high quality of the Illumina sequences.

Mudskippers are amphibious fishes that have developed morphological and physiological adaptations to match their unique lifestyles. Here we perform whole-genome sequencing of four representative mudskippers to elucidate the molecular mechanisms underlying these adaptations. We discover an expansion of innate immune system genes in the mudskippers that may provide defence against terrestrial pathogens. Several genes of the ammonia excretion pathway in the gills have experienced positive selection, suggesting their important roles in mudskippers’ tolerance to environmental ammonia. Some vision-related genes are differentially lost or mutated, illustrating genomic changes associated with aerial vision. Transcriptomic analyses of mudskippers exposed to air highlight regulatory pathways that are up- or down-regulated in response to hypoxia. The present study provides a valuable resource for understanding the molecular mechanisms underlying water-to-land transition of vertebrates., Mudskippers are amphibious fishes that have adapted to live on mudflats. Here, the authors sequence the genomes of four different mudskipper species and highlight genetic changes that may have had an evolutionary role in the water-to-land transition of vertebrates.

Neutropenia is common in patients receiving myelotoxic chemotherapy. BenegrastimTM(F-627), a recombinant human G-CSF dimer, is an once-per-cycle therapy for prophylactic neutropenia in cancer patients after chemotherapy. Two phase I dose finding studies of benegrastim were conducted in Chinese women with stage I-IV breast cancer receiving myelotoxic chemotherapy. The aims of the studies were to evaluate the safety profile and pharmacokinetics (PK) and pharmacodynamics (PD) properties of benegrastim. In the first study, a total of 18 patients were enrolled to receive 3 sequential dose levels of benegrastim at 80, 240 and 360 µg/kg (n=6). The patients received epirubicin/cyclophosphamide (EC) chemotherapy on day one. Benegrastim was administered to patients on day 3 by SC injection once per chemotherapy cycle for up to 4 cycles. In the second study, 15 patients were sequentially assigned to 240 µg/kg (n=7) and 320 µg/kg (n=8) of benegrastim. These patients received doxorubicin, docetaxel and cyclophosphamide (TAC) on day one, benegrastim was administered on day 2 by SC injection for up to 6 cycles. The PK/PD properties of benegrastim were evaluated in cycle one and cycle three. Benegrastim was well tolerated in both clinical studies. The treatment emergent adverse events related to benegrastim were back pain, arthralgia, musculoskeletal pain, and rash, commonly seen in rhG-CSF therapy. The PK/PD result in patients receiving TAC in the first chemotherapy cycle is shown in Fig 1. Dose-dependent benegrastim exposure and ANC increase were demonstrated in these two clinical trials. In breast cancer patients receiving EC or TAC, benegrastim showed a non-linear pharmacokinetics. Benegrastim shortened the duration of neutropenia post chemotherapy in a dose dependent manner. In conclusion, benegrastim may provide an alternative approach to manage neutropenia, especially, severe neutropenia in patients after chemotherapy. Figure 1. PK/PD of F-627 (benegrastim) in Chinese breast cancer patients receiving TAC in the first chemotherapy cycle. Figure 1. PK/PD of F-627 (benegrastim) in Chinese breast cancer patients receiving TAC in the first chemotherapy cycle. Disclosures Cao: Generon (Shanghai) Corporation Ltd.: Research Funding. Yuan:Generon (Shanghai) Corporation Ltd.: Research Funding. Huang:Generon (Shanghai) Corporation Ltd.: Employment. Ji:Generon (Shanghai) Corporation Ltd.: Research Funding. Peng:Generon (Shanghai) Corporation Ltd.: Research Funding. Yan:Generon (Shanghai) Corporation Ltd.: Employment. Tang:Generon (Shanghai) Corporation Ltd.: Employment.

The manufacturing processes of an optoelectronic printed circuit board (OEPCB) with an embedded board-level polymeric waveguide and vertical-optical channel interconnection are presented in this paper. The optoelectronic packages contain one vertical cavity surface emitting laser (VCSEL), one photo detector (PD), surface mount technology (SMT) components and one fully embedded board-level optical interconnects. The first step is to fabricate a polymeric waveguide structure with two 45-degree mirrors, and then embedded the waveguide in the center with two prepreg to form a horizontal optical channel inside a printing circuit board by a two-step laminating process. The vertical-optical channel is made by a three-step process, conformal mask forming, laser ablating and copper etching. This vertical channel is connected to the mirror of the horizontal waveguide. A wide, collimated optical beam couples a package board across a narrow, long air gap and provides a large tolerance to misalignment during the SMT process. Key process steps will be discussed and X-ray images will be presented in this paper. Also, characterization measurements of the important electrical and optical parameters are discussed in this paper.