Defects in the Fanconi Anemia Pathway in Head and Neck Cancer Cells Stimulate Tumor Cell Invasion through DNA-PK and Rac1 Signaling

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) remains a devastating disease, and Fanconi anemia (FA) gene mutations and transcriptional repression are common. Invasive tumor behavior is associated with poor outcome, but relevant pathways triggering invasion are poorly understood. There is a significant need to improve our understanding of genetic pathways and molecular mechanisms driving advanced tumor phenotypes, to develop tailored therapies. Here we sought to investigate the phenotypic and molecular consequences of FA pathway loss in HNSCC cells. EXPERIMENTAL DESIGN: Using sporadic HNSCC cell lines with and without FA gene knockdown, we sought to characterize the phenotypic and molecular consequences of FA deficiency. FA pathway inactivation was confirmed by the detection of classic hallmarks of FA following exposure to DNA cross-linkers. Cells were subjected to RNA sequencing with qRT-PCR validation, followed by cellular adhesion and invasion assays in the presence and absence of DNA-dependent protein kinase (DNA-PK) and Rac1 inhibitors. RESULTS: We demonstrate that FA loss in HNSCC cells leads to cytoskeletal reorganization and invasive tumor cell behavior in the absence of proliferative gains. We further demonstrate that cellular invasion following FA loss is mediated, at least in part, through NHEJ-associated DNA-PK and downstream Rac1 GTPase activity. CONCLUSIONS: These findings demonstrate that FA loss stimulates HNSCC cell motility and invasion, and implicate a targetable DNA-PK/Rac1 signaling axis in advanced tumor phenotypes

City wilderness: The pastoral topographies of literary Marxism in the United States, 1893-1950

City Wilderness: The Pastoral Topographies of Literary Marxism in the United States proposes a new assessment of the history and contemporary relevance of literary radicalism in the U.S. Contesting the critical assumptions underlying both the exclusion and the recent recovery of the radical literary heritage of the U.S., the project elucidates the literary Left\u27s unexpectedly deep affinity for a pastoral mode of expression, one which builds the radical\u27s vision of capitalist oppression and the exigency of social change around a distinctive topos that has never been adequately explored: the city wilderness as a metaphor for the proletarian slum. After sketching a political and literary-historical rationale for critical attention to the Left\u27s emphasis on topographical metaphor as a current resource for Left/Green politics, the author sketches an expanded range of cultural and historical contexts for radical literatures. Rereading a variety of texts within this matrix in later chapters (including texts by Jack London, Upton Sinclair, Mike Gold, William Attaway, Agnes Smedley, Jack Conroy, Robert Cantwell, Granville Hicks, and Mary McCarthy), the author contests the entrenched view of many radical novels as aesthetically disfigured by their radical agendas, arguing that critical attention to the scenic metaphors in many radical texts can yield a more positive and incisive assessment of their literary structure and political connotations. City Wilderness demonstrates that a critical approach sensitive to the topographical dimension of radical texts can contribute to a broader reassessment of the political and literary contributions and relevance of U.S. literary Marxism in the twentieth-century, and the project should be understood as a study of the historical, rhetorical resources for Left/Green politics in our own time

Measuring Ambulatory Racial and Ethnic Neurologic Disparities With the Axon Registry

BACKGROUND AND OBJECTIVES: The primary objective is to examine potential racial and ethnic (R/E) disparities in ambulatory neurology quality measures within the American Academy of Neurology Axon Registry. R/E disparities in neurologic US morbidity and mortality have been clearly documented. Despite these findings, there have been no nationwide examinations of how ambulatory neurologic care affects these negative health outcomes. METHODS: This was a retrospective nonrandomized cohort study of patients in the AAN Axon Registry. The Axon Registry is a neurology-specific outpatient quality registry that collects, reports, and analyzes real-world deidentified electronic health record (EHR) data. Patients were included in the study if they contributed toward one of the selected quality measures for multiple sclerosis, epilepsy, Parkinson disease, or headache during the study period of January 1, 2019-December 31, 2019. Descriptive analyses of patient demographics were performed and then stratified by race and ethnicity. RESULTS: There were a total of 633,672 patients included in these analyses. Separate analyses were performed for race (64% White, 8% Black, 1% Asian, and 27% unknown) and ethnicity (52% not Hispanic, 5% Hispanic, and 43% unknown). The mean age ranged from 18 to 55 years, with 61% female and 39% male. Quality measures were chosen based on completeness of R/E data and were either process or outcomes focused. Statistically significant differences were noted after controlling for multiple comparisons. DISCUSSION: The large proportion of missing or unknown R/E data and low overall rate of performance on these quality measures made the relevance of small differences difficult to determine. This analysis demonstrates the feasibility of using the Axon Registry to assess neurologic disparities in outpatient care. More education and training are required on the accurate capture of R/E data in the EHR

Measuring Ambulatory Racial and Ethnic Neurologic Disparities With the Axon Registry.

BACKGROUND AND OBJECTIVES: The primary objective is to examine potential racial and ethnic (R/E) disparities in ambulatory neurology quality measures within the American Academy of Neurology Axon Registry. R/E disparities in neurologic US morbidity and mortality have been clearly documented. Despite these findings, there have been no nationwide examinations of how ambulatory neurologic care affects these negative health outcomes. METHODS: This was a retrospective nonrandomized cohort study of patients in the AAN Axon Registry. The Axon Registry is a neurology-specific outpatient quality registry that collects, reports, and analyzes real-world deidentified electronic health record (EHR) data. Patients were included in the study if they contributed toward one of the selected quality measures for multiple sclerosis, epilepsy, Parkinson disease, or headache during the study period of January 1, 2019-December 31, 2019. Descriptive analyses of patient demographics were performed and then stratified by race and ethnicity. RESULTS: There were a total of 633,672 patients included in these analyses. Separate analyses were performed for race (64% White, 8% Black, 1% Asian, and 27% unknown) and ethnicity (52% not Hispanic, 5% Hispanic, and 43% unknown). The mean age ranged from 18 to 55 years, with 61% female and 39% male. Quality measures were chosen based on completeness of R/E data and were either process or outcomes focused. Statistically significant differences were noted after controlling for multiple comparisons. DISCUSSION: The large proportion of missing or unknown R/E data and low overall rate of performance on these quality measures made the relevance of small differences difficult to determine. This analysis demonstrates the feasibility of using the Axon Registry to assess neurologic disparities in outpatient care. More education and training are required on the accurate capture of R/E data in the EHR

Measuring Ambulatory Neurologic Health Disparities with the Axon Registry (P18-13.008)

Abstract onl

Measuring Ambulatory Racial and Ethnic Neurologic Disparities With the Axon Registry

The primary objective is to examine potential racial and ethnic (R/E) disparities in ambulatory neurology quality measures within the American Academy of Neurology Axon Registry. R/E disparities in neurologic US morbidity and mortality have been clearly documented. Despite these findings, there have been no nationwide examinations of how ambulatory neurologic care affects these negative health outcomes. This was a retrospective nonrandomized cohort study of patients in the AAN Axon Registry. The Axon Registry is a neurology-specific outpatient quality registry that collects, reports, and analyzes real-world deidentified electronic health record (EHR) data. Patients were included in the study if they contributed toward one of the selected quality measures for multiple sclerosis, epilepsy, Parkinson disease, or headache during the study period of January 1, 2019-December 31, 2019. Descriptive analyses of patient demographics were performed and then stratified by race and ethnicity. There were a total of 633,672 patients included in these analyses. Separate analyses were performed for race (64% White, 8% Black, 1% Asian, and 27% unknown) and ethnicity (52% not Hispanic, 5% Hispanic, and 43% unknown). The mean age ranged from 18 to 55 years, with 61% female and 39% male. Quality measures were chosen based on completeness of R/E data and were either process or outcomes focused. Statistically significant differences were noted after controlling for multiple comparisons. The large proportion of missing or unknown R/E data and low overall rate of performance on these quality measures made the relevance of small differences difficult to determine. This analysis demonstrates the feasibility of using the Axon Registry to assess neurologic disparities in outpatient care. More education and training are required on the accurate capture of R/E data in the EHR

Genomic analysis of two phlebotomine sand fly vectors of Leishmania from the New and Old World

Phlebotomine sand flies are of global significance as important vectors of human disease, transmitting bacterial, viral, and protozoan pathogens, including the kinetoplastid parasites of the genus Leishmania, the causative agents of devastating diseases collectively termed leishmaniasis. More than 40 pathogenic Leishmania species are transmitted to humans by approximately 35 sand fly species in 98 countries with hundreds of millions of people at risk around the world. No approved efficacious vaccine exists for leishmaniasis and available therapeutic drugs are either toxic and/or expensive, or the parasites are becoming resistant to the more recently developed drugs. Therefore, sand fly and/or reservoir control are currently the most effective strategies to break transmission. To better understand the biology of sand flies, including the mechanisms involved in their vectorial capacity, insecticide resistance, and population structures we sequenced the genomes of two geographically widespread and important sand fly vector species: Phlebotomus papatasi, a vector of Leishmania parasites that cause cutaneous leishmaniasis, (distributed in Europe, the Middle East and North Africa) and Lutzomyia longipalpis, a vector of Leishmania parasites that cause visceral leishmaniasis (distributed across Central and South America). We categorized and curated genes involved in processes important to their roles as disease vectors, including chemosensation, blood feeding, circadian rhythm, immunity, and detoxification, as well as mobile genetic elements. We also defined gene orthology and observed micro-synteny among the genomes. Finally, we present the genetic diversity and population structure of these species in their respective geographical areas. These genomes will be a foundation on which to base future efforts to prevent vector-borne transmission of Leishmania parasites. The leishmaniases are a group of neglected tropical diseases caused by protist parasites from the Genus Leishmania. Different Leishmania species present a wide clinical profile, ranging from mild, often self-resolving cutaneous lesions that can lead to protective immunity, to severe metastatic mucosal disease, to visceral disease that is ultimately fatal. Leishmania parasites are transmitted by the bites of sand flies, and as no approved human vaccine exists, available drugs are toxic and/or expensive and parasite resistance to them is emerging, new dual control strategies to combat these diseases must be developed, combining interventions on human infections and integrated sand fly population management. Effective vector control requires a comprehensive understanding of the biology of sand flies. To this end, we sequenced and annotated the genomes of two sand fly species that are important leishmaniasis vectors from the Old and New Worlds. These genomes allow us to better understand, at the genetic level, processes important in the vector biology of these species, such as finding hosts, blood-feeding, immunity, and detoxification. These genomic resources highlight the driving forces of evolution of two major Leishmania vectors and provide foundations for future research on how to better prevent leishmaniasis by control of the sand fly vectors