Search

Non-centrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CAMSAP family of molecules. Using exome sequencing on samples from five unrelated families, we show that bi-allelic CAMSAP1 loss-of-function variants cause a clinically recognizable, syndromic neuronal migration disorder. The cardinal clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, severe neurodevelopmental delay, cortical visual impairment, and seizures. The neuroradiological phenotype comprises a highly recognizable combination of classic lissencephaly with a posterior more severe than anterior gradient similar to PAFAH1B1(LIS1)-related lissencephaly and severe hypoplasia or absence of the corpus callosum; dysplasia of the basal ganglia, hippocampus, and midbrain; and cerebellar hypodysplasia, similar to the tubulinopathies, a group of monogenic tubulin-associated disorders of cortical dysgenesis. Neural cell rosette lineages derived from affected individuals displayed findings consistent with these phenotypes, including abnormal morphology, decreased cell proliferation, and neuronal differentiation. Camsap1-null mice displayed increased perinatal mortality, and RNAScope studies identified high expression levels in the brain throughout neurogenesis and in facial structures, consistent with the mouse and human neurodevelopmental and craniofacial phenotypes. Together our findings confirm a fundamental role of CAMSAP1 in neuronal migration and brain development and define bi-allelic variants as a cause of a clinically distinct neurodevelopmental disorder in humans and mice.

BackgroundLiver cancer is the second leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) risk factors include chronic hepatitis, cirrhosis, and alcohol abuse, whereby tumorigenesis is induced through inflammation and subsequent fibrotic response. However, a subset of HCC arises in non-cirrhotic livers. We characterized the genomic and transcriptomic landscape of non-cirrhotic HCC to identify features underlying the disease’s development and progression.MethodsWhole genome and transcriptome sequencing was performed on 30 surgically resectable tumors comprised of primarily of non-cirrhotic HCC and adjacent normal tissue. Using somatic variants, capture reagents were created and employed on an additional 87 cases of mixed cirrhotic/non-cirrhotic HCC. Cases were analyzed to identify viral integrations, single nucleotide variants (SNVs), insertions and deletions (INDELS), copy number variants, loss of heterozygosity, gene fusions, structural variants, and differential gene expression.ResultsWe detected 3,750 SNVs/INDELS and extensive CNVs and expression changes. Recurrent TERT promoter mutations occurred in >52% of non-cirrhotic discovery samples. Frequently mutated genes included TP53, CTNNB1, and APOB. Cytochrome P450 mediated metabolism was significantly downregulated. Structural variants were observed at MACROD2, WDPCP and NCKAP5 in >20% of samples. Furthermore, NR1H4 fusions involving gene partners EWSR1, GNPTAB, and FNIP1 were detected and validated in 2 non-cirrhotic samples.ConclusionGenomic analysis can elucidate mechanisms that may contribute to non-cirrhotic HCC tumorigenesis. The comparable mutational landscape between cirrhotic and non-cirrhotic HCC supports previous work suggesting a convergence at the genomic level during disease progression. It is therefore possible genomic-based treatments can be applied to both HCC subtypes with progressed disease.HighlightsNon-cirrhotic HCC genomically resembles cirrhotic HCCComprehensive genome- and transcriptome-wide profiling allows detection of novel structural variants, fusions, and undiagnosed viral infectionsNR1H4 fusions may represent a novel mechanism for tumorigenesis in HCCNon-cirrhotic HCC is characterized by genotoxic mutational signatures and dysregulated liver metabolismClinical history and comprehensive omic profiling incompletely explain underlying etiologies for non-cirrhotic HCC highlighting the need for further researchShort DescriptionThis study characterizes the genomic landscape of hepatocellular carcinomas (HCCs) in non-cirrhotic livers. Using 117 HCCs tumor/normal pairs, we identified 3,750 SNVs/INDELS with high variant frequency in TERT, TP53, CTNNB1, and APOB. CYP450 was significantly downregulated and many structural variants were observed. This characterization could assist in elucidating non-cirrhotic HCC tumorigenesis.

Background Intralesional injection of sterile medications remains a mainstay in dermatology, enabling a tailored, low-cost, in-office therapy. After the 2012 United States outbreak of fungal meningitis from contaminated intrathecally administered corticosteroids, there has been increased regulation of in-office compounding, regardless of the administration route. Studies demonstrating the safety data of in-office corticosteroid compounding for intradermal or subcutaneous use are lacking. Objective To assess the incidence of infection caused by compounded in-office intralesional triamcinolone. Methods A retrospective medical record review identified patients who received in-office intralesional corticosteroid injections in 2016. Medical documentation within 30 days of injection was reviewed for suspected infection. Results The records of 4370 intralesional triamcinolone injections were assessed, of which 2780 (64%) were compounded triamcinolone with bacteriostatic saline. We identified 11 (0.25%) suspected localized infections, with 4 of the 11 in the compounding cohort. Of these, 7 of 11 occurred after injection of an “inflamed cyst.” No hospitalizations or deaths occurred. No temporal or locational relationships were identified. Limitations This study was limited to 2 academic institutions. A 30-day postinjection time frame was used. Conclusion In-office compounding for intralesional dermal and subcutaneous administration is safe when sterile products are used by medical practitioners. There is no increased risk of compounded triamcinolone relative to noncompounded triamcinolone.

Continuous video electroencephalography (CEEG) monitoring of critically ill infants and children has expanded rapidly in recent years. Indications for CEEG include evaluation of patients with altered mental status, characterization of paroxysmal events, and detection of electrographic seizures, including monitoring of patients with limited neurological examination or conditions that put them at high risk for electrographic seizures (e.g., cardiac arrest or extracorporeal membrane oxygenation cannulation). Depending on the inclusion criteria and clinical characteristics of the population studied, the percentage of pediatric patients with electrographic seizures varies from 7% to 46% and with electrographic status epilepticus from 1% to 23%. There is also evidence that epileptiform and background CEEG patterns may provide important information about prognosis in certain clinical populations. Quantitative EEG techniques are emerging as a tool to enhance the value of CEEG to provide real-time bedside data for management and prognosis. Continued research is needed to understand the clinical value of seizure detection and identification of other CEEG patterns on the outcomes of critically ill infants and children.

Shoulder injury is one of the most common phenomena that occurs for astronauts when they are training for space flight. During training, astronauts are required to wear a full space suit, known as the extravehicular mobility unit (EMU). The major component of the EMU that attributes to shoulder injury is the hard upper torso (HUT). This component is primarily comprised of a rigid fiberglass shell with metal scye bearing joints. Placement of the scye bearing joints for the shoulders does not allow for enough range of motion, which can lead to rotator cuff tears. Additionally, shoulder injury also occurs when donning the suit and training in the Neutral Buoyancy Laboratory (NBL). The EMU currently does not contain any provision to account for this biomechanical interference to adjust for optimum range of motion. The objective of this paper is to propose a novel detection scheme using a wearable electromagnetic resonant spiral sensor that could allow for a quantitative value of proximity between the shoulder and the metallic scye bearing joint of the HUT. The presence of the liquid cooling and ventilation garment (LCVG) is also investigated in the environment to validate that accuracy of proximity detection is still achieved. Optimal location for the wearable proximity sensor would be on top the LCVG around the shoulder joint where the scye bearing joints are more likely to meet the shoulder. The first study investigated the ability of the wearable proximity sensor to detect the distance from an aluminum sheet (representing the scye bearing joint) with no LCVG present, while the second study incorporated the wearable proximity sensor on top of the LCVG for a simulated suit environment. Four scenarios were performed with two wearable proximity sensors, resonating at different frequencies, placed in an environment with and without the LCVG. Ten repeated tests were used to train and an additional ten tests to validate a regression learning algorithm to predict the distance for each scenario. Experimental results indicated that the wearable proximity sensors in both the open air and with the LCVG have enough accuracy to provide a root mean square error (RMSE) of approximately 1 mm or less. This accuracy is sufficient for use in the space suit to provide quantitative information for suit fit. The use of this proximity detection scheme incorporated into the suit will offer previously unknown information regarding suit fit, while also influencing optimum fit for future suit generations.

Elder mistreatment, affecting an estimated one in ten older adults, has devastating consequences for individuals, families and communities. The magnitude of the issue and known barriers to addressing it through formal systems necessitate innovative approaches to identification and response. This study explores network composition change following elder mistreatment in order to assess the viability of leveraging network members in future intervention efforts. Multiply imputed linear regression models show associations between elder mistreatment and small increases in net change and the number of specific network additions. No association between elder mistreatment and network member losses or network density were found. These findings highlight the complexity of social network change in older adulthood and point to a need for future research considering the influence of Adult Protective Service intervention as well as qualitative work assessing older adults’ own perceptions of mistreatment and network change.

The synthesis and characterization of ten new palladium(II) amine bis(phenolate) complexes is reported. Solution and single-crystal X-ray diffraction studies reveal the presence of both κ2-N,N and κ3-N,N,O binding modes in these square planar complexes. For complexes with sterically less demanding phenolate donors, addition of external acidic or basic reagents allows for the selective masking of a coordination site at Pd. Complexes bearing bulky cumyl substituents on phenolate donors exhibited unusual 1H NMR spectroscopic features that are consistent with an anagostic interaction with the palladium center. Computational analysis at the ωB97X-D/LAN2LDZ level of theory supported the assertion that such an anagostic interaction may play a role in stabilizing κ2 complexes bearing a cumyl-substituted amine bis(phenolate) ligand. X-ray crystallographic data for H21a-PdCl2, H22a-PdCl2, H1b-PdCl, H2b-PdCl, H1d-PdCl, and H1e-PdCl are reported.

Highlights • A comprehensive high-throughput viral sequencing strategy (ViroCap) was adapted for use with feline tumors. • Papillomavirus was not commonly associated with feline oral squamous cell carcinoma. • Feline oral squamous cell carcinoma is a good model for HPV-negative head and neck squamous cell carcinoma in people. • The virome of FOSCC and normal feline oral mucosa included feline foamy virus, torque teno virus, herpes and papillomavirus, FIV and EBV. • Co-occurrence of Epstein Barr Virus and feline papillomavirus-3 was found found in a feline oral squamous cell carcinoma sample., Feline oral squamous cell carcinoma (FOSCC) may be the best naturally-occurring model of human head and neck squamous cell carcinoma (HNSCC). HNSCC can be broadly divided into human papillomavirus (HPV)-negative cancers and HPV-positive cancers where HPV is the causative agent. Previous studies in FOSCC have used both species-specific and species-nonspecific PCR primers that may be insensitive to the detection of PVs and other viruses that may be divergent from known sequences. ViroCap is a targeted capture and next generation sequencing tool that was designed to identify all known vertebrate DNA and RNA viruses. In this study we used a metagenomic approach using ViroCap for DNA viruses in 20 FOSCC, 9 normal feline oral mucosal, and 8 suspected PV positive control samples. We tested the hypothesis that viruses would be enriched in FOSCC compared to normal oral mucosa. The virome of the FOSCC and normal feline oral mucosa consisted of feline foamy virus in 7/20 and 2/9 (35% and 22%), feline torque teno virus in 2/20 and 0/9 (10% and 0%), alphaherpesvirus in 2/10 and 0/9 (10% and 0%), FIV (0% and 22%), Epstein-Barr virus in 1/20 and 0/9 (5% and 0%) and feline papillomavirus in 1/20 and 0/9 samples (5% and 0% respectively). Felis catus papillomavirus-3 was found in 1 of 20 FOSCC samples. A virus was not associated consistently with FOSCC. If PVs have a role in FOSCC it is at most a supplementary or uncommon role. FOSCC appears most closely related to HPV-negative HNSCC. Future research on FOSCC should focus on identifying genetic and environmental causes.

Purpose The study objective was to test the utilization of a crosslinked, thiolated hyaluronic acid (CMHA-S) film for treating corneal chemical burns. Methods Burns 5.5 mm in diameter were created on 10 anesthetized, male New Zealand white rabbits by placing a 1N NaOH soaked circular filter paper onto the cornea for 30 s. Wounds were immediately rinsed with balanced salt solution (BSS). CMHA-S films were placed in the left inferior fornix of five injured and five uninjured animals. Five animals received no treatment. At 0 h, 48 h, 96 h, and on day 14 post chemical burn creation, eyes were evaluated by white light imaging, fluorescein staining, and optical coherence tomography (OCT). Corneal histology was performed using H&E and Masson's Trichrome stains. Results Image analysis indicated biocompatible CMHA-S treatment resulted in significant decreases in the areas of corneal opacity at 48 h, 96 h, and on day 14 postoperatively. A significant increase in re-epithelialization was seen 14 days post injury. CMHA-S treated corneas showed significantly less edema than untreated burns. No pathological differences were observed in corneal histological samples as a result of CMHA-S treatment. Conclusions CMHA-S films facilitate re-epithelialization and decrease the area of corneal opacity in our corneal alkali burn rabbit model.

SUMMARY Herein, we report an oral cavity squamous cell carcinoma (OCSCC) patient-derived xenograft (PDX) platform, with genomic annotation useful for co-clinical trial and mechanistic studies. Genomic analysis included whole-exome sequencing (WES) and transcriptome sequencing (RNA-seq) on 16 tumors and matched PDXs and additional whole-genome sequencing (WGS) on 9 of these pairs as a representative subset of a larger OCSCC PDX repository (n = 63). In 12 models with high purity, more than 90% of variants detected in the tumor were retained in the matched PDX. The genomic landscape across these PDXs reflected OCSCC molecular heterogeneity, including previously described basal, mesenchymal, and classical molecular subtypes. To demonstrate the integration of PDXs into a clinical trial framework, we show that pharmacological intervention in PDXs parallels clinical response and extends patient data. Together, these data describe a repository of OCSCC-specific PDXs and illustrate conservation of primary tumor genotypes, intratumoral heterogeneity, and co-clinical trial application., In Brief Campbell et al. report the genomic fidelity of patient-derived xenograft models from oral cavity squamous cell carcinomas. These models conserve the mutation and expression profile of their matched tumors, validating their use for co-clinical trial and mechanistic studies., Graphical Abstract

The paper presents a brief overview of the role of metal hydride complexes in understanding the dynamics of hydrogen generation in homogeneous water reduction catalysts. In addition, the kinetics of protonation of [Os(phen)2(CO)(H)]+ and the one-electron reduced form of the complex, [Os(phen)(phen−)(CO)(H)], in acetonitrile solution were examined. The monocationic complex reacted with tosylic acid to form a distinct intermediate species which was found to be a dihydrogen complex; this went on to produce hydrogen and the solvento complex. The one-electron reduced complex was prepared by reduction of the photoexcited monocationic complex with the sacrificial donor BIH. Protonation of the reduced complex by tosylic acid occurred with a rate constant approximately 100 million times larger. The results are used to address possible mechanistic pathways of existing homogeneous catalysts.

Despite indications that there are differences in rates of child maltreatment (CM) cases in the child protection system between urban and rural areas, there are no published studies examining the differences in self-reported CM prevalence and its correlates by urbanicity. The present study aimed to: (1) identify the distribution of self-reported childhood experiences of maltreatment by urbanicity, (2) assess whether differences by urbanicity persist after adjusting for known risk factors, and (3) explore whether the associations between these risk factors and CM are modified by urban-rural designation. Using nationally representative data from waves I and III of the National Longitudinal Study of Adolescent to Adult Health, the prevalence of six maltreatment outcomes was estimated for rural, minor urban, and major urban areas (N = 14,322). Multivariable logistic models were estimated identifying if risk associated with urbanicity persisted after adjusting for other risk factors. Interactions between urbanicity and main effects were explored. Prevalence estimates of any CM, poly-victimization, supervision neglect, and physical abuse were significantly higher in major urban areas. Those from major urban areas were more likely to report any maltreatment and supervision neglect even after adjusting for child and family risk factors. The association between race/ethnicity, welfare receipt, low parental educational attainment, and disability status and CM were modified by urbanicity. Significant differences in the prevalence and correlates of CM exist between urban and rural areas. Future research and policy should use self-reported prevalence, in conjunction with official reports, to inform child maltreatment prevention and intervention.

We use a dataset of first-year engineering students from a selective research-intensive public university to examine the impact of same-gender teaching assistants on course grades and major field choice. Our sample consists of students who were randomly assigned to a section of an introductory engineering course and a graduate teaching assistant. Results suggest there may be small positive effects on course grades and the probability of majoring in a high-earning field for female students assigned to a female teaching assistant. Although the difference is marginally significant, the impact of a teaching assistant gender match for female students’ choice of a high-earning field is more pronounced in classrooms with a female instructor and above-median representation of female peers. Our results show limited evidence that female teaching assistants can provide the same benefits of a female instructor in STEM fields.

Although rising average grades appear to be common at post-secondary institutions in the U.S., there is still little work examining mechanisms driving this increase in grades. This paper uses data from a public research university to examine one mechanism in particular: instructor level incentives that are linked to gender and contract status. We hypothesize that instructors with more job uncertainty due to their rank will be most incentivized to award higher grades, as this may lead to better evaluations of teaching and an increase in retention probability. Our results indicate that students receive higher grades when their class is taught by a female instructor with more job uncertainty than if the class were taught by a tenured female faculty member. These higher grades appear to reflect more lenient grading rather than better preparation for follow-on courses. However, for students taking classes with male instructors, there is no significant difference across instructor rank in grades received. Our results have important implications for thinking about the role faculty contracts may play in affecting grading distributions.

To detect diverse and novel RNA species comprehensively, we compared deep small RNA and RNA sequencing (RNA-seq) methods applied to a primary acute myeloid leukemia (AML) sample. We were able to discover previously unannotated small RNAs using deep sequencing of a library method using broader insert size selection. We analyzed the long noncoding RNA (lncRNA) landscape in AML by comparing deep sequencing from multiple RNA-seq library construction methods for the sample that we studied and then integrating RNA-seq data from 179 AML cases. This identified lncRNAs that are completely novel, differentially expressed, and associated with specific AML subtypes. Our study revealed the complexity of the noncoding RNA transcriptome through a combined strategy of strand-specific small RNA and total RNA-seq. This dataset will serve as an invaluable resource for future RNA-based analyses.

The habitat-adapted symbiosis hypothesis predicts that the most positive effects of symbiosis are expected in the most stressful sites for a plant host. Stress varies with site characteristics but also during the life cycle of a plant, with winter annuals experiencing the most stress after fall emergence. For Bromus tectorum, fecundity can vary tremendously from a few to thousands of seeds per plant. We used endophytic Sordaria fimicola to test the hypothesis in three sites in western Montana. We hypothesized that the effects of S. fimicola inoculation would be most positive in the most stressful site after fall application. As predicted, the most positive effects on growth and fecundity were observed in the most stressful site after fall application of S. fimicola. However, the effects of treatments varied within and between sites considerably, and are best understood as an example of context-dependency in plant-microbe interactions rather than habitat-adapted symbiosis.

Melorheostosis (MEL) is the rare sporadic dysostosis characterized by monostotic or polyostotic osteosclerosis and hyperostosis often distributed in a sclerotomal pattern. The prevailing hypothesis for MEL invokes postzygotic mosaicism. Sometimes scleroderma-like skin changes, considered a representation of the pathogenetic process of MEL, overlie the bony changes, and sometimes MEL becomes malignant. Osteopoikilosis (OPK) is the autosomal dominant skeletal dysplasia that features symmetrically distributed punctate osteosclerosis due to heterozygous loss-of-function mutation within LEMD3. Rarely, radiographic findings of MEL occur in OPK. However, germline mutation of LEMD3 does not explain sporadic MEL. To explore if mosaicism underlies MEL, we studied a boy with polyostotic MEL and characteristic overlying scleroderma-like skin, a few bony lesions consistent with OPK, and a large epidermal nevus known to usually harbor a HRAS, FGFR3, or PIK3CA gene mutation. Exome sequencing was performed to ~100× average read depth for his two dermatoses, two areas of normal skin, and peripheral blood leukocytes. As expected for non-malignant tissues, the patient's mutation burden in his normal skin and leukocytes was low. He, his mother, and his maternal grandfather carried a heterozygous, germline, in-frame, 24-base-pair deletion in LEMD3. Radiographs of the patient and his mother revealed bony foci consistent with OPK, but she showed no MEL. For the patient, somatic variant analysis, using four algorithms to compare all 20 possible pairwise combinations of his five DNA samples, identified only one high-confidence mutation, heterozygous KRAS Q61H (NM_033360.3:c.183A>C, NP_203524.1:p.Gln61His), in both his dermatoses but absent in his normal skin and blood. Thus, sparing our patient biopsy of his MEL bone, we identified a heterozygous somatic KRAS mutation in his scleroderma-like dermatosis considered a surrogate for MEL. This implicates postzygotic mosaicism of mutated KRAS, perhaps facilitated by germline LEMD3 haploinsufficiency, causing his MEL.

The recent success of immunotherapies has demonstrated the potency of tumor-specific immune cells in mediating tumor rejection and generating durable tumor immunity. Our understanding of the scientific basis of these responses results from the confluence of a better comprehension of the cancer immunoediting process and the revolution in next generation sequencing of cancer genomes. Recent evidence suggests that T cell specificity for cancer cell expressed mutant proteins – termed neoantigens – is an important component of immune mediated tumor rejection. Improved neoantigen prediction algorithms have made it possible to predict and monitor immune responses to checkpoint inhibitors and adoptively transferred autologous lymphocytes and have enabled the development of tumor-specific therapeutic vaccines. Herein, we review the current research on cancer neoantigens in immunotherapies and its implications for the future of head and neck cancer management.

Background HER2 (ERBB2) gene amplification and its corresponding overexpression are present in 15–30% of invasive breast cancers. While HER2-targeted agents are effective treatments, resistance remains a major cause of death. The American College of Surgeons Oncology Group Z1041 trial (NCT00513292) was designed to compare the pathologic complete response (pCR) rate of distinct regimens of neoadjuvant chemotherapy and trastuzumab, but ultimately identified no difference. Patients and methods In supplement to tissues from 37 Z1041 cases, 11 similarly treated cases were obtained from a single institution study (NCT00353483). We have extracted genomic DNA from both pre-treatment tumor biopsies and blood of these 48 cases, and performed whole genome (WGS) and exome sequencing. Coincident with these efforts, we have generated RNA-seq profiles from 42 of the tumor biopsies. Among patients in this cohort, 24 (50%) achieved a pCR. Results We have characterized the genomic landscape of HER2-positive breast cancer and investigated associations between genomic features and pCR. Cases assigned to the HER2-enriched subtype by RNA-seq analysis were more likely to achieve a pCR compared to the luminal, basal-like, or normal-like subtypes (19/27 versus 3/15; P=0.0032). Mutational events led to the generation of putatively active neoantigens, but were overall not associated with pCR. ERBB2 and GRB7 were the genes most commonly observed in fusion events, and genomic copy number analysis of the ERBB2 locus indicated that cases with either no observable or low-level ERBB2 amplification were less likely to achieve a pCR (7/8 versus 17/40; P=0.048). Moreover, among cases that achieved a pCR, tumors consistently expressed immune signatures that may contribute to therapeutic response. Conclusion The identification of these features suggests that it may be possible to predict, at the time of diagnosis, those HER2-positive breast cancer patients who will not respond to treatment with chemotherapy and trastuzumab. ClinicalTrials.gov identifiers NCT00513292, NCT00353483