bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-289: Genomic instability and the development of high-grade gliomas
Authors: Pribyl Lee J. , Downing Susanna M. , Camacho Cristel V. , Larson Jon D. , Baker Suzanne J. , McKinnon Peter J.
Published: August 2019

Genome stability is crucial for normal mammalian development. Broadly, genome maintenance is carried out by two distinct mechanisms; functional integration of DNA replication and DNA damage response signaling. Neural cells are particularly sensitive to DNA strand breaks and defective DNA damage responses can result in detrimental effects to the nervous system, including neurodegenerative disease and cancer. It remains unclear which DNA repair pathways are critical for preventing DNA damage accumulation in stem and progenitor cells. The same mechanisms that protect progenitor genomes also suppress DNA mutations that can result in cancer. A primary objective of the current study is delineation of key factors for genome stability that prevent tumorigenesis during cortical neurogenesis. We have compared the differential effects of inactivation of homologous recombination (HR) and non-homologous end-joining (NHEJ) towards tumorigenesis by directing their deletion specifically to early cortical progenitors in mouse models. We recently found that coincident loss of either of these repair pathways result in high-grade glioma formation. Furthermore, modelling histone H3 mutations found in human high-grade glioma, specifically the H3.3 K27M mutation, we found that gliomagenesis was accelerated after defective HR (Brca2 loss) or NHEJ (Lig4 loss), although the resultant cancers showed distinct differences in penetrance and diffusion throughout the cortex. Interestingly, gliomas resulting from NHEJ inhibition were more penetrant and diffuse than brain tumors subsequent from HR loss. Gene expression analysis through RNA sequencing is currently being used to identify causative events that drive these individual tumor identities. Embryonic analysis has further shown that inhibition of these repair pathways in combination with the H3.3 K27M mutation results in distinct spatiotemporal DNA damage early in cortical development. Our recent discoveries support cortical progenitor susceptibility to genomic damage is not only influenced by a critical early period of development but also the suppression of specific tumorigenic mutations involving DNA damage repair pathways and histone modifications during neurogenesis.

Citation Format: Lee J. Pribyl, Susanna M. Downing, Cristel V. Camacho, Jon D. Larson, Suzanne J. Baker, Peter J. McKinnon. Genomic instability and the development of high-grade gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-289.
Abstract LB-303: Transposable element insertions impact the mutational landscape of breast cancer genomes and disease onset
Authors: Paul Robin , Radovich Milan , Solzak Jeffrey P.
Published: August 2019

More than 50% of the human genome consists of transposable elements (TE), which mostly remain inactive and relatively stable in healthy individuals. These elements, commonly known as “jumping genes,” are sequences of DNA that are mobile and can change positions in the genome. However, only certain classes of retrotransposons (ALU, SVA, ERV and L1) are believed to be active in the human genome. Most TEs transpose by a “copy-and-paste” mechanism via transcription from DNA to an RNA intermediate followed by reverse transcription back to DNA and subsequent insertion of the copied DNA into the genome. In healthy individuals, this mechanism is silenced by various epigenetic pathways such as the piRNA pathway which helps silence the transcribed TE RNA intermediates. However during cancer, some retrotransposons are believed to become active due to loss of this epigenetic silencing and DNA damage repair mechanisms. In this study, we analyzed somatic and germline TE insertions in 77 TCGA breast cancer whole genomes and performed association analysis with corresponding somatic and germline variants. In our analysis, we identified a subset of patients who harbored a high number of germline TE insertions. Statistical burden testing of germline TE insertions with germline genetic variants (SNPs and Indels), revealed an enrichment of deleterious variants in the NRDE2 and TNKS1BP1 genes. NRDE2 gene involved in the piRNA pathway is known to regulate TEs using RNA silencing whereas, TNKS1BP1 gene is known to be involved in DNA damage repair mechanisms and also helps maintain genomic integrity. Further, patients with high germline TE insertions had a lower median age of diagnosis (top quartile vs bottom 75%, p-value=0.019), suggesting a potential novel role of germline TE insertions in cancer predisposition. Lastly, comparison of somatic TE insertion burdenpattern against somatic tumor mutation burden revealed an inverse correlation, indicating that analysis of TE insertions is critical to breast cancer diagnosis in the clinic. Our results definitively argue that characterization of TEs is essential for elucidating the complete mutational profile of a breast cancer genome.

Citation Format: Robin Paul, Milan Radovich, Jeffrey P. Solzak. Transposable element insertions impact the mutational landscape of breast cancer genomes and disease onset [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-303.
Abstract PL04-01: Screening for nasopharyngeal carcinoma using plasma Epstein-Barr virus DNA: Technological and clinical insights
Authors: Lo Yuk Ming Dennis
Published: August 2019

Epstein-Barr virus (EBV) DNA is released by a number of EBV-associated malignancies into the plasma. Examples of such malignancies include nasopharyngeal carcinoma (NPC), certain lymphomas and EBV-associated gastric carcinoma. Plasma EBV DNA in such malignancies exhibits a strong correlation with tumor stage, clinical progress and prognosis; and is thus an archetypal circulating tumor DNA species.

Our group is interested in exploring the use of plasma EBV DNA to screen for NPC. We have recently completed a prospective population screening project involving over 20,000 middle aged men in Hong Kong. Using plasma EBV DNA as a screening tool, NPC could be found at a much earlier stage than was normally possible. Furthermore, the prognosis of the NPC patients identified through such screening was much more favorable than those diagnosed without such screening. The positive predictive value of this approach was 11%.

False-positive results were observed a proportion of subjects without NPC. Factors that contributed to increased false-positive results included advancing age and surprisingly, the ambient temperature of the day when samples were collected. Hence, a higher percentage of false-positive results were observed when samples were collected in colder weather. We hypothesized that such results might be related to the fluctuations in the effectiveness of the immune system in certain individuals due to ambient temperature.

Since the reporting of the above-mentioned results, we have been exploring approaches for further enhancing the positive predictive value. Through the use of targeted massively parallel paired-end sequencing, we found that the size profiles of plasma EBV DNA in subjects with NPC and those without were different. Indeed, by combining such size profile and the concentration of plasma EBV DNA as measured by sequencing, the positive predictive value could be further enhanced.

Very recently, we investigated the epigenetic profile of plasma EBV DNA in subjects with NPC and those without cancer, in an attempt to further enhance the positive predictive value of the approach.

We believe that the development of a robust approach for NPC screening using circulating EBV DNA would have major public health impact, allowing the earlier detection and treatment of NPC in high prevalence areas. We also believe that such developments would also guide the development of other circulating tumor DNA markers for early cancer detection.

Citation Format: Yuk Ming Dennis Lo. Screening for nasopharyngeal carcinoma using plasma Epstein-Barr virus DNA: Technological and clinical insights [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr PL04-01.
Abstract SY17-02: Solid tumor cancer stem cells: From bench to bedside
Authors: Clarke Michael F.
Published: August 2019

Stem cells are essential for maintenance of multiple tissues including the intestine, skin, brain and breast. Remarkably, cancers invariably arise in tissues that contain stem cells whose function is to maintain and repair tissues for the life of the animal. Self renewal, the mechanisms by which stem cells regenerate themselves, is the fundamental property by which stem cells maintain themselves. Our laboratory investigates the fundamental molecular mechanisms of self renewal. Our studies have found that stem cells can be identified by the expression of genes required for self renewal AND by the lack of expression of genes that suppress self renewal. The specific components of self renewal pathways in normal and malignant colon and mammary gland stem cells will be discussed. Stem cell pathways contribute to minimal residual disease after cancer therapy will be discussed. Finally, the application of stem cell biology to cancer therapy will be described. Approximately 4-7% of stage 2 colon cancers consist of homogeneous populations of undiffentiated CDX2- cancer cells. Stage 2 colon cancer patients are generally not thought to benefit from adjuvant chemotherapy. However, stage 2 colon cancer patients with CDX 2- cancer do appear to benefit.

Citation Format: Michael F. Clarke. Solid tumor cancer stem cells: From bench to bedside [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY17-02.
Abstract SY18-03: Single cells and therapy resistance in cancer
Authors: Raj Arjun
Published: August 2019

Cancer is a disease that originates from single cells, and the treatment of cancer also is a problem of single cells: anti-cancer therapies can often kill the vast majority of tumor cells but a few rare cells remain and grow despite treatment. Often, it is thought that the underlying basis for the behavior of these rare cells is a genetic difference. However, we and others have shown that non-genetic differences may be a key driver of rare, drug resistant cells, yet the precise molecular nature of these differences often remains mysterious. We here describe the development of a cellular “time machine” that allows us to link the ultimate cellular fate to the initial cellular state on a single cell basis, thus revealing markers for pre-resistant cells in the population. Further, we use genetic screening technologies to elucidate the pathways that control the formation of these rare cells and discuss their therapeutic implications.

Citation Format: Arjun Raj. Single cells and therapy resistance in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY18-03.
Abstract SY20-02: The SIRT3-MnSOD-Ac axis in carcinogenesis and tumor resistance
Authors: Gius David R. , Zhu Yueming
Published: August 2019

ABSTRACT The molecular mechanism by which acetylation regulates manganese superoxide dismutase (MnSOD) activity, and its oncogenic and/or physiological significance, is unclear. Here we show that expression of the MnSOD-K68 acetylation (Ac) mimic mutant (MnSODK68Q) transformed wild-type primary mouse embryonic fibroblasts (pMEFs) when co-infected with either c-Myc or Ras, as measured by in vitro transformation assays and xenograft formation. Immortalized MnSOD-/- mouse embryonic fibroblasts (MEFs) infected with lenti-MnSODK68Q also exhibited an in vitro transformation permissive phenotype. In addition, MCF7 and T47D cells expressing MnSODK68Q demonstrated increased in vitro and xenograft oncogenic properties. These findings collectively identify MnSODK68Q as a tumor promoter. MCF7, T47D, and MnSOD-/- cells expressing MnSODK68Q displayed a monomeric form of MnSOD, distinct from the well-established homotetramer, and MnSOD-K68-Ac functions as a peroxidase, determined using a bacterial system for site-specific incorporation of N-(ε)-acetyl-l-lysine. Finally, tamoxifen resistant MCF7 and T47D cells, and a subgroup of human breast malignancies, displayed a MnSOD-K68-Ac signature.

Citation Format: David R. Gius, Yueming Zhu. The SIRT3-MnSOD-Ac axis in carcinogenesis and tumor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY20-02.
Abstract SY23-02: Actions of the EMT Program in fostering malignant progression
Authors: Weinberg Robert A.
Published: August 2019

The cell-biological program commonly termed the epithelial-mesenchymal transition (EMT) confers a variety of distinct traits on epithelial cells that express it, including many that enable primary carcinoma cells to complete most of the steps of the invasion-metastasis cascade. Among other traits, it confers increased resistance to various forms of therapy and a stem-cell phenotype, which appears to be tightly linked to tumor-initiating ability. In addition, mammary carcinoma cells expressing an EMT program show a reduced susceptibility to elimination by anti-CTLA4 checkpoint blockade relative to their more mesenchymal counterparts. Carcinoma cells rarely if ever execute a complete EMT program but instead venture only partway toward the mesenchymal state, resulting in cells that co-express both epithelial and mesenchymal traits. Moreover, tumor-initiating cells appear to co-express both epithelial and mesenchymal traits, indicating that cells that have moved too far into the mesenchymal state actually lose stemness and thus tumor-initiating powers.

Citation Format: Robert A. Weinberg. Actions of the EMT Program in fostering malignant progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY23-02.
Abstract SY42-01: Chemical biology-based approach to understanding and overcoming resistance of cancers to therapies
Authors: Schreiber Stuart L.
Published: August 2019

The ability of cancer cells to resist apoptotic death induced by radiation, chemotherapy, targeted therapies and immunotherapy has been a primary impediment to achieving long-lasting clinical responses. Cancer resistance is often studied through the lens of genetics, and thus on a drug-by-drug basis. I will discuss an alternative approach - studying resistance through the lens of cellular plasticity. As part of the NCI’s Cancer Target Discovery & Development Network, we use the Cancer Therapeutics Response Portal (CTRP), which enables small molecule sensitivity-cancer cell feature relationships to be explored on a broad basis. One insight gained from this resource suggests that a similar form of plasticity appears recurrently in multiple cancer contexts, and in response to multiple modalities (chemotherapy; targeted therapy; immunotherapy) thus opening the possibility of a pan-cancer explanation of resistance. Here, cell plasticity provides access to an apoptosis-deficient state and thus resistance, and then subsequent cancer mutations, rather than being the basis of resistance, are needed to optimize the fitness of the resistant state for growth. We found that this myofibroblastic-like cell state has profound changes in lipid biology that result in a novel vulnerability to ferroptotic cell death and a dependency on the activity of GPX4, a potentially druggable lipid hydroperoxidas. We hope this research will provide a blueprint for the cure of cancers in the future.

Citation Format: Stuart L. Schreiber. Chemical biology-based approach to understanding and overcoming resistance of cancers to therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY42-01.
Abstract SY44-02: Aberrant polycomb repression in midline and hindbrain tumors
Authors: Lewis Peter W.
Published: August 2019

The discovery of high-frequency histone H3 missense mutations (‘oncohistones’) in pediatric gliomas was the first time that histone mutations were linked to any disease. Since the original discovery, monoallelic missense mutations in genes encoding histone H3 have been found in a variety of cancer types. Previous studies have led to mechanistic insights into how one class of oncohistones promotes tumorigenesis by demonstrating that lysine-to-methionine (K-to-M) substitutions transform histones from serving as substrates into specific and potent inhibitors of lysine methyltransferases.

Approximately 84% of diffuse intrinsic pontine glioma (DIPG) and 60% of high-grade non-brainstem pediatric midline gliomas contain a lysine 27-methionine (K27M) mutation. DIPG and other midline tumors have extremely low H3K27me3 levels caused by the action of the H3 K27M oncohistone. The H3 K27M protein binds to and inhibits the catalytic subunit (EZH2) of the Polycomb Repressive Complex 2 (PRC2), a conserved protein complex involved in gene silencing. Polycomb group (PcG) proteins are essential for development and are frequently misregulated in human cancers. Polycomb Repressive Complexes (PRC1, PRC2) function in a collaborative epigenetic cross-talk with H3K27me3 to initiate and maintain transcriptional silencing.

Posterior fossa type A (PFA) ependymomas also exhibit very low H3K27 methylation but lack the K27M oncohistone. Instead, PFA tumors express high levels of KIP75 (K27M-like inhibitor of PRC2, 75kDa, also termed CXORF67). We find that a highly conserved sequence within the C-terminus of KIP75 is necessary and sufficient to inhibit the catalytic activity of PRC2 in vitro and in vivo. Our biochemical experiments indicate that KIP75 directly interacts with the active site of the EZH2 subunit in a mechanism that is remarkably similar to the K27M oncohistone. Furthermore, expression of H3 K27M or KIP75 promote similar chromatin landscapes and gene expression profiles in cell culture. Our data indicate that PFA ependymoma and DIPG tumors are driven in part by the action of peptidyl PRC2 inhibitors that dysregulate gene silencing to promote tumorigenesis.

Citation Format: Peter W. Lewis. Aberrant polycomb repression in midline and hindbrain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY44-02.
Abstract SY45-02: Harnessing genetic interactions to advance whole-exome precision cancer treatment
Authors: Ruppin Eytan
Published: August 2019

Much of the current focus in cancer research is on studying cancer driver genes. In search for new and effective cancer drugs, this has been translated into searching for ‘actionable’ mutations in these genes, aiming at their therapeutic targeting. However, identifying novel genetic interactions occurring between cancer genes may open new drug treatment opportunities across the whole cancer genome. This talk will focus on studying the utility of two fundamental types of genetic interactions: The first are the well-known Synthetic Lethal interactions, describing the relationship between two genes whose combined inactivation is lethal to the cell. The second type are the much less studied Synthetic Rescues interactions, where a change in the activity of one gene is lethal to the cell but an alteration of its SR partner gene can rescue cell viability. I shall describe a new approach for the data-driven identification of these two types of genetic interactions by directly mining patients’ tumor data. Applying it to analyze the Cancer Genome Atlas (TCGA) data, we have identified the first pan-cancer genetic interaction networks shared across many types of cancer, which we then validated via existing and new experimental in vitro and in vivo screens. We find that: (a) Synthetic Lethal interactions offer an exciting venue for personalized selective anticancer treatments enabling the prediction of patients’ drug response and providing new selective drug target candidates, and (b) targeting Synthetic Rescue genes can mitigate resistance emerging to primary cancer therapy, including both targeted and immunotherapy. (c) Finally, I shall present recent unpublished results showing that we can quite accurately predict the context specificity of emerging synthetic-lethal based combination therapies, both in terms of the cancer types that are sensitive to them and re. the specific sensitivity of individual patients within a cancer type. Importantly, these results are obtained without the need for specific training on the datasets predicted and are derived directly from patients data, thus increasing the likelihood of their translational relevance.

Citation Format: Eytan Ruppin. Harnessing genetic interactions to advance whole-exome precision cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY45-02.
Correlation between Vestibular Evoked Myogenic Potentials and Disease Progression in Ménière’s Disease
Authors: Kharkheli Eka , Japaridze S. , Kevanishvili Zuriko , Oz Isilay , Ozluoglu Levent Naci
Published: August 2019

Objective: To assess the relationship between ocular (oVEMPs) and cervical (cVEMPs) vestibular evoked myogenic potentials and audiometrically determined clinical stage in Ménière’s disease (MD). Methods: Thirty-four unilateral MD patients and 30 healthy volunteers were included in the study. Pure-tone hearing levels, oVEMPs, cVEMPs, and videonystagmography results were analyzed and compared between the groups. Results: Both oVEMPs and cVEMPs were highly reproducible in the control group. At the early stages of MD, cVEMPs were particularly disturbed, while at the advanced stages both oVEMPs and cVEMPs were altered pathologically. In the study group, oVEMP and cVEMP amplitudes and interaural amplitude difference (IAD) statistically differed from those in the control sample. oVEMPs were absent in 7.7% of stage III and in 44.5% of stage IV MD patients, while cVEMPs were absent in 15.4% of stage III and in 54.5% of stage IV MD patients, respectively. In stage III and IV MD patients in whom oVEMPs and cVEMPs were obtained, IADs were increased. Caloric asymmetry was found in 64.7% of MD patients. Caloric weakness was more prominent in cases with advanced MD. Conclusion: VEMPs can be used for objective validation of the stage of MD.
Cellular Dynamics during Spinal Cord Regeneration in Larval Zebrafish
Authors: Anguita-Salinas Consuelo , Sánchez Mario , Morales Rodrigo A. , Ceci María Laura , Rojas-Benítez Diego , Allende Miguel L.
Published: August 2019

The study of spinal cord regeneration using diverse animal models, which range from null to robust regenerative capabilities, is imperative for understanding how regeneration evolved and, eventually, to treat spinal cord injury and paralysis in humans. In this study, we used electroablation to fully transect the spinal cord of zebrafish larvae (3 days postfertilization) and examined regeneration of the tissue over time. We used transgenic lines to follow immune cells, oligodendrocytes, and neurons in vivo during the entire regenerative process. We observed that immune cells are recruited to the injury site, oligodendrocytes progenitor cells (olig2-expressing cells) invade, and axons cross the gap generated upon damage from anterior to reinnervate caudal structures. Together with the recovery of cell types and structures, a complete reversal of paralysis was observed in the lesioned larvae indicating functional regeneration. Finally, using transplantation to obtain mosaic larvae with single-labeled neurons, we show that severed spinal axons exhibited varying regenerative capabilities and plasticity depending on their original dorsoventral position in the spinal cord.
Female Power: A New Framework for Understanding “Female Dominance” in Lemurs
Authors: Lewis Rebecca J.
Published: August 2019

Female dominance is often associated with lemurs. However, consensus does not exist among primatologists on how to define, measure, or explain female dominance. This review explores the utility of applying a broader concept of power to understanding lemur intersexual relationships. In this framework, power is defined as arising from an asymmetry in a dyadic relationship and can be divided into 2 types: dominance and leverage. Intersexual asymmetries based upon females having superior fighting ability are considered female dominance. However, economic power also exists, and females with resource-based power exhibit female leverage. Additionally, power has 4 characteristics (base, means, amount, and scope) that describe the precise nature of observed phenomena. This article utilizes the 4 characteristics outlined in the power framework to review the existing “female dominance” literature for lemurs and highlights the value of adopting both an expanded concept of power and a more precise language. By placing the multiple phenomena currently labeled under the single term “female dominance” within the power framework, much of the confusion disappears. Thus, not only is the debate reframed, facilitating endeavors to find evolutionary explanations, but the uniqueness of female power in lemurs can be determined empirically rather than by definition.
Do Patients with Extrinsic Black Tooth Stains Have a Lower Dental Caries Experience? A Systematic Review and Meta-Analysis
Authors: de Rezende Vanessa Silva , Fonseca-Silva Thiago , Drumond Clarissa Lopes , Ramos-Jorge Maria Letícia , Paiva Saul Martins , Vieira-Andrade Raquel Gonçalves
Published: August 2019

Studies have suggested that individuals affected by extrinsic black tooth stains have less dental caries experience in comparison to those without this condition. The aim of the present study was to perform a systematic review and meta-analysis to determine whether there is scientific evidence demonstrating that extrinsic black stains are a protective factor for the occurrence of dental caries. This systematic review was developed in accordance with the PRISMA statement and the research question was determined using the PECO strategy. Electronic searches were conducted in the PubMed, Science Direct, Virtual Health Library, Cochrane, Web of Science, and Google Scholar databases for relevant articles published up to September 2018. All articles included were submitted to an appraisal of methodological quality using the Newcastle-Ottawa Scale and the data were extracted for meta-analysis. The search strategy resulted in the retrieval of 9,108 publications. After the application of the eligibility criteria, 18 articles were selected for analysis, 13 of which were included in the meta-analysis. The meta-analysis demonstrated that individuals with extrinsic black stains involving primary (median, MD: –0.78 [–1.09; –0.48]; I2 = 44%) and permanent (MD: –0.50 [–0.93; –0.08]; I2 = 86%) teeth have a lower dental caries experience in comparison to those without this condition. Patients with extrinsic black tooth stains have a lower dental caries experience in cross-sectional studies.
Thromboelastography-Guided Therapy of Hemorrhagic Complications after Craniopharyngioma Resection: Case-Based Update
Authors: Fulkerson Daniel H. , Weyhenmeyer Jonathan , Archer Jacob B. , Shaikh Kashif A. , Walsh Mark
Published: August 2019

Purpose: Thromboelastography (TEG) is a point-of-care test that evaluates the entire hemostatic process. The use of TEG is expanding in multiple pediatric surgical disciplines. However, there is very little literature regarding its application in pediatric neurosurgical patients. Methods: The authors provide a case-based update and literature review regarding potential applications of TEG to pediatric neurosurgical patients. Results: The authors describe a 12-year-old female who experienced a number of complications after a craniopharyngioma resection. The patient suffered multiple new intraventricular hemorrhages with removal of external ventricular drains. Standard coagulopathy tests did not reveal any abnormalities. However, an abnormal TEG value suggested primary hyperfibrinolysis, which led to a change in medical management. The patient did not suffer any further bleeding episodes after the change in treatment. Conclusions: The authors discuss a case where TEG influenced patient management and identified a problem despite normal values of standard laboratory tests. Neurosurgeons should be aware of the potential benefits for TEG testing in pediatric patients.
Distribution of Neuroendocrine Marker-Positive Cells in Colorectal Cancer Tissue and Normal Mucosal Tissue: Consideration of Histogenesis of Neuroendocrine Cancer
Authors: Ogimi Takashi , Sadahiro Sotaro , Kamei Yutaro , Chan Lin Fung , Miyakita Hiroshi , Saito Gota , Okada Kazutake , Suzuki Toshiyuki , Kajiwara Hiroshi
Published: August 2019

Background: Colorectal neuroendocrine carcinoma (NEC) is a rare disease, and mixed cases with colorectal adenocarcinoma also exist. The histogenesis of this disease remains unclear. We studied the numbers of neuroendocrine marker-positive cells in adenocarcinoma tissue and in normal ­mucosal tissue to investigate the relation between adenocarcinoma and NEC and to discuss the histogenesis of NEC. Methods: We studied a total of 354 curatively resected cases of stage II or III colon cancer and 36 cases of rectal cancer treated at the Tokai University Hospital between 2007 and 2012. Adenocarcinoma tissue and normal mucosal tissue were immunohistochemically stained with chromogranin A, synaptophysin, and CD56. Cases in which neuroendocrine marker-positive cells were found in cancer tissue were defined as positive. In normal mucosa, the numbers of positive cells per 15 high-power fields (HPF) were counted. Results: Among the 390 cases, 181 cases had right sided colon cancer, 173 cases had left sided colon cancer, and 36 cases had rectal cancer. The rates of positive staining for chromogranin A, synaptophysin, and CD56 were significantly higher in the right sided colon than in the left sided colon, consistent with the preferred sites of NEC as reported previously. Cells positive for chromogranin A and synaptophysin in normal mucosa were significantly more common in the rectum and the left sided colon than in the right sided colon. No site-specific differences were found for CD56. Conclusions: Neuroendocrine marker-positive cells in colorectal cancer tissue are more common in the right sided colon, whereas neuroendocrine marker-positive cells in normal mucosa are more common in the rectum. These results suggest that NEC may arise from preceding adenocarcinomas.
Health Data in Dentistry: An Attempt to Master the Digital Challenge
Authors: Joda Tim , Waltimo Tuomas , Probst-Hensch Nicole , Pauli-Magnus Christiane , Zitzmann Nicola U.
Published: August 2019

Background: Biomedical research has recently moved through three stages in digital healthcare: (1) data collection; (2) data sharing; and (3) data analytics. With the explosion of stored health data (HD), dental medicine is edging into its fourth stage of digitization using artificial intelligence (AI). This narrative literature review outlines the challenge of managing HD and anticipating the potential of AI in oral healthcare and dental research by summarizing the current literature. Summary: The basis of successful management of HD is the establishment of a generally accepted data standard that will guide its implementation within electronic health records (EHR) and health information technology ecosystems (HIT Eco). Thereby continuously adapted (self-) learning health systems (LHS) can be created. The HIT Eco of the future will combine (i) the front-end utilization of HD in clinical decision-making by providers using supportive diagnostic tools for patient-centered treatment planning, and (ii) back-end algorithms analyzing the standardized collected data to inform population-based policy decisions about resource allocations and research directions. Cryptographic methods in blockchain enable a safe, more efficient, and effective dental care within a global perspective. Key Message: The interoperability of HD with accessible digital health technologies is the key to deliver value-based dental care and exploit the tremendous potential of AI.
Lenvatinib Long-Term Responses in Refractory Thyroid Cancer: Our Mono-Institutional Real-Life Experience with the Multidisciplinary Approach and Review of Literature
Authors: Denaro Nerina , Latina Adele , Cesario Flora , Bramardi Fabio , Corrado Lauro , Borretta Giorgio , Merlano Marco Carlo
Published: August 2019

Lenvatinib (LEN) is a multikinase inhibitor with antiangiogenic properties recently approved in radioactive iodine-refractory differentiated thyroid cancer, hepatocellular carcinoma, and renal cell carcinoma in combination with everolimus. LEN-treated patients frequently have adverse events (AEs) that generally require such dose modifications, including drug discontinuation. Hypertension, diarrhea, weight loss, proteinuria, fatigue, and palmar-plantar erythrodysesthesia are reported among the most frequent AEs, often leading to discontinuations or dose modifications. This paper reports a case series focusing on the role of the immediate multidisciplinary approach to manage AEs.
The Relationship between Restless Legs Syndrome and Quality of Life in Patients with Myasthenia Gravis
Authors: Ataide Monica F. , da Cunha-Correia Carolina , Petribú Katia C.L.
Published: August 2019

Background: Restless legs syndrome (RLS) is characterized for an uncomfortable sensation in legs and an irresistible desire to move them. This disorder has been more recently recognized in patients with myasthenia gravis (MG) and can interfere with the quality of life (QOL). Objectives: The aims of this study are to describe the prevalence of RLS and its severity and influence on the QOL in patients with MG. Method: This was a cross-sectional study conducted from May to June 2016 in Recife, Brazil. A sample of 42 patients was interviewed using a sociodemographic questionnaire, MG QOL questionnaire-15 and The RLS Rating Scale. Results: RLS was present in 47.6% of patients and of these 40.5% met moderate to severe RLS criteria. Patients were 45 years on average (SD ± 14.4) and women represented 57.1% of the study population. Among patients with RSL, the quality-of-life scores were worse (p = 0.010) on average. There was no association of RLS with the duration of MG, use of immunosuppressant or clinical conditions that could mimic the occurrence of RLS. Conclusion: RLS is a prevalent condition in patients with MG, and may be severe enough to negatively impact QOL.
Defects in the Exocyst-Cilia Machinery Cause Bicuspid Aortic Valve Disease and Aortic Stenosis
Authors: Fulmer Diana , Toomer Katelynn , Guo Lilong , Moore Kelsey , Glover Janiece , Moore Reece , Stairley Rebecca , Lobo Glenn , Zuo Xiaofeng , Dang Yujing , Su Yanhui , Fogelgren Ben , Gerard Patrick , Chung Dongjun , Heydarpour Mahyar , Mukherjee Rupak , Body Simon C. , Norris Russell A. , Lipschutz Joshua H.
Published: August 2019

Background:

Bicuspid aortic valve (BAV) disease is a congenital defect that affects 0.5% to 1.2% of the population and is associated with comorbidities including ascending aortic dilation and calcific aortic valve stenosis. To date, although a few causal genes have been identified, the genetic basis for the vast majority of BAV cases remains unknown, likely pointing to complex genetic heterogeneity underlying this phenotype. Identifying genetic pathways versus individual gene variants may provide an avenue for uncovering additional BAV causes and consequent comorbidities.

Methods:

We performed genome-wide association Discovery and Replication Studies using cohorts of 2131 patients with BAV and 2728 control patients, respectively, which identified primary cilia genes as associated with the BAV phenotype. Genome-wide association study hits were prioritized based on
P
value and validated through in vivo loss of function and rescue experiments, 3-dimensional immunohistochemistry, histology, and morphometric analyses during aortic valve morphogenesis and in aged animals in multiple species. Consequences of these genetic perturbations on cilia-dependent pathways were analyzed by Western and immunohistochemistry analyses, and assessment of aortic valve and cardiac function were determined by echocardiography.

Results:

Genome-wide association study hits revealed an association between BAV and genetic variation in human primary cilia. The most associated single-nucleotide polymorphisms were identified in or near genes that are important in regulating ciliogenesis through the exocyst, a shuttling complex that chaperones cilia cargo to the membrane. Genetic dismantling of the exocyst resulted in impaired ciliogenesis, disrupted ciliogenic signaling and a spectrum of cardiac defects in zebrafish, and aortic valve defects including BAV, valvular stenosis, and valvular calcification in murine models.

Conclusions:

These data support the exocyst as required for normal ciliogenesis during aortic valve morphogenesis and implicate disruption of ciliogenesis and its downstream pathways as contributory to BAV and associated comorbidities in humans.
Cross‐Sectional Study on the Management and Control of Hypertension Among Migrants in Primary Care: What Is the Impact of Segmented Health Insurance Schemes?
Authors: Li Haitao , Zhu Wu , Xia Hui , Wang Xuejun , Mao Chen
Published: August 2019

Background

Information is scarce regarding the impact of fragmented health insurance schemes on the management and control of hypertension among migrants in primary care. This study aimed to investigate the relationship between insurance status and management and control of hypertension among migrants in primary care and to examine whether social capital could facilitate migrants’ participation in local health insurance schemes.

Methods and Results

A site‐based, cross‐sectional, face‐to‐face patient survey was administered in Shenzhen, China. Hypertensive primary care users who were migrants were selected using a systematic sampling design. The participants covered by local health insurance schemes were more likely than those without coverage to be managed by primary care facilities (82.6% versus 62.0%; odds ratio=2.63, 95%
CI
1.41‐4.89) and to take antihypertensive medications (87.9% versus 76.4%; odds ratio=2.38, 95%
CI
1.34‐4.24), and they had higher scores in first contact use (3.49 versus 3.23; β=0.17, 95%
CI
0.05‐0.29) and continuity of care (3.17 versus 3.02; β=0.11, 95%
CI
0.01‐0.21). The participants covered by local insurance schemes had higher scores in perceived generalized trust than their counterparts (4.23 versus 3.95; β=0.16, 95%
CI
0.09‐0.40). The hypertension control rate was also higher among the participants with local health insurance coverage (48.8% versus 42.2%; odds ratio=1.38, 95%
CI
1.02‐2.12).

Conclusions

In conclusion, local health insurance schemes are associated with optimal control of hypertension for migrants compared with social health insurance schemes. Our study implies that one form of social capital, namely perceived general trust, contributes to migrant hypertensive patients’ participation in local health insurance schemes.
The Chilean Moment in the Global Cold War: International Reactions to Salvador Allende's Victory in the Presidential Election of 1970
Authors: Hurtado-Torres Sebastián
Published: August 2019

This article discusses the reactions of governments and political leaders around the world to the victory of Salvador Allende in the Chilean presidential election of 1970—reactions that were shaped by a combination of ideological considerations, the diplomatic interests of particular states in the context of the Cold War, and an image of Chilean democratic exceptionalism purveyed by Chilean diplomats and largely assumed by a surprising number of people abroad. Reactions to Allende's victory in 1970 reflected the ideological divisions in Chilean politics as well as the tensions and anxieties of an international order that was then beginning to experience a series of significant changes as a result of the East-West détente. Paradoxically, Allende's ideological foreign policy, one of the main reasons for which his election was both dreaded and welcomed in different parts of the world, foretold some of the changes that would take place in the international system in the 1970s.
Warsaw Pact Countries’ Involvement in Chile from Frei to Pinochet, 1964–1973
Authors: Yordanov Radoslav A.
Published: August 2019

This article examines the policies of Warsaw Pact countries toward Chile from 1964, when Eduardo Frei was elected Chilean president, until 1973, when Frei's successor, Salvador Allende, was removed in a military coup. The article traces the role of the Soviet Union and East European countries in the ensuing international campaign raised in support of Chile's left wing, most notably in support of the Chilean Communist Party leader Luis Corvalán. The account here adds to the existing historiography of this momentous ten-year period in Chile's history, one marked by two democratic presidential elections, the growing covert intervention of both Washington and Moscow in Chile's politics, mass strikes and popular unrest against Allende's government, a violent military coup, and intense political repression in the coup's aftermath. The article gives particular weight to the role of the East European countries in advancing the interests of the Soviet bloc in South America. By consulting a wide array of declassified documents in East European capitals and in Santiago, this article helps to explain why Soviet and East European leaders attached great importance to Chile and why they ultimately were unable to develop more comprehensive political, economic, and cultural relations with that South American country.
Replies to Commentators
Authors: DeRose Keith
Published: August 2019

Replies are given to comments, questions, and objections to The Appearance of Ignorance. The reply to Robin McKenna focuses mainly on his questions of whether, with the skeptical argument I’m focused on, a strong enough appearance of ignorance is generated to require an account of that appearance, and whether, to the extent that we do need to account for that appearance, we might do so without contextualism by adopting a solution proposed by Ernest Sosa. The reply to Michael Blome-Tillman focuses mainly on a counterexample he offers to my account of the operation of the “Rule of Sensitivity.” The reply to Elke Brendel focuses mainly on objections to contextualism from the phenomena of disagreement and retraction. The reply to Peter Baumann concerns several of his comments about my treatment of the Harman lottery puzzle.
Two Inversion Layers and Their Impacts on PM2.5 Concentration over the Yangtze River Delta, China
Authors: Xu Yiwen , Zhu Bin , Shi Shuangshuang , Huang Yong
Published: August 2019

An integrated winter field campaign was conducted to investigate the atmospheric boundary layer structure and PM2.5 concentration at three sites over the Yangtze River delta (YRD) in China: Shouxian (a rural area), a site in a northern suburb of Nanjing, and Dongshan (a residential area). Two temperature inversion layers and air pollution events occurred simultaneously from 30 to 31 December 2016, local time, over the YRD. It was found that the two inversion layers were related to the presence of a high pressure system, resulting in divergence in the upper boundary layer and radiative cooling near the ground at night. Dominated by agricultural and residential biomass burning, the surface emission sources from the Shouxian rural area were moderately strong. After the formation of the two inversions, the vertical distribution of PM2.5 concentration below the upper inversion layer was uniform as a result of thorough boundary layer mixing in the earlier hours. During nighttime at the Nanjing site, air pollutant plumes from nearby elevated point sources could not easily diffuse downward/upward between the two inversion layers, which led to a distinct peak in the PM2.5 concentration. At the Dongshan site, the emission sources were weak and the nighttime PM2.5 concentration above 100 m was high. The surface PM2.5 concentration gradually increased from early morning to noon, which was attributed to emissions related to the local residents. The results indicated that the vertical distribution of pollutants was affected by a combination of local emissions, vertical boundary layer structure, and horizontal and vertical transports.
Assessing Adaptive Mesh Refinement (AMR) in a Forced Shallow-Water Model with Moisture
Authors: Ferguson Jared O. , Jablonowski Christiane , Johansen Hans
Published: August 2019

Two forced shallow-water flow scenarios are explored in a 2D fourth-order finite-volume dynamical core with adaptive mesh refinement (AMR) to investigate AMR’s ability to track and resolve complex evolving features. Traditional shallow-water test cases are mainly characterized by large-scale smooth flows that do not effectively test the multiscale abilities of variable-resolution and AMR models to resolve sharp gradients and small-scale flow filaments. Therefore, adding forcing mechanisms to the shallow-water system to model key atmospheric processes adds complexity and creates small-scale phenomena. These can serve as foci for dynamic grid refinement while remaining simple enough to study the numerical design of a model’s dynamical core. The first shallow-water flow scenario represents a strengthening, tropical cyclone–like, vortex that is driven by a Betts–Miller-like convection scheme. The second shallow-water test is built upon a barotropically unstable jet with an added Kessler-like warm rain scheme that leads to precipitating frontal zones. The key feature of both tests is that there is significant sensitivity to the model grid while converging (structurally) at high resolution. Both test cases are investigated for a series of uniform resolutions and a variety of AMR tagging criteria. The AMR simulations demonstrate that grid refinement can resolve local features without requiring global high-resolution meshes. However, the results are sensitive to the refinement criteria. Criteria that trigger refinement early in a simulation reproduce the uniform-resolution reference solutions most reliably. In contrast, AMR criteria that delay refinement for several days require careful tuning of the AMR thresholds to improve results compared with uniform-resolution simulations.