Intermediate Copy Research Articles

SPECTRUM OF EMBRYO MOSAICISM DETECTED BY PREIMPLANTATION GENETIC TESTING FOR ANEUPLOIDY (PGT-A) DETERMINES REPRODUCTIVE OUTCOME

Historically, PGT-A results were applied in a binary fashion: embryos categorized as normal were transferred, and those categorized as abnormal were not. While embryos with euploid results have consistent reproductive outcomes, it has now become evident that “abnormal” results can be subcategorized, depending on whether an intermediate copy number is observed (“mosaic”), range of intermediate copy number (estimated percentage of biopsied cells with the abnormality), and type of abnormality (segmental or full monosomy/trisomy).

Update on preimplantation genetic testing for aneuploidy and outcomes of embryos with mosaic results.

Preimplantation genetic testing for aneuploidy (PGT-A) is used as a frequent add-on for in-vitro fertilization (IVF) to improve clinical outcomes. The purpose is to select a euploid embryo following chromosomal testing on embryo biopsies. The current practice includes comprehensive chromosome screening (CCS) technology applied on trophectoderm (TE) biopsies. Despite its widespread use, PGT-A remains a controversial topic mainly because all of the RCTs comprised only good prognosis patients with 2 or more blastocysts available; hence the results are not generalizable to all groups of patients. Furthermore, with the introduction of the highly-sensitive platforms into clinical practice (i.e. next-generation sequencing [NGS]), a result consistent with intermediate copy number surfaced and is termed "Mosaic," consistent with a mixture of euploid and aneuploid cells within the biopsy sample. The optimal disposition and management of embryos with mosaic results is still an open question, as many 'mosaics' generated healthy live births with no identifiable congenital anomalies. The present article provides a complete and comprehensive up-to-date review on PGT-A. It discusses in detail the findings of all the published RCTs on PGT-A with CCS, comments on the subject of "mosaicism" and its current management, and describes the latest technique of non-invasive PGT-A.

CLINICAL AND EMBRYOLOGICAL FACTORS ASSOCIATED WITH A HIGH PROPORTION OF MOSAIC EMBRYOS: CAN WE IDENTIFY ANYONE AT RISK?

Mosaicism is defined as the presence of more than one cell line in a single embryo and is inferred on preimplantation genetic testing for aneuploidy (PGT-A) by an intermediate copy number on next generation sequencing (NGS). The estimated rate of reported mosaicism is between 3-20%1. However, there are selected patients who experience higher proportions of mosaic embryos than expected compared to the general patient population who undergoes in vitro fertilization (IVF) with PGT-A. The objective of this study was to investigate whether there are risk factors associated with patients who have an increased proportion of embryos reported to be mosaic in a single IVF with PGT-A cycle.

O-076 Genomic and morphokinetic blueprint of mosaic embryos is evidence supporting their distinct clinical category

Abstract Study question Is there a correlation between blastocyst mosaicism, morphokinetic and morphologic characteristics and can it inform the clinical outcome of mosaic embryo transfers? Summary answer Mosaic (diploid/aneuploid) embryos have a distinct genetic, morphokinetic and morphologic signature that distinguishes them from euploid and abnormal embryos and supports their unique clinical identity. What is known already Advances in technologies for preimplantation aneuploidy testing (PGT-A) as the ultimate test for embryo selection has increased the resolution and sensitivity to detect intermediate chromosomal copy number as low as 20%. This has brought to light a biological phenomenon that has created clinical dilemma. Current recommendations support mosaic embryo transfer but with conflicting standpoints ranging from complete dismissal of mosaic embryos to arguing their existence. Time-lapse imaging technologies allow collection of morphokinetic data as a non-invasive assessment tool for embryo development. The aim of this study was to correlate genomic and morphokinetic data with clinical outcomes of mosaic embryos. Study design, size, duration This is a retrospective cohort study that took place in a single academic IVF centre, where we analysed the results from high resolution PGT-A, morphokinetic, morphologic and cell division features of 4113 embryos cultured in the time lapse imaging incubator (Embryoscope™) from 2016-2021. Associated patient data and transfer outcome of 770 euploid and 147 mosaic embryo transfers were analyzed. Participants/materials, setting, methods High resolution NGS PGT-A was performed using the Illumina platform and BluGnome and NxClinical for data analysis. Clinically relevant findings were aberrations >10Mb and mosaicism from 25%-75%. Time-lapse imaging was performed with an Embryoscope™. Comparison of clinical, morphological, morphokinetic characteristics of euploid, aneuploid, low-level mosaic (25%-<50% aneuploid cells in trophectoderm biopsy), and high-level mosaics (50% -75%) was done with R-statistical package, Mathlab and SSPS software were used, and p < 0.05 with CI 95% was considered significant. Main results and the role of chance Aneuploidy was detected in 26.2%, euploidy in 56.7% and diploid-aneuploid mosaicism in 17.1% of embryos included in this study. Compared with euploid embryos, mosaic embryos had significant delays in t2 (27.04±0.35vs.26.4±0.17 h-post-ICSI(hpi), p = 0.0029), which was not correlated with transfer outcome. Embryos with whole chromosome mosaicism (WCM) had longer t2 compared to those with segmental chromosome mosaicism (SCM) (27.29±0.59vs.26.4±0.3hpi,p=0.013). The time to first mitosis was also longer for mosaic vs. euploid embryos (4.57± 0.59vs.3.4±0.25hpi,p=0.000056) and for mosaic embryos with WCM vs SCM embryos (4.64± 0.9 vs 3.5 ±0.5hpi,p=0.04). Mosaic embryos had longer tB &tSB than euploid embryos (110.12±0.69vs.109.13hpi±0.4,p=0.01). Embryos with WCM had longer tB &tSB than those with SCM (111.07±1.09vs.108.7±0.8hpi,p=0.0006). Time to blast was longer for mosaic vs euploid embryos (13.69±0.52vs.12.7±0.4hpi,p=0.0035) and for mosaic WCM vs. SCM embryos (14.3±0.7vs.12.8±0.5hpi,p=0.00084). Both euploid and mosaic embryos that implanted had shorter time to tB&tSB than mosaic embryos that didn’t (p = 0.029; p = 0.007 and p = 0.002; p = 0.006 and p = 0.029 respectively); and mosaic embryos that implanted had shorter time to first mitosis than euploid embryos that didn’t (p = 0.00228). High level mosaic embryos had significantly more multinucleation at 2-cell stage (MN2) vs. euploid (p = 0.04,OD1.58-95%CI[1.01-2.45]),aneuploid (p = 0.02,OD1.7-95%CI[1.08-2.8]), as well as MN at 4-cell stage (euploid-p=0.0007,OD2.6-95CI1.4-4.7] and aneuploid-p=0.039,OD1.8-95CI1.02-3.4]). Limitations, reasons for caution Although this is the largest study to date that evaluated genomic, morphokinetic and outcome data of mosaic transfers, the numbers are still low to analyze the impact of specific chromosomal aberrations on morphokinetics and pregnancy outcome. The retrospective nature and cohort design limited the generalizability of our results. Wider implications of the findings Mosaic embryos have significant developmental potential and result in birth of healthy babies. Our study reveals the genomic interconnection of genomic and morphokinetic features of mosaic embryos and provides further evidence that mosaic embryos are a distinct category that requires specific clinical attention. Trial registration number Not applicable

Six-year absolute invasive disease-free survival benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the APHINITY (BIG 4-11) trial

AimThe APHINITY trial showed that adding adjuvant pertuzumab (P) to trastuzumab and chemotherapy, compared with adding placebo (Pla), significantly improved invasive disease-free survival (IDFS) for patients with HER2+ early breast cancer both overall and for the node-positive (N+) cohort. We explored whether adding P could benefit some N− subpopulations and whether to consider de-escalation for some N+ subpopulations. MethodsSubpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest. We used STEPP to estimate Kaplan–Meier differences in 6-year IDFS percentages (P minus Pla: Δ ± standard error [SE]), both overall and by nodal status, for overlapping subpopulations defined by (1) a clinical composite risk score, (2) tumour infiltrating lymphocytes (TILs) percentage, and (3) human epidermal growth factor receptor 2 (HER2) FISH copy number. Because of multiplicity, a Δ of at least three SE is required to warrant attention. ResultsThe average absolute gains in 6-year IDFS percentages were 2.8 ± 0.9 overall; 4.5 ± 1.2 for N+ and 0.1 ± 1.1 for N−. Largest gains were for patients with intermediate clinical composite risk (5.3 ± 1.9 overall; 6.9 ± 2.3 N+; 4.0 ± 3.0 N−), highest TILs percentage (6.3 ± 1.7 overall; 7.4 ± 2.4 N+; 3.2 ± 1.7 N−), and intermediate HER2 copy number (2.8 ± 1.9 overall; 7.4 ± 2.5 N+; −1.3 ± 1.9 N−), but clear evidence indicating a pattern of differential subpopulation treatment effects was lacking. ConclusionsSTEPP plots for N− did not identify subpopulations clearly benefiting from adding P, and those for N+ did not identify subpopulations warranting de-escalation. TILs percentage appeared to be more predictive of P treatment effect than clinical composite risk score. Trial registrationclinicaltrials.gov Identifier NCT01358877.

Answer-Aware Question Generation from Tabular and Textual Data using T5

Automatic Question Generation (AQG) systems are applied in a myriad of domains to generate questions from sources such as documents, images, knowledge graphs to name a few. With the rising interest in such AQG systems, it is equally important to recognize structured data like tables while generating questions from documents. In this paper, we propose a single model architecture for question generation from tables along with text using “Text-to-Text Transfer Transformer” (T5) - a fully end-to-end model which does not rely on any intermediate planning steps, delexicalization, or copy mechanisms. We also present our systematic approach in modifying the ToTTo dataset, release the augmented dataset as TabQGen along with the scores achieved using T5 as a baseline to aid further research.

ACCURATE GENOMIC PREDICTION OF MOSAICISM THROUGH CELL DIVISION ORIGIN OF ANEUPLOIDY ANALYSIS IN THE PREIMPLANTATION EMBRYO

Simple intermediate copy number thresholds have proven to provide poor predictive value for diagnosing preimplantation mosaicism (both analytically and clinically). This study aims to validate a method to determine the cell division origin of aneuploidy from a single trophectoderm biopsy, and its ability to accurately predict mosaicism in the remaining embryo. A high throughput and PGT-validated DNA array platform was used to analyze over 800,000 SNPs within trophectoderm biopsies from a subset of PGT cases where parental DNA was available. Mendelian inheritance analyses were performed on embryonic genotypes within aneuploid chromosomes to predict their parental and cell division origins. Positive controls included embryos with a male karyotype (n=279) with known maternal origin of the X chromosome, and unbalanced embryos from PGT-SR cases (n=69) with known meiotic and parental origins of aneuploidy. The method was applied to clinical biopsies with aneuploidy and compared to rebiopsies (n=80) to evaluate the accuracy of predicting mosaicism (mitotic) and uniform (meiotic) aneuploidy. All samples were analyzed while blinded to prior results. Following validation, the incidence of mitotic origin of aneuploidy was investigated in 942 embryos. Blinded predictions of the X chromosome origin in male embryos, and parental and cell division origin of aneuploidy in PGT-SR derived unbalanced embryos were 100% concordant with expected results, demonstrating the validity of predicting parental and meiotic cell division origins of aneuploidy. Blinded analysis of rebiopsies showed that all embryos with mitotic origin of aneuploidy predicted in the original biopsy were confirmed as mosaic, and all embryos with meiotic origin were confirmed as uniform aneuploid, demonstrating the validity of predicting mitotic origins of aneuploidy and mosaicism. The overall incidence of mitotic whole chromosome aneuploidy (mosaicism) in embryos was 3%. The overall embryonic aneuploidy rate was 31% (mean maternal age 34.5+4). Aneuploid chromosomes primarily originated from the maternal genome (80%) and maternal whole chromosome aneuploidy primarily originated from meiotic errors (95%), while paternal aneuploidy more often originated from mitotic errors (35%)(p<0.05). These data indicate very high specificity in predicting mosaicism from a single aneuploid trophectoderm biopsy and a low prevalence of mosaicism (3%) in the human blastocyst. This is in stark contrast to existing methods of predicting mosaicism with intermediate copy number thresholds, where rebiopsy confirmation rates are ∼40%, and prevalence is estimated to be ∼20%. Improving the specificity of predicting mosaicism (reducing false positives) from a single biopsy may provide a unique opportunity to investigate the true clinical consequence of transferring bona fide mosaic embryos for the first time.

The relative order of foci and polarity complementizers

AbstractAccording toRizzi &amp; Bocci’s (2017)suggested hierarchy of the left periphery, fronted foci (FOC) can never precede polarity complementizers (PolC); yet languages like Bulgarian and Macedonian appear to display precisely such an ordering configuration. On the basis of a cross-linguistic comparison of ten Slavic languages, I argue that in the Slavic subgroup the possibility of having a focus precede PolC is dependent on the morphological properties of the complementizer itself: in languages where the order FOC &lt; PolC is acceptable, PolC is a complex morpheme derived through the incorporation of a lower functional head with a higher one. The order FOC &lt; PolC is then derived by giving overt spell-out to the intermediate copy of PolC rather than to the topmost one. In turn, this option is linked to the possibility, recorded in all languages which allow for FOC &lt; PolC, to also realize the morpheme expressing interrogative polarity as an enclitic particle attaching to fronted foci.

Clinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: a committee opinion

Since the advent of preimplantation genetic testing for aneuploidy (PGT-A) in the 1990s, substantial changes in test methodology and technology now allow the detection and reporting of intermediate chromosome copy number (commonly referred to as mosaicism) for aneuploidy in a trophectoderm biopsy sample. Clinicians are grappling with how to interpret such findings and how to counsel patients about embryo transfer decision-making. This document reviews the available literature and outlines the various issues surrounding the reporting of intermediate copy number and consideration of storage or transfer of blastocysts with intermediate copy number results. This document does not endorse, nor does it suggest that PGT-A is appropriate for all cases of invitro fertilization.

IPsec for high speed network links: Performance analysis and enhancements

Network packets security has always been significantly important and well researched topic but the network throughput and latency are not optimal on high speed network links, when using existing IPsec solutions. Network packet processing in Linux kernel is significantly slow (especially for 10-G/40-G link speed) due to context switching associated with system calls, and transitional copy operations in packet traversal through all network layers. Control plane layered packet processing involve copy operation per layer, which increases the packet processing time and consequently decreases the throughput of the network. In contrast to the kernel networking, data plane solutions like DPDK (Data Plane Development Kit) provide direct access to packets (from NIC) in user-space bypassing kernel stack, with zero intermediate copy operations and no context switching. For the normal packets, Intel DPDK claims 10x improvement in the throughput over kernel networking. Being inspired by that remarkable efficiency, we have done empirical evaluation of IPsec performance in data plane. Towards this goal, primarily we have analyzed the performance effect by individual bottleneck modules of strongSwan (an IPsec implementation); by redesigning them with data plane equivalent modules. Secondarily, we have proposed an efficient solution for strongSwan using DPDK API; which eliminates all previously identified bottleneck modules. In the proposed design, multi-cores design has been incorporated in the crypto module and performance is analyzed in terms of throughput and latency. There is an improvement of up to 3.54x in throughput and 2.54x improvement in latency as compared to existing control plane design. With AES128GCM as encryption scheme, a maximum throughput of 4.795 Gbps is achieved, while using only two cores.

Лицевые Толковые Пророчества 1887–1888 гг. Г. М. Прянишникова и их место в рукописной истории памятника

The Illustrated Commentaries on the Prophets were made to order for the Old Believer G. M. Prianishnikov on the basis of the book that had been made in 1599—1600 and belonged to Hermogenes, Metropolitan of Kazan. The latter derives, through an intermediate copy, from a manuscript made at the very beginning of the 1490s in the circle of Archbishop Gennadius of Novgorod. This fifteenth-century manuscript has preserved the text of the ancient antigraph that dates from the beginning of the 12th century at the latest and derives from the codex of 1047 written by the priest Upyr’ Lykhoi. The article describes client’s requirements, techniques used by the scribe and the artists who worked on the manuscript, and the textual value of annotations to the miniatures

POLAR BODY ANALYSIS FOR PREIMPLANTATION GENETIC TESTING

The use of polar bodies for preimplantation genetic testing for both single gene defects (PGT-M) and aneuploidy (PGT-A) was pioneered by Verlinsky and colleagues beginning in the late 1980s. For many years, it was applied clinically to diagnose the inheritance of maternal mutations and, using fluorescence in situ hybridisation (FISH) with chromosome specific probes, to detect maternal meiotic segregation errors resulting in aneuploidy. Most clinics now culture to the blastocyst stage and with the advent of vitrification, biopsied blastocysts can be cryopreserved efficiently while the samples are sent to a genetics lab for testing. However, polar body biopsy continues to be used in several European countries with legal or ethical restrictions on the testing of embryos. Although the second polar body can persist to the blastocyst stage, both polar bodies are eventually lost and do not form part of the embryo. Removing both of the polar bodies is therefore minimally invasive. Polar body analysis by NGS-based copy number analysis or SNP genotyping and either karyomapping or meiomapping is highly effective for both aneuploidy and linkage-based testing for maternal mutations. The advantage for PGT-A, in particular, is that only maternal meiotic aneuploidies are identified avoiding the problem of interpreting intermediate copy number changes associated with chromosome mosaicism in multiple cell biopsies. Polar body biopsy therefore remains a valuable alternative strategy for PGT.

Graph Theory Teaches Us Something About Grammaticality

Abstract Graph theory, which quantitatively measures the precise structure and complexity of any network, uncovers an optimal force balance in sentential graphs generated by the computational procedures of human natural language (CHL). It provides an alternative way to evaluate grammaticality by calculating ‘feature potential’ of nodes and ‘feature current’ along edges. An optimal force balance becomes visible by expressing ‘feature current’ through different point sizes of lines. Graph theory provides insights into syntax and contradicts Chomsky’s current proposal to discard tree notations. We propose an error minimization hypothesis for CHL: a good sentential network possesses an error-free self-organized force balance. CHL minimizes errors by (a) converting bottom-up flow (structure building) to top-down flow (parsing), (b) removing head projection edges, (c) preserving edges related to feature checking, (d) deleting DPmovement trajectories headed by an intermediate copy, (e) ensuring that covert wh-movement trajectories have infinitesimally small currents and conserving flow directions, and (f) robustly remedying a gap in wh-loop by using infinitesimally inexpensive wh-internally-merged (wh- IM) edge with the original flow direction. The CHL compels the sensorimotor (SM) interface to ground nodes so that Kirchhoff’s current law (a fundamental balance law) is satisfied. Internal merges are built-in grounding operations at the CHL–SM interface that generate loops and optimal force balance in sentential networks.

VP-fronting with and without remnant movement

In this paper, we consider two kinds ofvP-fronting constructions in English and argue that they receive quite different analyses. First, we show that EnglishvP-preposing does not have the properties that would be expected of a movement-derived dependency. Evidence for this conclusion is adduced from the licensing conditions on its occurrence, from the availability of morphological mismatches, and from reconstruction facts. By contrast, we show that English participle preposing is a well-behaved case ofvP-movement, contrasting withvP-preposing with respect to reconstruction properties in particular. We propose that the differences between the two constructions follow from the interaction of two constraints: the excluded middle constraint (EMC), which rules out derivations involving spellout of linearly intermediate copies only, and the N-only constraint, which restricts movement to occurring where the trace position would license a nominal. The EMC rules out derivingvP-fronting by true movement and instead necessitates a base-generation analysis, while the N-only constraint ensures that participle preposing is only possible in limited circumstances.

High frequency of intermediate and poor risk copy number abnormalities in pediatric cohort of B-ALL correlate with high MRD post induction

Copy number abnormalities (CNAs) and recurrent fusion transcripts are important genetic events which define and prognosticate B-Cell Acute Lymphoblastic Leukemia (B-ALL). We evaluated CNAs and fusion transcripts in 67 pediatric B-ALL cases and correlated the data with standard risk factors and early treatment outcome parameters. Common fusion transcripts ETV6-RUNX1, E2A-PBX, BCR-ABL1 and MLL-AF4 were examined by RT-PCR and noted in 15%, 15%, 13% and 1.4% of all cases respectively. CNAs in IKZF1, PAX5, EBF1, BTG1, RB1, CDKN2A/B and genes from PAR1 region viz., CSF2RA, IL3RA,P2RY8, SHOX region and CRLF2 were analyzed by multiplex ligation dependent probe amplification assay and were detected in 70% (47/67) of cases, with predominantly deletions in CDKN2A/B (36%), PAX5 (18%) and IKZF1 (16%). A statistically significant association of intermediate/poor risk CNAs was noted with high WBC count (p = 0.001), NCI group (p = 0.02) and minimal residual disease at Day35 (p < 0.0001). IKZF1 and CDKN2A/B deletion revealed poor EFS of 56% at 24 months as compared to EFS of 80% in rest of the cases (p = 0.05) suggesting their potential role in early risk stratification.

Pronoun copying in Dinka Bor and the Copy Theory of Movement

A fundamental question in contemporary minimalist approaches to movement is why copies left by phrasal movement are not realized. Particularly puzzling from this perspective is the observation that pronouns, in a range of environments, appear to function as spell-outs of gaps (e.g. Zaenen et al. 1981; Koopman 1982, 1984; Sells 1984; Engdahl 1985; Pesetsky 1998; Boeckx 2003; Kandybowicz 2007; Holmberg and Nikanne 2008; Harizanov 2014; Sichel 2014), a phenomenon I refer to as pronoun copying. This paper first presents a novel pronoun copying pattern in the Nilotic language Dinka Bor, in which a 3rd person plural pronoun spells out intermediate copies at the verb phrase edge. I then show that Dinka pronoun copying displays two unusual number asymmetries that provide a unique insight into the link between pronoun copying and copy deletion: (i) the pronoun matches only in number, not person, and (ii) only plural DPs initiate copying. Importantly, this number sensitivity mirrors a general asymmetry in the expression of singular and plural. I argue that this parallel reveals that pronoun copying in Dinka reflects partial deletion in a DP copy, deleting everything but the structure that hosts number information. The availability of partial deletion in multiple copy spell-out is shown to follow from an approach to copy deletion based on economy, as developed by Landau (2006). In support of this, I demonstrate that Dinka’s asymmetries in fact have their counterparts across pronoun copying constructions and develop a unified account of pronoun copying crosslinguistically.

Spell-out, Chains, and Long Distance Wh-movement in Seereer

Author(s): Baier, Nicholas | Abstract: In this paper, I examine novel data from long distance wh-dependencies in Seereer, an Atlantic language of Senegal. Seereer long distance wh-questions are characterized by (a) the presence of an obligatory pronoun at the edge of each embedded clause and (b) the presence of special morphology on each verb along the path of the extraction. Thus, Seereer provides striking evidence that long distance wh-movement proceeds successive cyclically through the edge of each clause. I argue that this verbal morphology spells out a valued wh-probe on C, which triggers the movement of a wh-phrase to its Spec. I show that the pronouns present at the edge of each embedded clause have the properties of copies and not of resumptive pronouns, and argue that they are in fact spelled out intermediate copies of the moved wh-phrase. I propose that such multiple copy spell out is possible precisely because they enter into a feature valuation relationship with C. Specifically, I propose that valuation of an wh-probe defines a copy as the head of an A’-chain. Thus, the application of successive cyclic movement does not result in one long chain, but instead in a series of smaller chains. This view of the structure of long A’-chains, when combined with the independently motivated principle of spelling out the heads of chains, results in the pattern of multiple copy spell out that occurs in Seereer.

Preimplantation embryonic mosaicism: origin, consequences and the reliability of comprehensive chromosome screening.

Embryonic mosaicism represents an ongoing challenge for contemporary comprehensive chromosome screening platforms due to the unknown reproductive potential of mosaic embryos and technical difficulties of its detection from a single embryo biopsy. Mosaicism in preimplantation embryos is a product of mitotic errors arising primarily from anaphase lag and chromosome nondisjunction. To date, there is high variability among estimations of prevalence of mosaicism in blastocysts, the most recent ranging from 3.3 to 83%. It has been reported that alleged mosaic embryos can develop into healthy babies, although the proper study evaluating this question remains to be completed. Technical artefacts from comprehensive chromosome screening platforms may also hinder correct classification of embryos as genuine mosaics. Although complex, embryonic mosaicism is a phenomenon that deserves further investigation. Many embryos classified as mosaic may have actual reproductive potential. The predictive value of intermediate chromosome copy number assignments for the remaining embryo and for ongoing reproductive potential needs more careful consideration. In addition, recent advancements in extended embryo culture raise the possibility of investigating whether preferential segregation, selective advantage of normal cells or surveillance of abnormal chromosome numbers occur at postimplantation stages.

Identification of a novel predictive genomic biomarker for response to combination bevacizumab in metastatic colorectal cancer (mCRC).

3580 Background: Somatic copy number alterations (SCNA) are genomic alterations evident in cancers including mCRC. These alterations support biomarker discovery, allowing identification of variants that can be used to predict response to therapy. Herein, we studied the impact of SCNAs on mCRC patient response to bevacizumab (BVZ). Methods: SCNA data was assembled from mCRC tumors in the TCGA cohort (n = 676), from the CAIRO 2 study [n = 143] and from the ANGIOPREDICT cohort (n = 258) [Betge et al. Digestion 2016 94(3):129-137]. GISTIC v2.0 was used to identify the most frequent and overrepresented chromosomal aberrations. A region was considered deleted if the logR value was &lt; 0.1 and amplified when the logR was &gt; 0.1. A cutoff q-value of 0.25 was used to select significantly overrepresented SCNAs. To further explore the impact of new ANGIOPREDICT clusters and consensus molecular subtypes (CMS), [Guinney J et al Nat Med. 2015 21(11):1350-6], a panel of seven xenografts representing each CMS subtype was treated with FOLFOX (40mg/kg 5-FU, 13.4mg/kg folinic acid &amp; 2.4mg/kg oxaliplatin) + B20 antibody (mouse avastin, 10mg/kg) for 4 weeks. Results: Unsupervised hierarchical clustering classified all 1077 tumors into 3 consensus SCNA subgroups termed ‘ANGIOPREDICT’ clusters 1-3. Concordance between CMS and ANGIOPREDICT clusters was evident: CMS1 - Cluster 1 78%, CMS3 - Cluster 1 50%. CMS2 - Cluster 2/3 92% and CMS4 - Cluster 2/3 84%. Tumors with intermediate or high copy number instability (ANGIOPREDICT cluster 2 &amp; 3) showed improved progression free survival (PFS): 369d vs. 227d p = 1.36e-7) whereas tumors with low copy number alterations displayed a poor response to BVZ therapy (PFS: 147d vs 152d p = 0.906). Xenografts corresponding to CMS 2&amp;4/ ANGIOPREDICT cluster 2-3 showed improved response to FOLFOX + B20 therapy and increased PFS (p &lt; 0.001) vs. CMS1&amp;3/ ANGIOPREDICT cluster 1. Conclusions: For the first time, in a large test and validation cohort including retrospectively collected and randomized controlled trial patient samples, we have identified a predictive genomic biomarker for BVZ therapy in mCRC. We have further demonstrated the utility of CMS subtyping to stratify patients to BVZ .

Selective Surface Smoothening of Polymer Microlenses by Depth Confined Softening

Polymeric refractive micro‐optical devices simultaneously demand striking smooth 3D topographies and precise shape accuracy for high performance and low stray light. Here, a surface selective smoothening of thermoplastic, polymeric material has been established while maintaining the high curvature corners required for a 50 µm tall, refractive, optical diffuser device. The 3D master structures are fabricated using direct write laser‐lithography with two‐photon absorption. Master structures are replicated into poly(methyl methacrylate) through a poly(dimethyl siloxane) intermediate copying step and subsequently smoothed out. Here, various high‐energy radiations have been considered to have a surface selective exposure and have been narrowed down to 172 nm ultraviolet exposure to be the ideal fit for this application. The 172 nm exposure provides selective modification of an up to 400 nm thick surface skin layer and negligible etching, which allows smoothening out up to 420 nm surface steps and reducing the RMS roughness from 22 nm down to below 10 nm by thermally driven material displacement, the so–called reflow, on a global pattern scale. Extreme ultraviolet exposure, as an alternative method, shows a higher modification efficiency than the 172 nm but has severe practical limitations.