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Truancy and dropout are major problems for Cambodian high school students in the United States. The project described in this article investigated student explanations of truancy and dropout and associated demographic and academic variables among a random sample of 23 Cambodian students at a comprehensive high school. Chronic truancy typically preceded dropout. Findings indicated that truancy occurred primarily as a group activity. No students reported parental support or tolerance for truant behavior. The main reasons given for truancy were boredom and wanting to socialize with friends. Earning money and taking care of a spouse and child were major considerations for dropout, but not truancy. Results suggest that students at high risk of truancy can he identified before they start high school on the basis of their behavior in middle school. The results support providing counseling and educational programming to at-risk friendship groups and hiring Cambodian staff to facilitate the school adjustment of Cambodian students. [ABSTRACT FROM AUTHOR]

Substance-abusing women are a diverse group, but some of them are among the most disadvantaged individuals in the United States. This article reviews and interprets some recent literature on substance abuse problems and treatments among women. Contrary to popular stereotypes, alcohol and drug abuse among women occurs at similar rates among poor and nonpoor people and among white people and people of color. Major risk factors include childhood sexual or physical abuse, adult victimization by domestic violence, and a spouse or partner who abuses substances. Standard treatment programs are based on male processes of recovery, and there are enormous problems of access to treatment for women with minor children. Although most studies have found that white women and women of color use substances during pregnancy at similar rates, women of color are disproportionately tested for drug use and receive more child protective services interventions. The findings discussed in this article indicate that prevention of substance abuse-related problems among women requires more than just education. [ABSTRACT FROM AUTHOR]

Visuomotor association involves linking an arbitrary visual cue to a well-learned movement. Transient inactivation of Crus I/II impairs primates' ability to learn new associations and delays motor responses without affecting the kinematics of the movement. The simple spikes of Purkinje cells in the Crus regions signal cognitive errors as monkeys learn to associate specific fractal stimuli with movements of the left or right hand. Here we show that as learning progresses, the simple spike activity of individual neurons becomes more selective for stimulus-response associations, with selectivity developing closer to the appearance of visual stimuli. Initially, most neurons respond to both associations, irrespective of the identity of the stimulus and the associated movement, but as learning advances, more neurons distinguish between specific stimulus-hand associations. Using a linear decoder, it was found that in early learning stages, the visual stimulus can be decoded only when the choice can also be decoded. As learning improves, the visual stimulus is decoded earlier than the choice. A simple model can replicate the observed simple spike signals and the monkeys' behavior in both the early and late learning stages.

Using five complementary short- and long-read sequencing technologies, we phased and assembled >95% of each diploid human genome in a four-generation, 28-member family (CEPH 1463) allowing us to systematically assess de novo mutations (DNMs) and recombination. From this family, we estimate an average of 192 DNMs per generation, including 75.5 de novo single-nucleotide variants (SNVs), 7.4 non-tandem repeat indels, 79.6 de novo indels or structural variants (SVs) originating from tandem repeats, 7.7 centromeric de novo SVs and SNVs, and 12.4 de novo Y chromosome events per generation. STRs and VNTRs are the most mutable with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations, documenting de novo SVs, and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length, and sequence identity. We show a strong paternal bias (75-81%) for all forms of germline DNM, yet we estimate that 17% of de novo SNVs are postzygotic in origin with no paternal bias. We place all this variation in the context of a high-resolution recombination map (~3.5 kbp breakpoint resolution). We observe a strong maternal recombination bias (1.36 maternal:paternal ratio) with a consistent reduction in the number of crossovers with increasing paternal (r=0.85) and maternal (r=0.65) age. However, we observe no correlation between meiotic crossover locations and de novo SVs, arguing against non-allelic homologous recombination as a predominant mechanism. The use of multiple orthogonal technologies, near-telomere-to-telomere phased genome assemblies, and a multi-generation family to assess transmission has created the most comprehensive, publicly available "truth set" of all classes of genomic variants. The resource can be used to test and benchmark new algorithms and technologies to understand the most fundamental processes underlying human genetic variation., Competing Interests: Conflicts of interest E.E.E. is a scientific advisory board (SAB) member of Variant Bio, Inc. C.Lee is an SAB member of Nabsys and Genome Insight. D.P. has previously disclosed a patent application (no. EP19169090) relevant to Strand-seq. Z.K., C.N., E.D., C.F., C.Lambert, T.M., W.J.R., and M.A.E. are employees and shareholders of PacBio. Z.K. is a private shareholder in Phase Genomics. The other authors declare no competing interests.

Short tandem repeats (STRs) are hotspots of genomic variability in the human germline because of their high mutation rates, which have long been attributed largely to polymerase slippage during DNA replication. This model suggests that STR mutation rates should scale linearly with a father's age, as progenitor cells continually divide after puberty. In contrast, it suggests that STR mutation rates should not scale with a mother's age at her child's conception, since oocytes spend a mother's reproductive years arrested in meiosis II and undergo a fixed number of cell divisions that are independent of the age at ovulation. Yet, mirroring recent findings, we find that STR mutation rates covary with paternal and maternal age, implying that some STR mutations are caused by DNA damage in quiescent cells rather than polymerase slippage in replicating progenitor cells. These results echo the recent finding that DNA damage in oocytes is a significant source of de novo single nucleotide variants and corroborate evidence of STR expansion in postmitotic cells. However, we find that the maternal age effect is not confined to known hotspots of oocyte mutagenesis, nor are postzygotic mutations likely to contribute significantly. STR nucleotide composition demonstrates divergent effects on de novo mutation (DNM) rates between sexes. Unlike the paternal lineage, maternally derived DNMs at A/T STRs display a significantly greater association with maternal age than DNMs at G/C-containing STRs. These observations may suggest the mechanism and developmental timing of certain STR mutations and contradict prior attribution of replication slippage as the primary mechanism of STR mutagenesis., Competing Interests: Conflicts of interest EEE is a Scientific Advisory Board (SAB) member of Variant Bio, Inc., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

The nature and function of perisaccadic receptive field (RF) remapping have been controversial. We use a delayed saccade task to reduce previous confounds and examine the remapping time course in the lateral intraparietal area and frontal eye fields. In the delay period, the RF shift direction turns from the initial fixation to the saccade target. In the perisaccadic period, RFs first shift toward the target (convergent remapping), but around the time of saccade onset/offset, the shifts become predominantly toward the post-saccadic RF locations (forward remapping). Thus, unlike forward remapping that depends on the corollary discharge (CD) of the saccade command, convergent remapping appears to follow attention from the initial fixation to the target. We model the data with attention-modulated and CD-gated connections and show that both sets of connections emerge automatically in neural networks trained to update stimulus retinal locations across saccades. Our work thus unifies previous findings into a mechanism for transsaccadic visual stability., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Consensus is rapidly building to support a role for the cerebellum beyond motor function, but its contributions to non-motor learning remain poorly understood. Here, we provide behavioral, anatomical and computational evidence to demonstrate a causal role for the primate posterior lateral cerebellum in learning new visuomotor associations. Reversible inactivation of the posterior lateral cerebellum of male monkeys impeded the learning of new visuomotor associations, but had no effect on movement parameters, or on well-practiced performance of the same task. Using retrograde transneuronal transport of rabies virus, we identified a distinct cerebro-cerebellar network linking Purkinje cells in the posterior lateral cerebellum with a region of the prefrontal cortex that is critical in learning visuomotor associations. Together, these results demonstrate a causal role for the primate posterior lateral cerebellum in non-motor, reinforcement learning., (© 2024. The Author(s).)

Single-nucleotide variants (SNVs) in segmental duplications (SDs) have not been systematically assessed because of the limitations of mapping short-read sequencing data 1,2 . Here we constructed 1:1 unambiguous alignments spanning high-identity SDs across 102 human haplotypes and compared the pattern of SNVs between unique and duplicated regions 3,4 . We find that human SNVs are elevated 60% in SDs compared to unique regions and estimate that at least 23% of this increase is due to interlocus gene conversion (IGC) with up to 4.3 megabase pairs of SD sequence converted on average per human haplotype. We develop a genome-wide map of IGC donors and acceptors, including 498 acceptor and 454 donor hotspots affecting the exons of about 800 protein-coding genes. These include 171 genes that have 'relocated' on average 1.61 megabase pairs in a subset of human haplotypes. Using a coalescent framework, we show that SD regions are slightly evolutionarily older when compared to unique sequences, probably owing to IGC. SNVs in SDs, however, show a distinct mutational spectrum: a 27.1% increase in transversions that convert cytosine to guanine or the reverse across all triplet contexts and a 7.6% reduction in the frequency of CpG-associated mutations when compared to unique DNA. We reason that these distinct mutational properties help to maintain an overall higher GC content of SD DNA compared to that of unique DNA, probably driven by GC-biased conversion between paralogous sequences 5,6 ., (© 2023. The Author(s).)

Sensory processing is often studied by examining how a given neuron responds to a parameterized set of stimuli (tuning curve) or how a given stimulus evokes responses from a parameterized set of neurons (population response). Although tuning curves and the corresponding population responses contain the same information, they can have different properties. These differences are known to be important because the perception of a stimulus should be decoded from its population response, not from any single tuning curve. The differences are less studied in the spatial domain where a cell's spatial tuning curve is simply its receptive field (RF) profile. Here, we focus on evaluating the common belief that perrisaccadic forward and convergent RF shifts lead to forward (translational) and convergent (compressive) perceptual mislocalization, respectively, and investigate the effects of three related factors: decoders' awareness of RF shifts, changes of cells' covering density near attentional locus (the saccade target), and attentional response modulation. We find that RF shifts alone produce either no shift or an opposite shift of the population responses depending on whether or not decoders are aware of the RF shifts. Thus, forward RF shifts do not predict forward mislocalization. However, convergent RF shifts change cells' covering density for aware decoders (but not for unaware decoders) which may predict convergent mislocalization. Finally, attentional modulation adds a convergent component to population responses for stimuli near the target. We simulate the combined effects of these factors and discuss the results with extant mislocalization data. We speculate that perisaccadic mislocalization might be the flash-lag effect unrelated to perisaccadic RF remapping but to resolve the issue, one has to address the question of whether or not perceptual decoders are aware of RF shifts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Qian, Goldberg and Zhang.)

Although the cerebellum has been traditionally considered to be exclusively involved in motor control, recent anatomic and clinical studies show that it also has a role in reward-processing. However, the way in which the movement-related and the reward-related neural activity interact at the level of the cerebellar cortex and contribute toward learning is still unclear. Here, we studied the simple spike activity of Purkinje cells in the mid-lateral cerebellum when 2 male monkeys learned to associate a right or left-hand movement with one of two visual symbolic cues. These cells had distinctly different discharge patterns between an overtrained symbol-hand association and a novel symbol-hand association, responding in association with the movement of both hands, although the kinematics of the movement did not change between the two conditions. The activity change was not related to the pattern of the visual symbols, the movement kinematics, the monkeys' reaction times, or the novelty of the visual symbols. The simple spike activity changed throughout the learning process, but the concurrent complex spikes did not instruct that change. Although these neurons also have reward-related activity, the reward-related and movement-related signals were independent. We suggest that this mixed selectivity may facilitate the flexible learning of difficult reinforcement learning problems. SIGNIFICANCE STATEMENT The cerebellum receives both motor-related and reward-related information. However, it is unclear how these two signals interact at the level of cerebellar cortex and contribute to learning nonmotor skills. Here we show that in the mid-lateral cerebellum, the reward information is encoded independently from the motor information such that during reward-based learning, only the reward information carried by the Purkinje cells inform learning while the motor information remains unchanged with learning., (Copyright © 2022 the authors.)

Great ape clades exhibit variation in the relative mutation rates of different three-base-pair genomic motifs, with closely related species having more similar mutation spectra than distantly related species. This pattern cannot be explained by classical demographic or selective forces, but imply that DNA replication fidelity has been perturbed in different ways on each branch of the great ape phylogeny. Here, we use whole-genome variation from 88 great apes to investigate whether these species' mutation spectra are broadly differentiated across the entire genome, or whether mutation spectrum differences are driven by DNA compartments that have particular functional features or chromatin states. We perform principal component analysis (PCA) and mutational signature deconvolution on mutation spectra ascertained from compartments defined by features including replication timing and ancient repeat content, finding evidence for consistent species-specific mutational signatures that do not depend on which functional compartments the spectra are ascertained from. At the same time, we find that many compartments have their own characteristic mutational signatures that appear stable across the great ape phylogeny. For example, in a mutation spectrum PCA compartmentalized by replication timing, the second principal component explaining 21.2% of variation separates all species' late-replicating regions from their early-replicating regions. Our results suggest that great ape mutation spectrum evolution is not driven by epigenetic changes that modify mutation rates in specific genomic regions, but instead by trans-acting mutational modifiers that affect mutagenesis across the whole genome fairly uniformly., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Although the cerebellum has been implicated in simple reward-based learning recently, the role of complex spikes (CS) and simple spikes (SS), their interaction and their relationship to complex reinforcement learning and decision making is still unclear. Here we show that in a context where a non-human primate learned to make novel visuomotor associations, classifying CS responses based on their SS properties revealed distinct cell-type specific encoding of the probability of failure after the stimulus onset and the non-human primate's decision. In a different context, CS from the same cerebellar area also responded in a cell-type and learning independent manner to the stimulus that signaled the beginning of the trial. Both types of CS signals were independent of changes in any motor kinematics and were unlikely to instruct the concurrent SS activity through an error based mechanism, suggesting the presence of context dependent, flexible, multiple independent channels of neural encoding by CS and SS. This diversity in neural information encoding in the mid-lateral cerebellum, depending on the context and learning state, is well suited to promote exploration and acquisition of wide range of cognitive behaviors that entail flexible stimulus-action-reward relationships but not necessarily motor learning., (© 2021. The Author(s).)

Background: Nearly one-third of colorectal cancers (CRC) arise via the serrated pathway. CT colonography (CTC) is a CRC screening examination. Endoscopic detection of sessile serrated polyps (SSPs) varies widely; it is unknown whether CTC effectively detects SSPs. The aim of this study is to determine whether CTC detects SSPs at an institution that performs a large volume of CTC., Methods: We conducted a search of pathology records to identify serrated polyps (SPs) from 2005 to 2012. We extracted demographic data from the electronic health records (EHRs) of subjects with an SSP and examined endoscopy reports for location and size of each SSP. We identified subjects with a CTC within 1 year prior to the colonoscopy that found an SSP, and determined if the CTC identified the SSP., Results: Our search found 3978 subjects with SP over the 7-year period. Seven hundred thirty-two subjects had at least 1 SSP. Eightytwo subjects had CTC done within 1 year prior to the colonoscopy that identified SSP. Seventy-nine subjects' polyps were identified on CTC. CT colonography was done an average of 38 ± 54 days prior to colonoscopy. One hundred fifteen SSPs were identified endoscopically. A total of 48.7% of all SSPs were identified via CTC; larger SSPs were more likely to be seen on CTC (P < .001), and 69.6% of SSPs larger than 10 mm were found via CTC. Proximal SSPs were more often identified than distal SSPs (P = .005)., Conclusion: Given the miss rate for SSPs on CTC, endoscopists should be vigilant about examining the proximal colon in subjects referred after CTC, even if the imaging does not reveal a proximal polyp.

Background: Non-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome., Methods: Three cohorts of NSCLC patients with oncogene alterations (n=4189 total) were analyzed. Two clinical cohorts of advanced NSCLC patients treated with ICB monotherapy [MD Anderson (MDACC; n=172) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB; n=894 patients)] were analyzed for clinical outcome. The FMI biomarker cohort (n=4017) was used to assess the association of oncogene alterations with TMB and PD-L1 expression., Results: High PD-L1 expression (PD-L1 ≥50%) rate was 19%-20% in classic EGFR , EGFR exon 20 and HER2 -mutant tumors, and 34%-55% in tumors with ALK , BRAF V600E, ROS1 , RET , or MET alterations. Compared with KRAS- mutant tumors, BRAF non-V600E group had higher TMB (9.6 vs KRAS 7.8 mutations/Mb, p=0.003), while all other oncogene groups had lower TMB (p<0.001). In the two clinical cohorts treated with ICB, molecular groups with EGFR , HER2 , ALK , ROS1 , RET , or MET alterations had short progression-free survival (PFS; 1.8-3.7 months), while BRAF V600E group was associated with greater clinical benefit from ICB (CGDB cohort: PFS 9.8 months vs KRAS 3.7 months, HR 0.66, p=0.099; MDACC cohort: response rate 62% vs KRAS 24%; PFS 7.4 vs KRAS 2.8 months, HR 0.36, p=0.026). KRAS G12C and non-G12C subgroups had similar clinical benefit from ICB in both cohorts. In a multivariable analysis, BRAF V600E mutation (HR 0.58, p=0.041), PD-L1 expression (HR 0.57, p=0.022), and high TMB (HR 0.66, p<0.001) were associated with longer PFS., Conclusions: High TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboring BRAF mutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. Meanwhile EGFR and HER2 mutations and ALK , ROS1 , RET , and MET fusions define NSCLC subsets with minimal benefit from ICB despite high PD-L1 expression in NSCLC harboring oncogene fusions. These findings indicate a TMB/PD-L1-independent impact on sensitivity to ICB for certain oncogene alterations., Competing Interests: Competing interests: MVN is a consultant for Mirati and Merck/MSD, and reports funding to the institution from Mirati, Novartis, Pfizer, Ziopharm, AstraZeneca, and Checkmate; MM is an employee of Foundation Medicine, and owns stock in Roche; KS is an employee of Genentech, and owns stock in Roche; IB is an employee of Genentech, owns stock in Roche; VS is an employee of Roche, and owns stock in Roche; HX is an employee of Roche, and owns stock in Roche; HS is an employee of Genentech, and owns stock in Roche; XL is a Consultant for Eli Lilly, AstraZeneca, and EMD Serono; MEG is a former employee of Foundation Medicine; KM is an employee of Foundation Medicine, and owns stock in Roche; JPR reports licensing/royalties from Spectrum Pharmaceuticals; TC has received speaker’s fees from the Society for Immunotherapy of Cancer and Bristol-Myers Squibb, receives consulting fees from MedImmune and Bristol-Myers Squibb, and reports research funding to MD Anderson Cancer Center from Boehringer Ingelheim, MedImmune and Bristol-Myers Squibb; AT reports research grants from Eli Lilly, Millennium, Polaris, Genentech, Merck, Boehringer-Ingelheim, BMS, Ariad, Epizyme, Seattle Genetics, Takeda, and EMD Serono; advisory board member for BMS, Eli Lilly, Genentech, Roche, Novartis, Ariad, EMD Serono, Merck, Seattle Genetics, Astra-Zeneca, Boehringer-Ingelheim, Sellas Life Science, Takeda, Epizyme, and Huron; VP is an employee of Pfizer; DLG reports research grants from AstraZeneca, Jenssen R & D, Takeda, Ribun Therapeutics; and honoraria member of Senofi, AstraZeneca, Ribun Therapeutics; GS is an employee of Foundation Medicine, and owns stock in Roche; VAM is an employee of Foundation Medicine, and owns stock in Roche; BA is an employee of Foundation Medicine, and owns stock in Roche; GF is an employee of Foundation Medicine, and owns stock in Roche; LAA is an employee of Foundation Medicine, and owns stock in Roche; DS is an employee of Genentech, and owns stock in Roche; JZ reports research funding from Merck, Johnson and Johnson, and consultant fees from BMS, Johnson and Johnson, AstraZeneca, Geneplus, OrigMed, Innovent outside the submitted work; JVH reports research grants from NIH/NCI, American Cancer Society, Cancer Prevention & Research Institute of Texas, AACR Johnson & Johnson Lung Cancer, AZ, Spectrum, Checkmate Pharmaceuticals; Advisory Committees – AZ, BMS, GSK, Guardant Health, Kairos Venture Investments, BrightPath Biotherapeutics Hengrui Therapeutics, Eli Lilly, Spectrum, EMD Serono, Roche, Foundation One Medicine; Royalties & Licensing – Spectrum & Bio-Tree Systems, Inc., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

What are the cortical neural correlates that distinguish goal-directed and non-goal-directed movements? We investigated this question in the monkey frontal eye field (FEF), which is implicated in voluntary control of saccades. Here, we compared FEF activity associated with goal-directed (G) saccades and non-goal-directed (nG) saccades made by the monkey. Although the FEF neurons discharged before these nG saccades, there were three major differences in the neural activity: First, the variability in spike rate across trials decreased only for G saccades. Second, the local field potential beta-band power decreased during G saccades but did not change during nG saccades. Third, the time from saccade direction selection to the saccade onset was significantly longer for G saccades compared with nG saccades. Overall, our results reveal unexpected differences in neural signatures for G versus nG saccades in a brain area that has been implicated selectively in voluntary control. Taken together, these data add critical constraints to the way we think about saccade generation in the brain., Competing Interests: The authors declare no competing interest.

Background: Metastatic breast cancer is the leading cause of cancer death in women, but the genomics of metastasis in breast cancer are poorly studied., Methods: We explored a set of 11,616 breast tumors, including 5,034 metastases, which had undergone targeted sequencing during standard clinical care., Results: Besides the known hotspot mutations in ESR1, we observed a metastatic enrichment of previously unreported, lower-prevalence mutations in the ligand-binding domain, implying that these mutations may also be functional. Furthermore, individual ESR1 hotspots are significantly enriched in specific metastatic tissues and histologies, suggesting functional differences between these mutations. Other alterations enriched across all metastases include loss of function of the CDK4 regulator CDKN1B, and mutations in the transcription factor CTCF. Mutations enriched at specific metastatic sites generally reflect biology of the target tissue and may be adaptations to growth in the local environment. These include PTEN and ASXL1 alterations in brain metastases and NOTCH1 alterations in skin. We observed an enrichment of KRAS, KEAP1, STK11 and EGFR mutations in lung metastases. However, the patterns of other mutations in these tumors indicate that these are misdiagnosed lung primaries rather than breast metastases., Conclusions: An order-of-magnitude increase in samples relative to previous studies allowed us to detect novel genomic characteristics of metastatic cancer and to expand and clarify previous findings., Competing Interests: All authors were employees and may have held shares of Genentech/Roche or Foundation Medicine at the time this work was completed. Both companies are involved in the development of cancer drugs and clinical assays for metastatic breast cancer, and have multiple patents in related areas. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The PI3K signaling pathway serves as a central node in regulating cell survival, proliferation, and metabolism. PIK3CA , the gene encoding the PI3K catalytic subunit p110-alpha, is commonly altered in breast cancer resulting in the constitutive activation of the PI3K pathway. Using an unbiased cell line screening approach, we tested the sensitivity of breast cancer cell lines to taselisib, a potent PI3K inhibitor, and correlated sensitivity with key biomarkers ( PIK3CA , HER2, PTEN, and ESR1 ). We further assessed how taselisib modulates downstream signaling in the different genomic backgrounds that occur within breast cancer. We found that sensitivity to taselisib correlated with the presence of PIK3CA mutations, but was independent of HER2 status. We further showed that HER2-amplified/ PIK3CA wild-type cell lines are not as sensitive to taselisib when compared with HER2-amplified/ PIK3CA -mutant cell lines. In a PIK3CA- mutant/PTEN null background, PI3K downstream signaling rebounded in the presence of taselisib correlating with decreased sensitivity at later time points. Finally, we observed that PIK3CA mutations cooccurred with mutations in the estrogen receptor (ER; ESR1 ) in metastatic tumors from patients with ER + breast cancer. However, the cooccurrence of an ESR1 mutation with a PIK3CA mutation did not affect response to taselisib in a single agent setting or in combination with fulvestrant. In summary, these data suggest that development of taselisib in breast cancer should occur in a PIK3CA -mutant setting with cotreatments determined by the specific subtypes under investigation., (©2019 American Association for Cancer Research.)

This report discusses how a number of currently incurable diseases might be treated by advances developed as the result of current ongoing research on monkeys. The diseases discussed include Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, peripheral neuropathy, and stroke. Finally, the report discusses the devastating effect the animal rights movement and adverse publicity can have on basic neurobiological research on monkeys.

Purpose: The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood. Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes., Results: Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P < 0.001), were associated with rapid disease progression following tumor recurrence (HR = 2.6, P = 0.02), and likely preceded the acquisition of alkylating therapy-associated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAF -mutant gliomas, response to agents targeting the RAF/MEK/ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context., Conclusions: These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma., (©2019 American Association for Cancer Research.)

After sequential treatment with first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), EGFR-mutant non-small cell lung cancers frequently harbor multiple resistance mutations in exon 20 of EGFR including T790M, mediating resistance to first-generation TKIs, and at codons 792, 796, or 797 mediating resistance to third-generation TKIs. However, whether these resistance mutations are in cis or trans has therapeutic implications for patients. We analyzed a cohort of 29 patients with NSCLC harboring EGFR mutations at codons 792, 796, or 797 to establish the configuration of these mutations. We performed hybrid capture-based, next-generation sequencing on formalin-fixed paraffin-embedded biopsy tissue or liquid biopsy. 27 samples had both a T790M mutation and a mutation at codons 792, 796, or 797. In all of these cases, the mutations were found in the cis configuration; the trans configuration was not observed. Two patients' samples harbored a mutation at codon 797 but no T790M mutation. In these two cases, longitudinal analysis showed earlier biopsies harbored EGFR T790M, which was undetectable following osimertinib treatment. Treatment of one these patients with both first- and third-generation EGFR TKIs resulted in a mixed response. Here we describe multiple configurations of EGFR T790M and third-generation TKI resistance mutations at codons 792, 796, and 797. These mutations are most commonly found in cis, which confers resistance to all current EGFR TKIs. We also describe two patients that exhibited T790M loss with acquisition of a mutation at codon 797. In addition, one of these patients, with an EGFR C797S in a lung biopsy was subsequently found to have EGFR C797N in a later biopsy of pleural fluid, highlighting the dynamic multiclonal nature of advanced NSCLC., Competing Interests: We have read the journal's policy and the authors of this manuscript have the following competing interests: All authors affiliated with Foundation Medicine were employees and owned FMI stock (MEG, MM, LY, JS, JG, MK, VAM, PJS, GMF, SA, LAA). JPG is an External Speaker and consultant for Foundation Medicine Inc. This affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have no other financial conflicts to disclose.

KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations define distinct subgroups of KRAS -mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups ( P < 0.001) in the Stand Up To Cancer (SU2C) cohort (174 patients) with KRAS -mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase III trial (0% vs. 57.1% vs. 18.2%; P = 0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free ( P < 0.001) and overall ( P = 0.0015) survival compared with KRAS MUT ; STK11/LKB1 WT LUAC. Among 924 LUACs, STK11/LKB1 alterations were the only marker significantly associated with PD-L1 negativity in TMB Intermediate/High LUAC. The impact of STK11/LKB1 alterations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1-positive non-small cell lung cancer. In Kras -mutant murine LUAC models, Stk11/Lkb1 loss promoted PD-1/PD-L1 inhibitor resistance, suggesting a causal role. Our results identify STK11/LKB1 alterations as a major driver of primary resistance to PD-1 blockade in KRAS -mutant LUAC. Significance: This work identifies STK11/LKB1 alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS -mutant lung adenocarcinoma. Genomic profiling may enhance the predictive utility of PD-L1 expression and tumor mutation burden and facilitate establishment of personalized combination immunotherapy approaches for genomically defined LUAC subsets. Cancer Discov; 8(7); 822-35. ©2018 AACR. See related commentary by Etxeberria et al., p. 794 This article is highlighted in the In This Issue feature, p. 781 ., (©2018 American Association for Cancer Research.)

Background: Estrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer., Patients and Methods: To identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287-395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots., Results: We identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3' partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations., Conclusions: Collectively, these data indicate that N-terminal ESR1 fusions involving exons 6-7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies.

Humans effortlessly establish a gist-like memory of their environment whenever they enter a new place, a memory that can guide action even in the absence of vision. Neurons in the lateral intraparietal area (LIP) of the monkey exhibit a form of this environmental memory. These neurons respond when a monkey makes a saccade that brings the spatial location of a stimulus that appeared on a number of prior trials, but not on the present trial, into their receptive fields (RFs). The stimulus need never have appeared in the neuron's RF. This memory response is usually weaker, with a longer latency than the neuron's visual response. We suggest that these results demonstrate that LIP has access to a supraretinal memory of space, which is activated when the spatial location of the vanished stimulus can be described by a retinotopic vector from the center of gaze to the remembered spatial location., Competing Interests: MS, SS, MG No competing interests declared, (© 2018, Semework et al.)