H2 in Antarctic firn air: Atmospheric reconstructions and implications for anthropogenic emissions.

The atmospheric history of molecular hydrogen (H2) from 1852 to 2003 was reconstructed from measurements of firn air collected at Megadunes, Antarctica. The reconstruction shows that H2 levels in the southern hemisphere were roughly constant near 330 parts per billion (ppb; nmol H2 mol-1 air) during the mid to late 1800s. Over the twentieth century, H2 levels rose by about 70% to 550 ppb. The reconstruction shows good agreement with the H2 atmospheric history based on firn air measurements from the South Pole. The broad trends in atmospheric H2 over the twentieth century can be explained by increased methane oxidation and anthropogenic emissions. The H2 rise shows no evidence of deceleration during the last quarter of the twentieth century despite an expected reduction in automotive emissions following more stringent regulations. During the late twentieth century, atmospheric CO levels decreased due to a reduction in automotive emissions. It is surprising that atmospheric H2 did not respond similarly as automotive exhaust is thought to be the dominant source of anthropogenic H2. The monotonic late twentieth century rise in H2 levels is consistent with late twentieth-century flask air measurements from high southern latitudes. An additional unknown source of H2 is needed to explain twentieth-century trends in atmospheric H2 and to resolve the discrepancy between bottom-up and top-down estimates of the anthropogenic source term. The firn air-based atmospheric history of H2 provides a baseline from which to assess human impact on the H2 cycle over the last 150 y and validate models that will be used to project future trends in atmospheric composition as H2 becomes a more common energy source.

AuDrA: An automated drawing assessment platform for evaluating creativity.

The visual modality is central to both reception and expression of human creativity. Creativity assessment paradigms, such as structured drawing tasks Barbot (2018), seek to characterize this key modality of creative ideation. However, visual creativity assessment paradigms often rely on cohorts of expert or naïve raters to gauge the level of creativity of the outputs. This comes at the cost of substantial human investment in both time and labor. To address these issues, recent work has leveraged the power of machine learning techniques to automatically extract creativity scores in the verbal domain (e.g., SemDis; Beaty & Johnson 2021). Yet, a comparably well-vetted solution for the assessment of visual creativity is missing. Here, we introduce AuDrA - an Automated Drawing Assessment platform to extract visual creativity scores from simple drawing productions. Using a collection of line drawings and human creativity ratings, we trained AuDrA and tested its generalizability to untrained drawing sets, raters, and tasks. Across four datasets, nearly 60 raters, and over 13,000 drawings, we found AuDrA scores to be highly correlated with human creativity ratings for new drawings on the same drawing task (r = .65 to .81; mean = .76). Importantly, correlations between AuDrA scores and human raters surpassed those between drawings' elaboration (i.e., ink on the page) and human creativity raters, suggesting that AuDrA is sensitive to features of drawings beyond simple degree of complexity. We discuss future directions, limitations, and link the trained AuDrA model and a tutorial ( https://osf.io/kqn9v/ ) to enable researchers to efficiently assess new drawings.

Divergent semantic integration (DSI): Extracting creativity from narratives with distributional semantic modeling.

We developed a novel conceptualization of one component of creativity in narratives by integrating creativity theory and distributional semantics theory. We termed the new construct divergent semantic integration (DSI), defined as the extent to which a narrative connects divergent ideas. Across nine studies, 27 different narrative prompts, and over 3500 short narratives, we compared six models of DSI that varied in their computational architecture. The best-performing model employed Bidirectional Encoder Representations from Transformers (BERT), which generates context-dependent numerical representations of words (i.e., embeddings). BERT DSI scores demonstrated impressive predictive power, explaining up to 72% of the variance in human creativity ratings, even approaching human inter-rater reliability for some tasks. BERT DSI scores showed equivalently high predictive power for expert and nonexpert human ratings of creativity in narratives. Critically, DSI scores generalized across ethnicity and English language proficiency, including individuals identifying as Hispanic and L2 English speakers. The integration of creativity and distributional semantics theory has substantial potential to generate novel hypotheses about creativity and novel operationalizations of its underlying processes and components. To facilitate new discoveries across diverse disciplines, we provide a tutorial with code (osf.io/ath2s) on how to compute DSI and a web app ( osf.io/ath2s ) to freely retrieve DSI scores.

SMARC-B1 deficient sinonasal carcinoma metastasis to the brain with next generation sequencing data: a case report of perineural invasion progressing to leptomeningeal invasion.

BACKGROUND: SMARCB1-deficient sinonasal carcinoma (SDSC) is an aggressive subtype of head and neck cancers that has a poor prognosis despite multimodal therapy. We present a unique case with next generation sequencing data of a patient who had SDSC with perineural invasion to the trigeminal nerve that progressed to a brain metastasis and eventually leptomeningeal spread. CASE PRESENTATION: A 42 year old female presented with facial pain and had resection of a tumor along the V2 division of the trigeminal nerve on the right. She underwent adjuvant stereotactic radiation. She developed further neurological symptoms and imaging demonstrated the tumor had infiltrated into the cavernous sinus as well as intradurally. She had surgical resection for removal of her brain metastasis and decompression of the cavernous sinus. Following her second surgery, she had adjuvant radiation and chemotherapy. Several months later she had quadriparesis and imaging was consistent with leptomeningeal spread. She underwent palliative radiation and ultimately transitioned quickly to comfort care and expired. Overall survival from time of diagnosis was 13 months. Next generation sequencing was carried out on her primary tumor and brain metastasis. The brain metastatic tissue had an increased tumor mutational burden in comparison to the primary. CONCLUSIONS: This is the first report of SDSC with perineural invasion progressing to leptomeningeal carcinomatosis. Continued next generation sequencing of the primary and metastatic tissue by clinicians is encouraged toprovide further insights into metastatic progression of rare solid tumors.

Silodosin inhibits prostate cancer cell growth via ELK1 inactivation and enhances the cytotoxic activity of gemcitabine.

BACKGROUND: Biological significance of ELK1, a transcriptional factor whose phosphorylation is necessary for c-fos proto-oncogene activation, in prostate cancer remains far from fully understood. In this study, we aim to investigate the role of ELK1 in tumor growth as well as the efficacy of a selective α1A-adrenergic blocker, silodosin, in ELK1 activity in prostate cancer cells. METHODS: We first immunohistochemically determined the levels of phospho-ELK1 (p-ELK1) expression in radical prostatectomy specimens. We then assessed the effects of ELK1 knockdown via short hairpin RNA and silodosin on cell proliferation, migration, and invasion in prostate cancer lines. RESULTS: The levels of p-ELK1 expression were significantly higher in carcinoma than in benign (P < 0.001) or high-grade prostatic intraepithelial neoplasia (HGPIN) (P = 0.002) as well as in HGPIN than in benign (P < 0.001). Kaplan-Meier and log-rank tests revealed that moderate-strong positivity of p-ELK1 in carcinomas tended to correlate with biochemical recurrence after radical prostatectomy (P = 0.098). In PC3 and DU145 expressing ELK1 (mRNA/protein) but no androgen receptor (AR), ELK1 silencing resulted in considerable decreases in the expression of c-fos as well as in cell migration/invasion and matrix metalloproteinase-2 expression, but not in cell viability. Silodosin treatment reduced the expression/activity of ELK1 in these cells as well as the viability of AR-positive LNCaP and C4-2 cells and the migration of both AR-positive and AR-negative cells, but not the viability of AR-negative or ELK1-negative cells. Interestingly, silodosin significantly increased sensitivity to gemcitabine, but not to cisplatin or docetaxel, even in AR-negative cells. CONCLUSIONS: ELK1 is likely to be activated in prostate cancer cells and promote tumor progression. Furthermore, silodosin that inactivates ELK1 in prostate cancer cells not only inhibits their growth but also enhances the cytotoxic activity of gemcitabine. Thus, ELK1 inhibition has the potential of being a therapeutic approach for prostate cancer.

Leptomeningeal metastasis from neuroendocrine carcinoma of the cervix: illustrative case.

BACKGROUND: Leptomeningeal carcinomatosis is a rare feature of metastasis that is characterized by thickening and increased contrast enhancement throughout the meninges of the central nervous system (CNS). Leptomeningeal disease (LMD) can occur as spread from primary CNS tumors or as a manifestation of metastasis to the CNS from primary tumor sites outside the CNS. Leptomeningeal disease is, however, rare in cervical cancer, in which metastasis occurs typically from local invasion. OBSERVATIONS: The authors discuss the case of CNS metastasis with LMD from the rare neuroendocrine carcinoma of the cervix (NECC). Cervical cancer infrequently metastasizes to the CNS, but NECC is an aggressive variant with greater metastatic potential. Many of these patients will have previously received pelvic radiation, limiting their candidacy for craniospinal radiation for LMD treatment due to field overlap. This illustrative case documents the first known case of NECC CNS metastasis accompanied by LMD treated with intrathecal chemotherapy. LESSONS: Reported is the first known case of NECC with CNS metastasis accompanied by LMD. The authors highlight the potentially critical role of intrathecal chemotherapy, in addition to radiotherapy, in treating leptomeningeal metastasis from cervical cancer.

Primary thoracic intramedullary spinal cord tumor with likely metastases of glial origin to the lumbosacral vertebrae: Illustrative case.

Background: Metastasis of systemic neoplasms to the spine is common; however, the metastasis of primary spinal cord tumors to other regions in the body is an infrequent occurrence. A few case reports have described the metastasis of primary spinal cord tumors, and in most cases, patients were younger than 30 years of age. Case Description: We present an illustrative case of a 47-year-old female with metastatic lesions to the lumbosacral vertebrae years after the initial diagnosis of an intradural, intramedullary spinal cord tumor (IMSCT). Although the surgical biopsy of the IMSCT was nondiagnostic, the patient was not found to have a separate primary neoplastic source, and the specimens of the metastatic lesions from the lumbar vertebral body were of glial origin. Conclusion: Metastasis from primary IMSCTs is extremely rare. Distant vertebral body and intracranial metastasis are even rarer yet possible. The clinical course is highly aggressive and responds poorly to current standard treatment.

Magnetic Resonance-Guided Stereotaxy for Infusions to the Pig Brain.

The overall goal of this procedure is to perform stereotaxy in the pig brain with real-time magnetic resonance (MR) visualization guidance to provide precise infusions. The subject was positioned prone in the MR bore for optimal access to the top of the skull with the torso raised, the neck flexed, and the head inclined downward. Two anchor pins anchored on the bilateral zygoma held the head steady using the head holder. A magnetic resonance imaging (MRI) flex-coil was placed rostrally across the head holder so that the skull was accessible for the intervention procedure. A planning grid placed on the scalp was used to determine the appropriate entry point of the cannula. The stereotactic frame was secured and aligned iteratively through software projection until the projected radial error was less than 0.5 mm. A hand drill was used to create a burr hole for insertion of the cannula. A gadolinium-enhanced co-infusion was used to visualize the infusion of a cell suspension. Repeated T1-weighted MRI scans were registered in real time during the agent delivery process to visualize the volume of gadolinium distribution. MRI-guided stereotaxy allows for precise and controlled infusion into the pig brain, with concurrent monitoring of cannula insertion accuracy and determination of the agent volume of distribution.

Comparison-based learning of relational categories (you'll never guess).

In accord with structural alignment theory, same-category comparison opportunities within a classification learning task should promote relational category acquisition. However, a straightforward merging of the classification paradigm with copresentation of same-category item pairs does not yield an advantage relative to an equal number of single-item exposures. In 3 experiments, we explore the hypothesis that the traditional classification learning mode (guess-and-correct) and comparison have a previously unforeseen incompatibility. In Experiment 1, we test this hypothesis by contrasting classification with supervised observational learning (passive study of labeled examples) under 3 presentation formats: same-category pairs, mixed pairs, and single-item. We find an observational advantage with same-category pairs and produce the elusive advantage over single-item exposures. In Experiment 2, we assess the generality of the learning mode effect by testing both same- and different-category comparison. The observational advantage replicates and extends to different-category comparison-although, we do not find a significant difference between the 2 types of comparison. In Experiment 3, relative to the classification mode, we find enhanced performance in an intermediate learning mode between classification and observation in which participants are instructed to make a covert category guess (without making an actual response) before seeing the correct category label. Implications and interpretations-including our interpretation that the performance emphasis inherent in classification learning undermines the benefits that arise from comparison opportunities-are discussed. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

A Glioblastoma Genomics Primer for Clinicians.

New discoveries in Glioblastoma (GBM) biology have been made using genomics data. Genomic markers are routinely integrated into clinical neurosurgical practice. In this manuscript, we review the fundamentals of genomics such as the differences between first, second, and third generation sequencing technology. We also review the impact of single cell genomics in understanding the complex heterogenous GBM microenvironment. Finally, we will discuss advances in epigenetics that have lent insights into treatment resistance. The integration of genomics into neuro-oncology clinical practice is routine and will continue to expand with the expansion of precision of medicine. We provide a primer for clinicians.

CAR T Cell Therapy for Pediatric Brain Tumors.

Chimeric Antigen Receptor (CAR) T cell therapy has recently begun to be used for solid tumors such as glioblastoma multiforme. Many children with pediatric malignant brain tumors develop extensive long-term morbidity of intensive multimodal curative treatment. Others with certain diagnoses and relapsed disease continue to have limited therapies and a dismal prognosis. Novel treatments such as CAR T cells could potentially improve outcomes and ameliorate the toxicity of current treatment. In this review, we discuss the potential of using CAR therapy for pediatric brain tumors. The emerging insights on the molecular subtypes and tumor microenvironment of these tumors provide avenues to devise strategies for CAR T cell therapy. Unique characteristics of these brain tumors, such as location and associated morbid treatment induced neuro-inflammation, are novel challenges not commonly encountered in adult brain tumors. Despite these considerations, CAR T cell therapy has the potential to be integrated into treatment schema for aggressive pediatric malignant brain tumors in the future.

Neurosurgical management of perineural metastases: A case series and review of the literature.

BACKGROUND: Perineural invasion (PNI) and spread are one of the grimmest prognostic factors associated with primary skin and head-and-neck cancers, yet remain an often confused, and underreported, phenomenon. Adding complexity to reaching a diagnosis and treating perineural spread (PNS) is the finding that patients may have no known primary tumor, history of skin cancer, and/or incidental PNI in the primary tumor. These delays in diagnosis and treatment are further compounded by an already slow disease process and often require multidisciplinary care with combinations of stereotactic radiosurgery, surgical resection, and novel treatments such as checkpoint inhibitors. METHODS: Six patients with metastatic cancer to the cranial nerves who underwent Gamma Knife radiosurgery (GKRS) treatment were chosen for retrospective analysis. This information included age, gender, any past surgeries (both stereotactic and regular surgery), dose of radiation and volume of the tumor treated in the GKRS, date of PNS, comorbidities, the patient follow-up, and pre- and post-GKRS imaging. The goal of the follow-up with radiographing imaging was to assess the efficacy of GKSS. RESULTS: The clinical course of six patients with PNS is presented. Patients followed variable courses with mixed outcomes: two patients remain living, one was lost to follow-up, and three expired with a median survival of 12 months from date of diagnosis. Patients at our institution are ideally followed for life. CONCLUSION: Given the morbidity and mortality of PNS of cancer, time is limited, and further understanding is required to improve outcomes. Here, we provide a case series of patients with PNS treated with stereotactic radiosurgery, discuss their clinical courses, and review the known literature.

Continuous Developmental and Early Life Trichloroethylene Exposure Promoted DNA Methylation Alterations in Polycomb Protein Binding Sites in Effector/Memory CD4+ T Cells.

Trichloroethylene (TCE) is an industrial solvent and drinking water pollutant associated with CD4+ T cell-mediated autoimmunity. In our mouse model, discontinuation of TCE exposure during adulthood after developmental exposure did not prevent immunotoxicity. To determine whether persistent effects were linked to epigenetic changes we conducted whole genome reduced representation bisulfite sequencing (RRBS) to evaluate methylation of CpG sites in autosomal chromosomes in activated effector/memory CD4+ T cells. Female MRL+/+ mice were exposed to vehicle control or TCE in the drinking water from gestation until ~37 weeks of age [postnatal day (PND) 259]. In a subset of mice, TCE exposure was discontinued at ~22 weeks of age (PND 154). At PND 259, RRBS assessment revealed more global methylation changes in the continuous exposure group vs. the discontinuous exposure group. A majority of the differentially methylated CpG regions (DMRs) across promoters, islands, and regulatory elements were hypermethylated (~90%). However, continuous developmental TCE exposure altered the methylation of 274 CpG sites in promoters and CpG islands. In contrast, only 4 CpG island regions were differentially methylated (hypermethylated) in the discontinuous group. Interestingly, 2 of these 4 sites were also hypermethylated in the continuous exposure group, and both of these island regions are associated with lysine 27 on histone H3 (H3K27) involved in polycomb complex-dependent transcriptional repression via H3K27 tri-methylation. CpG sites were overlapped with the Open Regulatory Annotation database. Unlike the discontinuous group, continuous TCE treatment resulted in 129 DMRs including 12 unique transcription factors and regulatory elements; 80% of which were enriched for one or more polycomb group (PcG) protein binding regions (i.e., SUZ12, EZH2, JARID2, and MTF2). Pathway analysis of the DMRs indicated that TCE primarily altered the methylation of genes associated with regulation of cellular metabolism and cell signaling. The results demonstrated that continuous developmental exposure to TCE differentially methylated binding sites of PcG proteins in effector/memory CD4+ cells. There were minimal yet potentially biologically significant effects that occurred when exposure was discontinued. These results point toward a novel mechanism by which chronic developmental TCE exposure may alter terminally differentiated CD4+ T cell function in adulthood.

Silodosin inhibits the growth of bladder cancer cells and enhances the cytotoxic activity of cisplatin via ELK1 inactivation.

Silodosin, a selective α1A-adrenergic blocker prescribed for the symptomatic treatment of benign prostatic hyperplasia, was previously shown to decrease the expression of ELK1, a c-fos proto-oncogene regulator and a well-described downstream target of the PKC/Raf-1/ERK pathway, in human prostate smooth muscle cells. PKC/Raf-1/ERK activation has also been implicated in drug resistance. In the current study, we assessed the effects of silodosin on ELK1 expression/activity in bladder cancer cells as well as on their proliferation in the presence or absence of chemotherapeutic drugs, including cisplatin and gemcitabine. In bladder cancer cell lines, silodosin reduced the expression of ELK1 (mRNA/protein) and its downstream target, c-fos gene, as well as the transcriptional activity of ELK1. While silodosin alone (up to 10 µM) insignificantly affected the growth of bladder cancer cells cultured in androgen depleted conditions or those expressing ELK1-short hairpin RNA, it considerably inhibited the viability of androgen receptor (AR)-positive/ELK1-positive cells in the presence of androgens. Silodosin also inhibited the migration of ELK1-positive cells with or without a functional AR, but not that of ELK1 knockdown cells. Interestingly, silodosin treatment or ELK1 silencing resulted in increases in drug sensitivity to cisplatin, but not to gemcitabine, even in AR-negative cells or AR-positive cells cultured in an androgen-depleted condition. In addition, silodosin decreased the expression of NF-κB, a key regulator of chemoresistance, and its transcriptional activity. Moreover, immunohistochemistry in bladder cancer specimens from patients who received neoadjuvant chemotherapy revealed that phospho-ELK1 positivity strongly correlated with chemoresistance. Silodosin was thus found to not only inhibit cell viability and migration but also enhance the cytotoxic activity of cisplatin in bladder cancer lines via inactivating ELK1. Our results suggest that combined treatment with silodosin is useful for overcoming chemoresistance in patients with ELK1-positive urothelial carcinoma receiving cisplatin.

Olecranon osteotomy fixation using a novel device: the olecranon sled.

A posterior approach to the elbow utilizing an olecranon osteotomy has been shown to provide excellent visualization of the distal humerus articular surface. However, many bony stabilization and fixation methods for the olecranon osteotomy are usually prominent, frequently symptomatic, and often require a second operation for removal. This paper evaluates the use of an innovative device, the olecranon sled, in fixation of olecranon osteotomies for exposure of intra-articular distal humerus fractures and provides follow-up results. A retrospective review of all patients with intra-articular distal humerus fracture treated through an olecranon osteotomy approach and fixed with an olecranon sled, between September 2008 and December 2011 was conducted. Charts and radiographs were reviewed to determine olecranon union or nonunion, presence of symptomatic hardware, and need for secondary surgery to remove symptomatic olecranon fixation. Fourteen patients were included in the study. Average clinical follow-up was 33.5 weeks (range, 6 to 118 wk). There were no olecranon nonunions. One patient underwent additional surgery for symptomatic hardware removal (7.1%). Two additional procedures were performed; 1 for revision open reduction and internal fixation of distal humerus fracture nonunion (7.1%) and 1 for release of elbow contracture (7.1%). Although follow-up is limited, the use of this device has been associated with excellent rates of olecranon union with a low rate of symptomatic hardware requiring removal.