Adaptive immune signature in HER2-positive breast cancer in NCCTG (Alliance) N9831 and NeoALTTO trials

Breast cancer; Predictive markersCáncer de mama; Marcadores predictivosCàncer de mama; Marcadors predictiusTrastuzumab acts in part through the adaptive immune system. Previous studies showed that enrichment of immune-related gene expression was associated with improved outcomes in HER2-positive (HER2+) breast cancer. However, the role of the immune system in response to lapatinib is not fully understood. Gene expression analysis was performed in 1,268 samples from the North Central Cancer Treatment Group (NCCTG) N9831 and 244 samples from the NeoALTTO trial. In N9831, enrichment of CD45 and immune-subset signatures were significantly associated with improved outcomes. We identified a novel 17-gene adaptive immune signature (AIS), which was found to be significantly associated with improved RFS among patients who received adjuvant trastuzumab (HR 0.66, 95% CI 0.49–0.90, Cox regression model p = 0.01) but not in patients who received chemotherapy alone (HR 0.96, 95% CI 0.67–1.40, Cox regression model p = 0.97). This result was validated in NeoALTTO. Overall, AIS-low patients had a significantly lower pathologic complete response (pCR) rate compared with AIS-high patients (χ2 p < 0.0001). Among patients who received trastuzumab alone, pCR was observed in 41.7% of AIS-high patients compared with 9.8% in AIS-low patients (OR of 6.61, 95% CI 2.09–25.59, logistic regression model p = 0.003). More importantly, AIS-low patients had a higher pCR rate with an addition of lapatinib (51.1% vs. 9.8%, OR 9.65, 95% CI 3.24–36.09, logistic regression model p < 0.001). AIS-low patients had poor outcomes, despite receiving adjuvant trastuzumab. However, these patients appear to benefit from an addition of lapatinib. Further studies are needed to validate the significance of this signature to identify patients who are more likely to benefit from dual anti-HER2 therapy. ClinicalTrials.gov Identifiers: NCT00005970 (NCCTG N9831) and NCT00553358 (NeoALTTO).Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180882 and U24CA196171 (to the Alliance for Clinical Trials in Oncology); UG1CA233180, UG1CA232760, UG1CA233373, and U10CA180821. https://acknowledgments.alliancefound.org. Also supported in part by funds from the Department of Defense W81XWH-18-1-0562 and −0563 and W81XWH-16-1-0265 and 0266, as well as the Breast Cancer Research Foundation (BCRF-19-161), Bankhead-Coley Research Program (6BC05), Susan G. Komen Foundation (SAC190091), and the DONNA Foundation. The content is solely the authors’ responsibility and does not necessarily represent the official views of the National Institutes of Health. Genentech/Roche supplied trastuzumab for both trials. Presented at the Spotlight Session at San Antonio Breast Cancer Symposium 2016 and the ASCO Annual Meeting 2018. Portions of this paper have been published in abstract form: Journal of Clinical Oncology 36, no. 15_suppl (May 20, 2018) 577

ERP Mismatch Negativity Amplitude and Asymmetry Reflect Phonological and Rapid Automatized Naming Skills in English-Speaking Kindergartners

The mismatch negativity (MMN), an electrophysiological response to an oddball auditory stimulus, is related to reading ability in many studies. There are conflicting findings regarding exactly how the MMN relates to risk or actual diagnosis of dyslexia/reading impairment, perhaps due to the heterogeneity of abilities in children with reading impairment. In this study, 166 English-speaking kindergarten children oversampled for dyslexia risk completed behavioral assessments and a speech-syllable MMN paradigm. We examined how early and late MMN mean amplitude and laterality were related to two established predictors of reading ability: phonological awareness (PA) and rapid automatized naming (RAN). In bootstrapped group analyses, late MMN amplitude was significantly greater in children with typical PA ability than low PA ability. In contrast, laterality of the early and late MMN was significantly different in children with low versus typical RAN ability. Continuous analyses controlling for child age, non-verbal IQ, and letter and word identification abilities showed the same associations between late MMN amplitude with PA and late MMN laterality with RAN. These findings suggest that amplitude of the MMN may relate to phonological representations and ability to manipulate them, whereas MMN laterality may reflect differences in brain processes that support automaticity needed for reading

Whole Genome Association Study in a Homogenous Population in Shandong Peninsula of China Reveals JARID2 as a Susceptibility Gene for Schizophrenia

DNA pooling can provide an economic and efficient way to detect susceptibility loci to complex diseases. We carried out a genome screen with 400 microsatellite markers spaced at approximately 10 cm in two DNA pools consisting of 119 schizophrenia (SZ) patients and 119 controls recruited from a homogenous population in the Chang Le area of the Shandong peninsula of China. Association of D6S289, a dinucleotide repeat polymorphism in the JARID2 gene with SZ, was found and confirmed by individual genotyping (X2 = 17.89; P = .047). In order to refine the signal, we genotyped 14 single nucleotide polymorphisms (SNPs) covering JARID2 and the neighboring gene, DNTBP1, in an extended sample of 309 cases and 309 controls from Shandong peninsula (including the samples from the pools). However, rs2235258 and rs9654600 in JARID2 showed association in allelic, genotypic and haplotypic tests with SZ patients from Chang Le area. This was not replicates in the extended sample, we conclude that JARID2 could be a susceptibility gene for SZ

Tracking the Roots of Reading Ability: White Matter Volume and Integrity Correlate with Phonological Awareness in Prereading and Early-Reading Kindergarten Children

Developmental dyslexia, an unexplained difficulty in learning to read, has been associated with alterations in white matter organization as measured by diffusion-weighted imaging. It is unknown, however, whether these differences in structural connectivity are related to the cause of dyslexia or if they are consequences of reading difficulty (e.g., less reading experience or compensatory brain organization). Here, in 40 kindergartners who had received little or no reading instruction, we examined the relation between behavioral predictors of dyslexia and white matter organization in left arcuate fasciculus, inferior longitudinal fasciculus, and the parietal portion of the superior longitudinal fasciculus using probabilistic tractography. Higher composite phonological awareness scores were significantly and positively correlated with the volume of the arcuate fasciculus, but not with other tracts. Two other behavioral predictors of dyslexia, rapid naming and letter knowledge, did not correlate with volumes or diffusion values in these tracts. The volume and fractional anisotropy of the left arcuate showed a particularly strong positive correlation with a phoneme blending test. Whole-brain regressions of behavioral scores with diffusion measures confirmed the unique relation between phonological awareness and the left arcuate. These findings indicate that the left arcuate fasciculus, which connects anterior and posterior language regions of the human brain and which has been previously associated with reading ability in older individuals, is already smaller and has less integrity in kindergartners who are at risk for dyslexia because of poor phonological awareness. These findings suggest a structural basis of behavioral risk for dyslexia that predates reading instruction

No evidence for association between polymorphisms in GRM3 and schizophrenia

BACKGROUND: Three studies have previously reported data that were interpreted by the authors as supportive of association between schizophrenia and polymorphisms in the gene encoding the metabotropic glutamate receptor GRM3. METHODS: In a bid to examine this hypothesis, we examined seven SNPs spanning GRM3 in a UK case-control sample (schizophrenic cases n = 674, controls n = 716). These included all SNPs previously reported to be associated, alone or in haplotypes, with schizophrenia in European or European American samples. RESULTS: Our data showed no evidence for association with single markers, or 2, 3, 4 and 5 marker haplotypes, nor did any specific haplotypes show evidence for association according to previously observed patterns. CONCLUSION: Examination of our own data and those of other groups leads us to conclude that at present, GRM3 should not be viewed as a gene for which there is replicated evidence for association with schizophrenia

Stepped-wedge randomised trial of laparoscopic ventral mesh rectopexy in adults with chronic constipation:Study protocol for a randomized controlled trial

Funding was from the UK National Institute of Health Research, funding reference PGfAR: RP-PG-0612-20001 (£1,971,934). The calculation of all costs and contracting has been performed in conjunction with the sponsor. Indemnity: Queen Mary University London has agreed to act as study sponsor. Insurance and indemnity will be provided by the sponsor

TRANSCRIPT: The Roberts Court and Free Speech Symposium

On April 9, 2021, the Brooklyn Law Review gathered a panel of First Amendment scholars for a symposium on the Roberts Court\u27s free speech jurisprudence. This transcript captures the panelists\u27 diverse perspectives on the free speech themes highlighted by the Roberts Court\u27s free speech jurisprudence

Connectivity precedes function in the development of the visual word form area

What determines the cortical location at which a given functionally specific region will arise in development? We tested the hypothesis that functionally specific regions develop in their characteristic locations because of pre-existing differences in the extrinsic connectivity of that region to the rest of the brain. We exploited the visual word form area (VWFA) as a test case, scanning children with diffusion and functional imaging at age 5, before they learned to read, and at age 8, after they learned to read. We found the VWFA developed functionally in this interval and that its location in a particular child at age 8 could be predicted from that child's connectivity fingerprints (but not functional responses) at age 5. These results suggest that early connectivity instructs the functional development of the VWFA, possibly reflecting a general mechanism of cortical development.National Institutes of Health (U.S.) (Grant F32HD079169)Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (Grant F32HD079169)National Institutes of Health (U.S.) (Grant R01HD067312)Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (Grant R01HD067312