Search

This paper aims to examine the direct and indirect impact of ambient air pollution (AAP) on employees’ performance. This study has used cross sectional survey design to collect the data from the outdoor employees of the pharmaceutical industry of Pakistan. The data were collected in time lags from 299. Partial least squares- structural equation modeling (PLS-SEM) approach was applied to analyze the data. The results show that AAP has a significant negative impact on the employees’ performance, and anxiety partially mediates the association between AAP and employees’ performance. This study reveals that AAP brings anxiety among outdoor employees, which in turn decreases their working performance. The implications, limitations, and future research directions are presented in the last section of this study.

Genetic studies of the nematode Caenorhabditis elegans have uncovered four genes, egl-1 (BH3 only), ced-9 (Bcl-2 related), ced-4 (apoptosis protease activating factor-1), and ced-3 (caspase), which function in a linear pathway to promote developmental cell death in this organism. While this core pathway functions in many cells, recent studies suggest that additional regulators, acting on or in lieu of these core genes, can promote or inhibit the onset of cell death. Here, we discuss the evidence for these noncanonical mechanisms of C. elegans cell death control. We consider novel modes for regulating the core apoptosis genes, and describe a newly identified cell death pathway independent of all known C. elegans cell death genes. The existence of these noncanonical cell death programs suggests that organisms have evolved multiple ways to ensure appropriate cellular demise during development.Cell Death and Differentiation (2008) 15, 1124–1131; doi:10.1038/cdd.2008.56; published online 25 April 2008 [ABSTRACT FROM AUTHOR]

The p53 tumor suppressor promotes apoptosis in response to DNA damage. Here we describe the Caenorhabditis elegans gene ced-13, which encodes a conserved BH3-only protein. We show that ced-13 mRNA accumulates following DNA damage, and that this accumulation is dependent on an intact C. elegans cep-1/p53 gene. We demonstrate that CED-13 protein physically interacts with the antiapoptotic Bcl-2-related protein CED-9. Furthermore, overexpression of ced-13 in somatic cells leads to the death of cells that normally survive, and this death requires the core apoptotic pathway of C. elegans. Recent studies have implicated two BH3-only proteins, Noxa and PUMA, in p53-induced apoptosis in mammals. Our studies suggest that in addition to the BH3-only protein EGL-1, CED-13 might also promote apoptosis in the C. elegans germ line in response to p53 activation. We propose that an evolutionarily conserved pathway exists in which p53 promotes cell death by inducing expression of two BH3-only genes.Cell Death and Differentiation (2005) 12, 153-161. doi:10.1038/sj.cdd.4401539 Published online 17 December 2004 [ABSTRACT FROM AUTHOR]

Extended abstract of a paper presented at Microscopy and Microanalysis 2011 in Nashville, Tennessee, USA, August 7–August 11, 2011. [ABSTRACT FROM PUBLISHER]

Extended abstract of a paper presented at Microscopy and Microanalysis 2011 in Nashville, Tennessee, USA, August 7–August 11, 2011. [ABSTRACT FROM AUTHOR]

Programmed cell death (PCD) is a crucial genetically-encoded and evolutionarily-conserved process for development and homeostasis. We previously identified a genetically non-apoptotic, highly ordered, and stereotyped killing program called Compartmentalized Cell Elimination (CCE) in the C. elegans tail-spike epithelial cell (TSC). Here we identify the transcription factor EOR-1/PLZF as promoting CCE. Loss of EOR-1 results in a persisting un-engulfed large soma with enlarged nuclei. We find that EOR-1 and its partners positively regulate the transcription of the Apoptosis Inducing Factor AIF homolog, WAH-1/AIF. We report stereotyped and sequential spatiotemporal dynamics of WAH-1/AIF1 during phagocytosis, with defined roles early and late. Mitochondrial to plasma membrane translocation is required for internalization, and plasma membrane to nuclear translocation for DNA degradation and ultimate corpse resolution. Our study expands our knowledge of PCD by describing a mechanistic contribution of EOR-1/PLZF and functional relevance to specific spatiotemporal contexts for WAH-1/AIF function, and by implying a correlation between DNA degradation with nuclear morphology during cell elimination., Summary Statement: This work describes the genetic control and cellular dynamics of a factor linked to cancer, metabolic and degenerative disease acting in developmentally dying cells to instruct their own removal.

The nematode Caenorhabditis elegans is a powerful experimental setting for uncovering fundamental tenets of nervous system organization and function. Its nearly invariant and simple anatomy, coupled with a plethora of methodologies for interrogating single-gene functions at single-cell resolution in vivo, have led to exciting discoveries in glial cell biology and mechanisms of glia-neuron interactions. Findings over the last two decades reinforce the idea that insights from C. elegans can inform our understanding of glial operating principles in other species. Here, we summarize the current state-of-the-art, and describe mechanistic insights that have emerged from a concerted effort to understand C. elegans glia. The remarkable acceleration in the pace of discovery in recent years paints a portrait of striking molecular complexity, exquisite specificity, and functional heterogeneity among glia. Glial cells affect nearly every aspect of nervous system development and function, from generating neurons, to promoting neurite formation, to animal behavior, and to whole-animal traits, including longevity. We discuss emerging questions where C. elegans is poised to fill critical knowledge gaps in our understanding of glia biology., (Copyright © 2024 Cold Spring Harbor Laboratory Press; all rights reserved.)

Primary (non-motile) cilia represent structurally and functionally diverse organelles whose roles as specialized cellular antenna are central to animal cell signaling pathways, sensory physiology and development. An ever-growing number of ciliary proteins, including those found in vertebrate photoreceptors, have been uncovered and linked to human disorders termed ciliopathies. Here, we demonstrate that an evolutionarily-conserved PPEF-family serine-threonine phosphatase, not functionally linked to cilia in any organism but associated with rhabdomeric (non-ciliary) photoreceptor degeneration in the Drosophila rdgC (retinal degeneration C) mutant, is a bona fide ciliary protein in C. elegans. The nematode protein, PEF-1, depends on transition zone proteins, which make up a 'ciliary gate' in the proximal-most region of the cilium, for its compartmentalization within cilia. Animals lacking PEF-1 protein function display structural defects to several types of cilia, including potential degeneration of microtubules. They also exhibit anomalies to cilium-dependent behaviors, including impaired responses to chemical, temperature, light, and noxious CO 2 stimuli. Lastly, we demonstrate that PEF-1 function depends on conserved myristoylation and palmitoylation signals. Collectively, our findings broaden the role of PPEF proteins to include cilia, and suggest that the poorly-characterized mammalian PPEF1 and PPEF2 orthologs may also have ciliary functions and thus represent ciliopathy candidates., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Programmed cell death (PCD) is an essential component of animal development, and aberrant cell death underlies many disorders. Understanding mechanisms that govern PCD during development can provide insight into cell death programs that are disrupted in disease. Key steps mediating apoptosis, a highly conserved cell death program employing caspase proteases, were first uncovered in the nematode Caenorhabditis elegans , a powerful model system for PCD research. Recent studies in C. elegans also unearthed conserved nonapoptotic caspase-independent cell death programs that function during development. Here, we discuss recent advances in understanding cell death during C. elegans development. We review insights expanding the molecular palette behind the execution of apoptotic and nonapoptotic cell death, as well as new discoveries revealing the mechanistic underpinnings of dying cell engulfment and clearance. A number of open questions are also discussed that will continue to propel the field over the coming years.

Introduction: Current literature lacks data regarding the influence of serous fluid volume (SFV) on next-generation sequencing (NGS) performed on malignant cases. In this study, we highlight the impact of SFV and other parameters influencing the outcome of NGS analysis., Materials and Methods: We evaluated 827 samples of serous fluids from 607 patients. Of these, 72 samples underwent NGS analysis. Effusion volume, tumor cellularity, DNA, and RNA quality metrics, as well as clinicopathologic and molecular data were evaluated. Pleural fluid accounted for 56.3% of the fluid samples collected. The most common primary tumor site was gastrointestinal/pancreatobiliary, adenocarcinoma was the most common histologic type. Overall mean volume was 293 mL. The mean Qubit DNA of the 72 effusion samples that underwent NGS analysis was 14.3 ng/μL and mean Qubit RNA was 28.2 ng/μL. The mean Qubit DNA concentration increases in SFV up to 100 mL only., Results: No correlation exists between SFV and mean tumor cellularity. In addition, 74.6% (50 of 67) of sequenced samples showed oncogenic drivers; KRAS was the most common driver followed by EGFR. Three cases displayed ALK fusions, and 1 case displayed NTRK1 fusion. The DNA yield is higher in SFV of 100 mL as a cutoff. Beyond 100 mL, there is no impact of SFV on DNA yield. SFV does not impact RNA yield and mean tumor cellularity. Effusion samples should be submitted for molecular testing despite low tumor cellularity., Conclusions: Our results as a pilot study are important in optimization of SFV for both diagnosis as well as NGS analysis for improving management., (Copyright © 2024 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Objectives: Few cytologically indeterminate thyroid fine-needle aspirations (FNAs) harbor BRAF V600E. Here, we assess interobserver agreement for The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) category III (atypia of undetermined significance [AUS]) FNAs harboring BRAF V600E and contrast their features with those harboring non-BRAF V600E alterations, with attention to cytopathology experience., Methods: Seven reviewers evaluated 5 AUS thyroid FNAs harboring BRAF V600E. To blind reviewers, cases were intermixed with 19 FNAs falling within other TBSRTC categories and in which genetic alterations other than BRAF V600E had been identified (24 FNAs total). Interobserver agreement against both "index" and most popular ("mode") diagnoses was calculated. Four additional BRAF V600E cases were independently reviewed., Results: Reviewers included 3 trainees and 3 American Board of Pathology (board)-certified cytopathologists. Board-certified cytopathologists, whose experience ranged from 2 to more than 15 subspecialty practice years, had known AUS rates. BRAF V600E was identified in 5 of 260 (2%) AUS FNAs. Interobserver agreement was higher among cytopathologists with more experience. Mode diagnosis differed from index diagnosis in 6 of 11 cases harboring RAS-like alterations; mode diagnosis was AUS in 4 of 5 BRAF V600E FNAs., Conclusions: Atypia of undetermined significance of thyroid FNAs harboring BRAF V600E is uncommon yet relatively reproducible, particularly among pathologists with experience. It is advisable to sequence BRAF across V600 in such cases., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Metal-semiconductor nanocomposites have emerged as a viable strategy for concurrently tailoring both thermal and electronic transport properties of established thermoelectric materials, ultimately achieving synergistic performance. In this investigation, a series of nanocomposite thin films were synthesized, embedding metallic cobalt telluride (CoTe 2 ) nanophase within the nanocrystalline ternary skutterudite (Co(Ge 1.22 Sb 0.22 )Te 1.58 or CGST) matrix. Our approach harnessed composition fluctuation-induced phase separation and in situ growth during thermal annealing to seamlessly integrate the metallic phase. The distinctive band structures of both materials have developed an ohmic-type contact characteristic at the interface, which raised carrier density considerably yet negligibly affected the mobility counterpart, leading to a substantial improvement in electrical conductivity. The intricate balance in transport properties is further influenced by the metallic CoTe 2 phase's role in diminishing lattice thermal conductivity. The presence of the metallic phase instigates enhanced phonon scattering at the interface boundaries. Consequently, a 2-fold enhancement in the thermoelectric figure of merit (zT ∼ 1.30) is attained with CGST-7 wt. % CoTe 2 nanocomposite film at 655 K compared to that of pristine CGST.

The molecular characteristics of metastatic upper tract urothelial carcinoma (UTUC) are not well understood, and there is a lack of knowledge regarding the genomic and transcriptomic differences between primary and metastatic UTUC. To address these gaps, we integrate whole-exome sequencing, RNA sequencing, and Imaging Mass Cytometry using lanthanide metal-conjugated antibodies of 44 tumor samples from 28 patients with high-grade primary and metastatic UTUC. We perform a spatially-resolved single-cell analysis of cancer, immune, and stromal cells to understand the evolution of primary to metastatic UTUC. We discover that actionable genomic alterations are frequently discordant between primary and metastatic UTUC tumors in the same patient. In contrast, molecular subtype membership and immune depletion signature are stable across primary and matched metastatic UTUC. Molecular and immune subtypes are consistent between bulk RNA-sequencing and mass cytometry of protein markers from 340,798 single cells. Molecular subtypes at the single-cell level are highly conserved between primary and metastatic UTUC tumors within the same patient., (© 2024. The Author(s).)

While most glial cell types in the central nervous system (CNS) arise from neuroectodermal progenitors, some, like microglia, are mesodermally derived. To understand mesodermal glia development and function, we investigated C. elegans GLR glia, which envelop the brain neuropil and separate it from the circulatory system cavity. Transcriptome analysis shows that GLR glia combine astrocytic and endothelial characteristics, which are relegated to separate cell types in vertebrates. Combined fate acquisition is orchestrated by LET-381/FoxF, a fate-specification/maintenance transcription factor also expressed in glia and endothelia of other animals. Among LET-381/FoxF targets, the UNC-30/Pitx2 transcription factor controls GLR glia morphology and represses alternative mesodermal fates. LET-381 and UNC-30 co-expression in naive cells is sufficient for GLR glia gene expression. GLR glia inactivation by ablation or let-381 mutation disrupts locomotory behavior and promotes salt-induced paralysis, suggesting brain-neuropil activity dysregulation. Our studies uncover mechanisms of mesodermal glia development and show that like neuronal differentiation, glia differentiation requires autoregulatory terminal selector genes that define and maintain the glial fate., (© 2024. The Author(s).)

Machine learning (ML) is playing an increasing role in decision-making tasks that directly affect individuals, e.g., loan approvals, or job applicant screening. Significant concerns arise that, without special provisions, individuals from under-privileged backgrounds may not get equitable access to services and opportunities. Existing research studies fairness with respect to protected attributes such as gender, race or income, but the impact of location data on fairness has been largely overlooked. With the widespread adoption of mobile apps, geospatial attributes are increasingly used in ML, and their potential to introduce unfair bias is significant, given their high correlation with protected attributes. We propose techniques to mitigate location bias in machine learning. Specifically, we consider the issue of miscalibration when dealing with geospatial attributes. We focus on spatial group fairness and we propose a spatial indexing algorithm that accounts for fairness. Our KD-tree inspired approach significantly improves fairness while maintaining high learning accuracy, as shown by extensive experimental results on real data.

Mobile apps that use location data are pervasive, spanning domains such as transportation, urban planning and healthcare. Important use cases for location data rely on statistical queries, e.g., identifying hotspots where users work and travel. Such queries can be answered efficiently by building histograms. However, precise histograms can expose sensitive details about individual users. Differential privacy (DP) is a mature and widely-adopted protection model, but most approaches for DP-compliant histograms work in a data-independent fashion, leading to poor accuracy. The few proposed data-dependent techniques attempt to adjust histogram partitions based on dataset characteristics, but they do not perform well due to the addition of noise required to achieve DP. In addition, they use ad-hoc criteria to decide the depth of the partitioning. We identify density homogeneity as a main factor driving the accuracy of DP-compliant histograms, and we build a data structure that splits the space such that data density is homogeneous within each resulting partition. We propose a self-tuning approach to decide the depth of the partitioning structure that optimizes the use of privacy budget. Furthermore, we provide an optimization that scales the proposed split approach to large datasets while maintaining accuracy. We show through extensive experiments on large-scale real-world data that the proposed approach achieves superior accuracy compared to existing approaches.

Accessing realistic human movements (aka trajectories) is essential for many application domains, such as urban planning, transportation, and public health. However, due to privacy and commercial concerns, real-world trajectories are not readily available, giving rise to an important research area of generating synthetic but realistic trajectories. Inspired by the success of deep neural networks (DNN), data-driven methods learn the underlying human decision-making mechanisms and generate synthetic trajectories by directly fitting real-world data. However, these DNN-based approaches do not exploit people's moving behaviors (e.g., work commute, shopping purpose), significantly influencing human decisions during the generation process. This paper proposes MBP-GAIL, a novel framework based on generative adversarial imitation learning that synthesizes realistic trajectories that preserve moving behavior patterns in real data. MBP-GAIL models temporal dependencies by Recurrent Neural Networks (RNN) and combines the stochastic constraints from moving behavior patterns and spatial constraints in the learning process. Through comprehensive experiments, we demonstrate that MBP-GAIL outperforms state-of-the-art methods and can better support decision making in trajectory simulations.

Introduction: Detection of malignant cells in serous fluids is an indicator of advanced stage of malignancy and is critical in clinical management decisions and prompt treatment initiation. The minimum volume which is ideal for detecting malignancy in serous fluid is not well established. In this study, we aim to identify optimal volume that will be ideal for adequate cytopathological diagnosis., Materials and Methods: A total of 1597 samples of serous fluids from 1134 patients were included in the study. Samples were diagnosed based on International System for Reporting Serous Fluid Cytopathology (ISRSFC). Clinicopathologic results from different diagnostic groups were compared and statistically analyzed., Results: Pleural fluids comprised 890 (55.7%) specimens, followed by 456 (28.6%) peritoneal, 128 (8%) ascites, and 123 (7.7%) pericardial fluid specimens. The majority were negative for malignancy (1138, 71.3%), followed by malignant (376, 23.5%), atypical (59, 3.7%), and suspicious for malignancy (24, 1.5%). Malignancy was identified in sample with volumes from 5 mL to 5000 mL. Rate of detection of malignant cells increased significantly with higher sample volumes. For malignancy detection the optimal volume for overall serous fluid is 70 mL. Pericardial fluid is an exception, with lower mean volume and significantly lower proportion of cases with malignant diagnosis., Conclusions: Our study indicates that higher fluid volumes have a higher rate of malignancy detection and a low false-negative rate. We recommend a minimum of 70 mL of serous fluid for optimal cytopathologic examination and malignancy detection. Pericardial fluid is an exception, with lower mean volume and thus lower requirement., (Copyright © 2023 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

In Caenorhabditis elegans worms, epigenetic information transmits transgenerationally. Still, it is unknown whether the effects transfer to the next generation inside or outside of the nucleus. Here, we use the tractability of gene-specific double-stranded RNA-induced silencing to demonstrate that RNA interference can be inherited independently of any nuclear factors via mothers that are genetically engineered to transmit only their ooplasm but not the oocytes' nuclei to the next generation. We characterize the mechanisms and, using RNA sequencing, chimeric worms, and sequence polymorphism between different isolates, identify endogenous small RNAs which, similarly to exogenous siRNAs, are inherited in a nucleus-independent manner. From a historical perspective, these results might be regarded as partial vindication of discredited cytoplasmic inheritance theories from the 19th century, such as Darwin's "pangenesis" theory.

Interview with Shai Shaham, who studies glia-neuron interactions in C. elegans at The Rockefeller University., Competing Interests: Declaration of interests The author declares no competing interests., (Copyright © 2023.)

Introduction: Noninvasive follicular thyroid neoplasm with papillary-like features (NIFTP), represents a distinct class of thyroid neoplasms with very low risk of adverse outcome and a set of strict histologic criteria. Introduction of NIFTP as a non-cancer has had an appreciable decrease in risk of malignancy and body of literature on this entity continues to grow. In this study, we reviewed clinical, fine-needle aspiration cytology (FNAC), imaging, and molecular findings of histologically proven NIFTPs at our institution., Materials and Methods: Thyroid resections during an 11-year period, with histologic diagnosis of follicular variant of papillary thyroid carcinoma (FVPTC), were retrospectively reviewed to identify NIFTP. Ultrasonographic appearance, FNA findings, and molecular findings were also reviewed., Results: Of 244 cases of FVPTC identified, 74 (30%) cases were reclassified as NIFTP. Mean tumor size was 2.5 cm. Of 33 patients with lymph node dissection, none had lymph node metastases. On imaging, 36 NIFTP (49%) showed vascularity, 25 (33%) were isoechoic to hypoechoic, there were calcifications in 14 cases (19%), and 7 cases (9%) showed a hypoechoic rim. Bethesda III/IV was the most common interpretation rendered on FNAC (31%). Seven cases had NRAS mutations and 1 case had BRAF V600E mutation. The remaining cases were either negative for BRAF V600E or had no identifiable molecular alterations., Conclusions: A significant percentage of tumors previously diagnosed as FVPTC were reclassified as NIFTP. This tumor cannot be reliably diagnosed preoperatively on FNAC, shows no characteristic features on ultrasound and has low suspicion of malignancy. BRAF V600E mutations are infrequent in NIFTP., (Copyright © 2022 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Fairness in data-driven decision-making studies scenarios where individuals from certain population segments may be unfairly treated when being considered for loan or job applications, access to public resources, or other types of services. In location-based applications, decisions are based on individual whereabouts, which often correlate with sensitive attributes such as race, income, and education. While fairness has received significant attention recently, e.g., in machine learning, there is little focus on achieving fairness when dealing with location data. Due to their characteristics and specific type of processing algorithms, location data pose important fairness challenges. We introduce the concept of spatial data fairness to address the specific challenges of location data and spatial queries. We devise a novel building block to achieve fairness in the form of fair polynomials . Next, we propose two mechanisms based on fair polynomials that achieve individual spatial fairness, corresponding to two common location-based decision-making types: distance-based and zone-based . Extensive experimental results on real data show that the proposed mechanisms achieve spatial fairness without sacrificing utility.

This paper aims to examine the direct and indirect impact of ambient air pollution (AAP) on employees' performance. This study has used cross sectional survey design to collect the data from the outdoor employees of the pharmaceutical industry of Pakistan. The data were collected in time lags from 299. Partial least squares- structural equation modeling (PLS-SEM) approach was applied to analyze the data. The results show that AAP has a significant negative impact on the employees' performance, and anxiety partially mediates the association between AAP and employees' performance. This study reveals that AAP brings anxiety among outdoor employees, which in turn decreases their working performance. The implications, limitations, and future research directions are presented in the last section of this study., 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 © 2022 Bari, Saleem, Bashir and Ahmad.)

Motoneurons and motoneuron-like pancreatic β cells arise from radial glia and ductal cells, respectively, both tube-lining progenitors that share molecular regulators. To uncover programs underlying motoneuron formation, we studied a similar, cell-division-independent transformation of the C. elegans tube-lining Y cell into the PDA motoneuron. We find that lin-12/Notch acts through ngn-1/Ngn and its regulator hlh-16/Olig to control transformation timing. lin-12 loss blocks transformation, while lin-12(gf) promotes precocious PDA formation. Early basal expression of ngn-1/Ngn and hlh-16/Olig depends on sem-4/Sall and egl-5/Hox. Later, coincident with Y cell morphological changes, ngn-1/Ngn expression is upregulated in a sem-4/Sall and egl-5/Hox-dependent but hlh-16/Olig-independent manner. Subsequently, Y cell retrograde extension forms an anchored process priming PDA axon extension. Extension requires ngn-1-dependent expression of the cytoskeleton organizers UNC-119, UNC-44/ANK, and UNC-33/CRMP, which also activate PDA terminal-gene expression. Our findings uncover cell-division-independent regulatory events leading to motoneuron generation, suggesting a conserved pathway for epithelial-to-motoneuron/motoneuron-like cell differentiation., Competing Interests: Declaration of interests S.S. is a member of the Cell Reports advisory board., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET-rearranged thyroid cancer., (© 2022 Raman et al.)

In castration-resistant prostate cancer (CRPC), the loss of androgen receptor (AR) dependence leads to clinically aggressive tumors with few therapeutic options. We used ATAC-seq (assay for transposase-accessible chromatin sequencing), RNA-seq, and DNA sequencing to investigate 22 organoids, six patient-derived xenografts, and 12 cell lines. We identified the well-characterized AR-dependent and neuroendocrine subtypes, as well as two AR-negative/low groups: a Wnt-dependent subtype, and a stem cell-like (SCL) subtype driven by activator protein-1 (AP-1) transcription factors. We used transcriptomic signatures to classify 366 patients, which showed that SCL is the second most common subtype of CRPC after AR-dependent. Our data suggest that AP-1 interacts with the YAP/TAZ and TEAD proteins to maintain subtype-specific chromatin accessibility and transcriptomic landscapes in this group. Together, this molecular classification reveals drug targets and can potentially guide therapeutic decisions.

Background: Molecular testing (MT) of thyroid fine-needle aspiration (FNA)-derived genetic material is commonly used to assess malignancy risk for indeterminate cases. The Bethesda System for Reporting Thyroid Cytopathology (TBS) provides limited guidance for the appropriate use of category III (atypia of undetermined significance [AUS]). The authors combined MT with cytomorphology to monitor AUS diagnoses in a cytopathology laboratory., Methods: Neoplasia-associated genetic alterations (NGAs) were determined by MT of preoperative FNA biopsies or resected malignancies and were categorized as BRAF V600E mutations, RAS-like mutations (HRAS, NRAS, or KRAS mutations or non-V600E BRAF mutations), or other mutations., Results: Among 7382 thyroid FNA biopsies, the AUS rate was 9.3% overall and ranged from 4.3% to 24.2% among 6 cytopathologists (CPs) who evaluated >150 cases. The ratio of specimens falling into TBS category III to specimens falling into category VI (malignant) (the III:VI ratio) was 2.4 overall (range, 1.1-8.1), and the ratio of specimens falling into TBS categories III and IV (follicular neoplasm or suspicious for follicular neoplasm) combined (III+IV) to specimens falling into category VI (the [III+IV]:VI ratio) was 2.9 overall (range, 1.4-9.5). MT was performed on 588 cases from 560 patients (79% women) with a median age of 56 years (range, 8-89 years). BRAF V600E mutation was the most common (76% of cases) in TBS category VI and was rare (3%) in category III. RAS-like mutations were most common in TBS categories III (13%), IV (25%), and V (suspicious for malignancy) (17.5%). The NGA rate in AUS cases fell between 5% and 20% for 5 of 6 CPs and did not correlate with the III:VI ratio or the (III+IV):VI ratio., Conclusions: Lack of correlation between the NGA rate and easily calculable diagnostic ratios enables the calibration of diagnostic thresholds, even for CPs who have normal metrics. Specifically, calculation of the NGA rate and the III:VI ratio may allow individual CPs to determine whether they are overcalling or undercalling cases that other CPs might otherwise recategorize., (© 2021 American Cancer Society.)

Ascertaining the function of in-plane intrinsic defects and edge atoms is necessary for developing efficient low-dimensional photocatalysts. We report the wireless photocatalytic CO 2 reduction to CH 4 over reconstructed edge atoms of monolayer 2H-WSe 2 artificial leaves. Our first-principles calculations demonstrate that reconstructed and imperfect edge configurations enable CO 2 binding to form linear and bent molecules. Experimental results show that the solar-to-fuel quantum efficiency is a reciprocal function of the flake size. It also indicates that the consumed electron rate per edge atom is two orders of magnitude larger than the in-plane intrinsic defects. Further, nanoscale redox mapping at the monolayer WSe 2 -liquid interface confirms that the edge is the most preferred region for charge transfer. Our results pave the way for designing a new class of monolayer transition metal dichalcogenides with reconstructed edges as a non-precious co-catalyst for wired or wireless hydrogen evolution or CO 2 reduction reactions., (© 2022. The Author(s).)

Background: It is unclear if different genetic drivers in papillary thyroid cancer (PTC) confer different phenotypic tumor behavior leading to more aggressive disease. We hypothesized that RET-driven cancers are more aggressive., Patients and Methods: We reviewed records of consecutive patients treated for newly diagnosed PTC at this single institution from 2015 to 2016. Tumor samples from these patients were genotyped to identify RET-translocated, BRAF V600E mutant, and HRAS, KRAS, and NRAS mutant tumors. Patient demographic, clinicopathologic, and outcomes data were compared to identify genotype-specific patterns of disease., Results: Of the 327 patients who underwent initial surgery for PTC during the study period, 192 (58.7%) had BRAF V600E mutant tumors (BRAF), 14 (4.3%) had RET-rearranged tumors (RET), 46 (14.1%) had RAS mutant tumors (RAS), and 75 (22.9%) had BRAF, RET, and RAS wildtype tumors. RET-driven tumors were more likely to have extrathyroidal extension (50.0% versus 27.0% for BRAF and 2.2% for RAS, P < 0.001), multifocal disease (85.7% versus 60.3%, and 44.4%, respectively, P = 0.017), and distant metastases (14.3% versus 1.1%, and 0%, respectively, P = 0.019). RET and BRAF patients also had worse disease-free survival than RAS patients (Kaplan-Meier log rank, P = 0.027)., Conclusions: Patients with RET-driven PTCs had higher rates of extrathyroidal extension, multifocal disease, and distant metastases than patients whose tumors had BRAF V600E or RAS mutations. Patients with RET-rearranged tumors had similar disease-free survival to patients with BRAF V600E mutant tumors. RET rearrangement may confer an aggressive phenotype in PTC., (© 2022. Society of Surgical Oncology.)

BACKGROUNDProstate cancer is multifocal with distinct molecular subtypes. The utility of genomic subtyping has been challenged due to inter- and intrafocal heterogeneity. We sought to characterize the subtype-defining molecular alterations of primary prostate cancer across all tumor foci within radical prostatectomy (RP) specimens and determine the prevalence of collision tumors.METHODSFrom the Early Detection Research Network cohort, we identified 333 prospectively collected RPs from 2010 to 2014 and assessed ETS-related gene (ERG), serine peptidase inhibitor Kazal type 1 (SPINK1), phosphatase and tensin homolog (PTEN), and speckle type BTB/POZ protein (SPOP) molecular status. We utilized dual ERG/SPINK1 immunohistochemistry and fluorescence in situ hybridization to confirm ERG rearrangements and characterize PTEN deletion, as well as high-resolution melting curve analysis and Sanger sequencing to determine SPOP mutation status.RESULTSBased on index focus alone, ERG, SPINK1, PTEN, and SPOP alterations were identified in 47.5%, 10.8%, 14.3%, and 5.1% of RP specimens, respectively. In 233 multifocal RPs with ERG/SPINK1 status in all foci, 139 (59.7%) had discordant molecular alterations between foci. Collision tumors, as defined by discrepant ERG/SPINK1 status within a single focus, were identified in 29 (9.4%) RP specimens.CONCLUSIONInterfocal molecular heterogeneity was identified in about 60% of multifocal RP specimens, and collision tumors were present in about 10%. We present this phenomenon as a model for the intrafocal heterogeneity observed in previous studies and propose that future genomic studies screen for collision tumors to better characterize molecular heterogeneity.FUNDINGEarly Detection Research Network US National Cancer Institute (NCI) 5U01 CA111275-09, Center for Translational Pathology at Weill Cornell Medicine (WCM) Department of Pathology and Laboratory Medicine, US NCI (WCM SPORE in Prostate Cancer, P50CA211024-01), R37CA215040, Damon Runyon Cancer Research Foundation, US MetLife Foundation Family Clinical Investigator Award, Norwegian Cancer Society (grant 208197), and South-Eastern Norway Regional Health Authority (grant 2019016 and 2020063).

It is unknown whether transient transgenerational epigenetic responses to environmental challenges affect the process of evolution, which typically unfolds over many generations. Here, we show that in C. elegans, inherited small RNAs control genetic variation by regulating the crucial decision of whether to self-fertilize or outcross. We found that under stressful temperatures, younger hermaphrodites secrete a male-attracting pheromone. Attractiveness transmits transgenerationally to unstressed progeny via heritable small RNAs and the Argonaute Heritable RNAi Deficient-1 (HRDE-1). We identified an endogenous small interfering RNA pathway, enriched in endo-siRNAs that target sperm genes, that transgenerationally regulates sexual attraction, male prevalence, and outcrossing rates. Multigenerational mating competition experiments and mathematical simulations revealed that over generations, animals that inherit attractiveness mate more and their alleles spread in the population. We propose that the sperm serves as a "stress-sensor" that, via small RNA inheritance, promotes outcrossing in challenging environments when increasing genetic variation is advantageous., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Salivary gland acinic cell carcinoma (AciCC) has recognizable cytomorphologic features that can overlap with benign and malignant entities, creating a diagnostic challenge. AciCC harbors a t(4;9) translocation increasing nuclear receptor subfamily 4 group A member 3 (NR4A3) expression, detectable by immunohistochemistry (IHC) on surgical resection (SR). NR4A3 IHC cytology data are limited. Here, we examine NR4A3 IHC on smears, cell blocks (CBs), and SRs of AciCC and its mimickers., Methods: Our cohort comprised AciCC (including high-grade transformation), secretory carcinoma, mucoepidermoid carcinoma (MEC), Warthin tumor, pleomorphic adenoma (PA), cellular PA, carcinoma ex-PA, oncocytic carcinoma, oncocytoma, and nodular oncocytosis. NR4A3 IHC (Santa Cruz Biotechnology and Origene antibodies) was positive if more than 5% tumor cells showed nuclear staining., Results: Among CBs, 90% of AciCC cases and none of the mimickers expressed NR4A3. Among SRs, 100% of AciCC cases showed diffuse NR4A3, whereas one high-grade MEC expressed focal NR4A3. Concordance was 95% with two antibody clones. Sensitivity, specificity, positive predictive value, and negative predictive value were 90%, 100%, 100%, and 94.7% for CBs and 100%, 98.8%, 92.3%, and 100% for SRs, respectively. NR4A3 immunostaining was demonstrable on smears from an AciCC case., Conclusions: NR4A3 IHC can be a robust diagnostic tool to identify AciCC, especially for cytology specimens., (© American Society for Clinical Pathology, 2021. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

Animals encounter microorganisms in their habitats, adapting physiology and behavior accordingly. The nematode Caenorhabditis elegans is found in microbe-rich environments; however, its responses to fungi are not extensively studied. Here, we describe interactions of C. elegans and Penicillium brevicompactum, an ecologically relevant mold. Transcriptome studies reveal that co-culture upregulates stress response genes, including xenobiotic-metabolizing enzymes (XMEs), in C. elegans intestine and AMsh glial cells. The nuclear hormone receptors (NHRs) NHR-45 and NHR-156 are induction regulators, and mutants that cannot induce XMEs in the intestine when exposed to P. brevicompactum experience mitochondrial stress and exhibit developmental defects. Different C. elegans wild isolates harbor sequence polymorphisms in nhr-156, resulting in phenotypic diversity in AMsh glia responses to microbe exposure. We propose that P. brevicompactum mitochondria-targeting mycotoxins are deactivated by intestinal detoxification, allowing tolerance to moldy environments. Our studies support the idea that C. elegans NHRs may be regulated by environmental cues., Competing Interests: Declarations of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Characterization of circulating tumor DNA (ctDNA) has been integrated into clinical practice. Although labs have standardized validation procedures to develop single locus tests, the efficacy of on-site plasma-based next-generation sequencing (NGS) assays still needs to be proved., Materials and Methods: In this retrospective study, we profiled DNA from matched tissue and plasma samples from 75 patients with cancer. We applied an NGS test that detects clinically relevant alterations in 33 genes and microsatellite instability (MSI) to analyze plasma cell-free DNA (cfDNA)., Results: The concordance between alterations detected in both tissue and plasma samples was higher in patients with metastatic disease. The NGS test detected 77% of sequence alterations, amplifications, and fusions that were found in metastatic samples compared with 45% of those alterations found in the primary tumor samples (p = .00005). There was 87% agreement on MSI status between the NGS test and tumor tissue results. In three patients, MSI-high ctDNA correlated with response to immunotherapy. In addition, the NGS test revealed an FGFR2 amplification that was not detected in tumor tissue from a patient with metastatic gastric cancer, emphasizing the importance of profiling plasma samples in patients with advanced cancer., Conclusion: Our validation experience of a plasma-based NGS assay advances current knowledge about translating cfDNA testing into clinical practice and supports the application of plasma assays in the management of oncology patients with metastatic disease. With an in-house method that minimizes the need for invasive procedures, on-site cfDNA testing supplements tissue biopsy to guide precision therapy and is entitled to become a routine practice., Implications for Practice: This study proposes a solution for decentralized liquid biopsy testing based on validation of a next-generation sequencing (NGS) test that detects four classes of genomic alterations in blood: sequence mutations (single nucleotide substitutions or insertions and deletions), fusions, amplifications, and microsatellite instability (MSI). Although there are reference labs that perform single-site comprehensive liquid biopsy testing, the targeted assay this study validated can be established locally in any lab with capacity to offer clinical molecular pathology assays. To the authors' knowledge, this is the first report that validates evaluating an on-site plasma-based NGS test that detects the MSI status along with common sequence alterations encountered in solid tumors., (© 2021 AlphaMed Press.)

Programmed cell death (PCD) is a common cell fate in metazoan development. PCD effectors are extensively studied, but how they are temporally regulated is less understood. Here, we report a mechanism controlling tail-spike cell death onset during Caenorhabditis elegans development. We show that the zinc-finger transcription factor BLMP-1, which controls larval development timing, also regulates embryonic tail-spike cell death initiation. BLMP-1 functions upstream of CED-9 and in parallel to DRE-1, another CED-9 and tail-spike cell death regulator. BLMP-1 expression is detected in the tail-spike cell shortly after the cell is born, and blmp-1 mutations promote ced-9-dependent tail-spike cell survival. BLMP-1 binds ced-9 gene regulatory sequences, and inhibits ced-9 transcription just before cell-death onset. BLMP-1 and DRE-1 function together to regulate developmental timing, and their mammalian homologs regulate B-lymphocyte fate. Our results, therefore, identify roles for developmental timing genes in cell-death initiation, and suggest conservation of these functions., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

During convergent differentiation, multiple developmental lineages produce a highly similar or identical cell type. However, few molecular players that drive convergent differentiation are known. Here, we show that the C. elegans Forkhead transcription factor UNC-130 is required in only one of three convergent lineages that produce the same glial cell type. UNC-130 acts transiently as a repressor in progenitors and newly-born terminal cells to allow the proper specification of cells related by lineage rather than by cell type or function. Specification defects correlate with UNC-130:DNA binding, and UNC-130 can be functionally replaced by its human homolog, the neural crest lineage determinant FoxD3. We propose that, in contrast to terminal selectors that activate cell type-specific transcriptional programs in terminally differentiating cells, UNC-130 acts early and specifically in one convergent lineage to produce a cell type that also arises from molecularly distinct progenitors in other lineages., Competing Interests: Competing interests M.L.B. is a co-inventor of patented PBM technology. All other authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Fanconi anemia is an inherited genome instability syndrome characterized by interstrand cross-link hypersensitivity, congenital defects, bone marrow failure, and cancer predisposition. Although DNA repair mediated by Fanconi anemia genes has been extensively studied, how inactivation of these genes leads to specific cellular phenotypic consequences associated with Fanconi anemia is not well understood. Here we report that Fanconi anemia stem cells in the C. elegans germline and in murine embryos display marked nonhomologous end joining (NHEJ)-dependent radiation resistance, leading to survival of progeny cells carrying genetic lesions. In contrast, DNA cross-linking does not induce generational genomic instability in Fanconi anemia stem cells, as widely accepted, but rather drives NHEJ-dependent apoptosis in both species. These findings suggest that Fanconi anemia is a stem cell disease reflecting inappropriate NHEJ, which is mutagenic and carcinogenic as a result of DNA misrepair, while marrow failure represents hematopoietic stem cell apoptosis. SIGNIFICANCE: This study finds that Fanconi anemia stem cells preferentially activate error-prone NHEJ-dependent DNA repair to survive irradiation, thereby conferring generational genomic instability that is instrumental in carcinogenesis., (©2021 American Association for Cancer Research.)

Background / Purpose . In the literature, no consensus about the duration of orthodontic treatment has been reached out. This study aimed to identify orthodontist's and patient's perception about the time of orthodontic treatment and their willingness to undergo and pay for various acceleration techniques and procedures. Materials and Methods . An electronic survey was conducted from August to October 2020. The questionnaire consisted of 20 multiple choice questions which was designed and emailed to members of the Iraqi Orthodontic Society and self-administered to patients in several orthodontic centers in Baghdad. The questionnaire included questions about the perception toward the duration of orthodontic treatment, approval of different procedures used to reduce treatment time, and how much fee increment they are able to pay for various techniques and appliances. Descriptive and chi-square test statistics were used, and the level of significance was set at p ≤ 0.05. Results . The response rate was 78.7%. The willingness for additional techniques and procedures was rated in the following order: customized appliances: 50.8% orthodontists and 38.4% patients, followed by intraoral vibrating devices: 49.2% orthodontists and 38.1% patients, piezocision: 10.2% orthodontists and 8.2% patients, and corticotomies: 8.1% orthodontists and 5.9% patients. Most orthodontists were willing to pay up to 40% of treatment income for the acceleration procedure, while the payment of patients was up to 20%. Conclusion . Both orthodontists and patients were interested in techniques that can decrease the treatment duration. Noninvasive accelerating procedures were more preferable by orthodontists and patients than invasive surgical procedures., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Ali M. Al-Attar et al.)

Glia in the central nervous system engulf neuron fragments to remodel synapses and recycle photoreceptor outer segments. Whether glia passively clear shed neuronal debris or actively prune neuron fragments is unknown. How pruning of single-neuron endings impacts animal behavior is also unclear. Here, we report our discovery of glia-directed neuron pruning in Caenorhabditis elegans. Adult C. elegans AMsh glia engulf sensory endings of the AFD thermosensory neuron by repurposing components of the conserved apoptotic corpse phagocytosis machinery. The phosphatidylserine (PS) flippase TAT-1/ATP8A functions with glial PS-receptor PSR-1/PSR and PAT-2/α-integrin to initiate engulfment. This activates glial CED-10/Rac1 GTPase through the ternary GEF complex of CED-2/CrkII, CED-5/DOCK180, CED-12/ELMO. Execution of phagocytosis uses the actin-remodeler WSP-1/nWASp. This process dynamically tracks AFD activity and is regulated by temperature, the AFD sensory input. Importantly, glial CED-10 levels regulate engulfment rates downstream of neuron activity, and engulfment-defective mutants exhibit altered AFD-ending shape and thermosensory behavior. Our findings reveal a molecular pathway underlying glia-dependent engulfment in a peripheral sense-organ and demonstrate that glia actively engulf neuron fragments, with profound consequences on neuron shape and animal sensory behavior., Competing Interests: SR, EB, AB, SM, MK, SS, AS No competing interests declared, (© 2021, Raiders et al.)

Astrocytes are a large and diverse population of morphologically complex cells that exist throughout nervous systems of multiple species. Progress over the last two decades has shown that astrocytes mediate developmental, physiological, and pathological processes. However, a long-standing open question is how astrocytes regulate neural circuits in ways that are behaviorally consequential. In this regard, we summarize recent studies using Caenorhabditis elegans, Drosophila melanogaster, Danio rerio, and Mus musculus. The data reveal diverse astrocyte mechanisms operating in seconds or much longer timescales within neural circuits and shaping multiple behavioral outputs. We also refer to human diseases that have a known primary astrocytic basis. We suggest that including astrocytes in mechanistic, theoretical, and computational studies of neural circuits provides new perspectives to understand behavior, its regulation, and its disease-related manifestations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Animal nervous systems remodel following stress. Although global stress-dependent changes are well documented, contributions of individual neuron remodeling events to animal behavior modification are challenging to study. In response to environmental insults, C. elegans become stress-resistant dauers. Dauer entry induces amphid sensory organ remodeling in which bilateral AMsh glial cells expand and fuse, allowing embedded AWC chemosensory neurons to extend sensory receptive endings. We show that amphid remodeling correlates with accelerated dauer exit upon exposure to favorable conditions and identify a G protein-coupled receptor, REMO-1, driving AMsh glia fusion, AWC neuron remodeling, and dauer exit. REMO-1 is expressed in and localizes to AMsh glia tips, is dispensable for other remodeling events, and promotes stress-induced expression of the remodeling receptor tyrosine kinase VER-1. Our results demonstrate how single-neuron structural changes affect animal behavior, identify key glial roles in stress-induced nervous system plasticity, and demonstrate that remodeling primes animals to respond to favorable conditions., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Frequency of clinically relevant mutations in solid tumors by targeted and whole-exome sequencing is ∼30%. Transcriptome analysis complements detection of actionable gene fusions in advanced cancer patients. Goal of this study was to determine the added value of anchored multiplex PCR (AMP)-based next-generation sequencing (NGS) assay to identify further potential drug targets, when coupled with whole-exome sequencing (WES)., Methods: Selected series of fifty-six samples from 55 patients enrolled in our precision medicine study were interrogated by WES and AMP-based NGS. RNA-seq was performed in 19 cases. Clinically relevant and actionable alterations detected by three methods were integrated and analyzed., Results: AMP-based NGS detected 48 fusions in 31 samples (55.4%); 31.25% (15/48) were classified as targetable based on published literature. WES revealed 29 samples (51.8%) harbored targetable alterations. TMB-high and MSI-high status were observed in 12.7% and 1.8% of cases. RNA-seq from 19 samples identified 8 targetable fusions (42.1%), also captured by AMP-based NGS. When number of actionable fusions detected by AMP-based NGS were added to WES targetable alterations, 66.1% of samples had potential drug targets. When both WES and RNA-seq were analyzed, 57.8% of samples had targetable alterations., Conclusions: This study highlights importance of an integrative genomic approach for precision oncology, including use of different NGS platforms with complementary features. Integrating RNA data (whole transcriptome or AMP-based NGS) significantly enhances detection of potential targets in cancer patients. In absence of fresh frozen tissue, AMP-based NGS is a robust method to detect actionable fusions using low-input RNA from archival tissue., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Ineffective esophageal motility (IEM) is a minor motor disorder with potential reflux implications. Contraction reserve, manifested as augmentation of esophageal body contraction after multiple rapid swallows (MRS), may affect esophageal acid exposure time (AET) in IEM., Methods: Esophageal high-resolution manometry (HRM) and ambulatory reflux monitoring studies were reviewed over 2 years to identify patients with normal HRM, IEM (≥50% ineffective swallows), and absent contractility (100% failed swallows). Single swallows and MRS were analyzed using HRM software tools (distal contractile integral, DCI) to determine contraction reserve (mean MRS DCI to mean single swallow DCI ratio >1). Univariate analysis and multivariable regression analyses were performed to determine motor predictors of abnormal AET in the context of contraction reserve., Results: Of 191 eligible patients, 57.1% had normal HRM, 37.2% had IEM, and 5.8% had absent contractility. Contraction reserve had no affect on AET in normal HRM. Nonsevere IEM (5-7 ineffective swallows) demonstrated significantly lower proportions with abnormal AET in the presence of contraction reserve (30.4%) compared with severe IEM (8-10 ineffective swallows) (75.0%, P = 0.03). Abnormal AET proportions in nonsevere IEM with contraction reserve (32.7%) resembled normal HRM (33.0%, P = 0.96), whereas that in severe IEM with (46.2%) or without contraction reserve (50.0%) resembled absent contractility (54.5%, P ≥ 0.6). Multivariable analysis demonstrated contraction reserve to be an independent predictor of lower upright AET in nonsevere (odds ratio 0.44, 95% confidence interval 0.23-0.88) but not severe IEM., Discussion: Contraction reserve affects esophageal reflux burden in nonsevere IEM. Segregating IEM into severe and nonsevere cohorts has clinical value.

Cell death is an important facet of animal development. In some developing tissues, death is the ultimate fate of over 80% of generated cells. Although recent studies have delineated a bewildering number of cell death mechanisms, most have only been observed in pathological contexts, and only a small number drive normal development. This Primer outlines the important roles, different types and molecular players regulating developmental cell death, and discusses recent findings with which the field currently grapples. We also clarify terminology, to distinguish between developmental cell death mechanisms, for which there is evidence for evolutionary selection, and cell death that follows genetic, chemical or physical injury. Finally, we suggest how advances in understanding developmental cell death may provide insights into the molecular basis of developmental abnormalities and pathological cell death in disease., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

BCOR has been recognized as a recurrently altered gene in a subset of pediatric tumors of the central nervous system (CNS). Here, we describe a novel BCOR-CREBBP fusion event in a case of pediatric infiltrating astrocytoma and further probe the frequency of related fusion events in CNS tumors. We analyzed biopsy samples taken from a 15-year-old male with an aggressive, unresectable and multifocal infiltrating astrocytoma. We performed RNA sequencing (RNA-seq) and targeted DNA sequencing. In the index case, the fused BCOR-CREBBP transcript comprises exons 1-4 of BCOR and exon 31 of CREBBP. The fused gene thus retains the Bcl6 interaction domain of BCOR while eliminating the domain that has been shown to interact with the polycomb group protein PCGF1. The fusion event was validated by FISH and reverse transcriptase PCR. An additional set of 177 pediatric and adult primary CNS tumors were assessed via FISH for BCOR break apart events, all of which were negative. An additional 509 adult lower grade infiltrating gliomas from the publicly available TCGA dataset were screened for BCOR or CREBBP fusions. In this set, one case was found to harbor a CREBBP-GOLGA6L2 fusion and one case a CREBBP-SRRM2 fusion. In a third patient, both BCOR-L3MBTL2 and EP300-BCOR fusions were seen. Of particular interest to this study, EP300 is a paralog of CREBBP and the breakpoint seen involves a similar region of the gene to that of the index case; however, the resultant transcript is predicted to be completely distinct. While this gene fusion may play an oncogenic role through the loss of tumor suppressor functions of BCOR and CREBBP, further screening over larger cohorts and functional validation is needed to determine the degree to which this or similar fusions are recurrent and to elucidate their oncogenic potential.