tbuckley/cabot-search huggingface dataset:
Prevalence of Oral Human Papillomavirus Infection Among Australian Indigenous Adults
Authors: Lisa M. Jamieson, Annika Antonsson, Gail Garvey, Xiangqun Ju, Megan Smith, Richard M. Logan, Newell W. Johnson, Joanne Hedges, Sneha Sethi, Terry Dunbar, Cathy Leane, Isaac Hill, Alex Brown, David Roder, Marjorie De Souza, Karen Canfell
Journal: JAMA Network Open (2020)

Human papillomavirus (HPV) infection is associated with oropharyngeal squamous cell carcinoma. International estimates suggest overall oral HPV prevalence is 7.5%, with prevalence of oral HPV types 16 and 18 being 1.6%; prior Australian estimates suggest oral HPV prevalence is 2.3%, with HPV-16 and HPV-18 being 1.3%.To estimate the prevalence of oral HPV infection among Indigenous Australians and to report the prevalence of factors associated with high-risk HPV types (ie, HPV-16 and HPV-18) and HPV types linked with Heck disease (ie, HPV-13 and HPV-32).This cross-sectional study analyzed HPV screening results from saliva samples collected from 1011 Indigenous Australians between February 2018 and January 2019. Data were analyzed from May 2018 to May 2019. Recruitment occurred through Aboriginal Community Controlled Health Organisations in South Australia. Eligibility included identifying as Indigenous, residing in South Australia, and being aged 18 years or older.Saliva samples were collected, with microbial DNA for genotyping extracted. Sociodemographic parameters, health-related behaviors, and sexual history data were collected. Analyses were stratified by sex as well as by HPV types 13 and 32 (Heck disease) and 16 and 18 (high risk of oropharyngeal squamous cell carcinoma). Multivariable analyses were conducted to obtain adjusted odds ratios (ORs).Data were obtained for 910 participants (median [interquartile range] age, 37 [27-51] years); 595 participants (65%) were female and 572 (63%) resided in nonmetropolitan locations. In all, 321 saliva samples (35.3%; 95% CI, 32.2%-38.4%) were positive for oral HPV (106 [33.7%] men; 215 [36.1%] women). The highest prevalence was found for HPV types 13 and 32 (207 [22.7%] total; 60 [19.0%] men; 147 [24.7%] women) followed by HPV types 16 and 18 (30 [3.3%] total; 9 [2.9%] men; 21 [3.5%] women). After multivariable analysis, risk factors associated with HPV types 13 and 32 included nonmetropolitan residential status (OR, 2.06; 95% CI, 1.10-3.88) and not having had a tonsillectomy (OR, 2.74; 95% CI, 1.05-7.16). Among women, having obtained a high school education or less was associated with lower odds of HPV-16 and HPV-18 infection (OR, 0.16; 95% CI, 0.03-0.97).Prevalence of oral HPV infection in a large sample of Indigenous Australians was high, with one-third testing positive. The most prevalent HPV types were those associated with Heck disease. The prevalence of HPV types associated with oropharyngeal squamous cell carcinoma exceeded both Australian and international population-level estimates.
Direct-seq: programmed gRNA scaffold for streamlined scRNA-seq in CRISPR screen
Authors: Qingkai Song, Ke Ni, Min Liu, Yini Li, Lixia Wang, Yingying Wang, Yingzheng Liu, Zhenxing Yu, Yinyao Qi, Zhike Lu, Lijia Ma
Journal: Genome biology (2020)

Abstract CRISPR-based genome perturbation provides a new avenue to conveniently change DNA sequences, transcription, and epigenetic modifications in genetic screens. However, it remains challenging to assay the complex molecular readouts after perturbation at high resolution and at scale. By introducing an A/G mixed capture sequence into the gRNA scaffold, we demonstrate that gRNA transcripts could be directly reverse transcribed by poly (dT) primer together with the endogenous mRNA, followed by high-content molecular phenotyping in scRNA-seq (Direct-seq). With this method, the CRISPR perturbation and its transcriptional readouts can be profiled together in a streamlined workflow.
Biologics, spondylitis and COVID-19
Authors: James Todd Rosenbaum, Hedley Hamilton, Dongseok Choi, Michael H Weisman, John D Reveille, Kevin L Winthrop
Journal: Annals of the Rheumatic Diseases (2020)

The COVID-19 pandemic has been especially challenging for patients with rheumatic diseases because immune-mediated diseases as well as their treatment could adversely impact susceptibility to or severity of a viral infection.1 2 A recent study from New York City on 86 patients with COVID-19 infection and a history of immune-mediated disease seemed to show that the use of methotrexate, oral glucocorticoids or hydroxychloroquine increased the risk for hospitalisation,3 although the authors still concluded that the overall risk for hospitalisation is comparable to that described in the community. Since data to advise patients on these issues are scant and inconclusive, the Spondylitis Association of America (SAA) is conducting a survey to gather information from patient experience.

The SAA contacted by email nearly 40 000 individuals who had previous interaction with the SAA. Between 10 April 2020 and 7 May 2020, 2992 patients completed an online survey and reported a history of spondylitis confirmed by a physician. The survey had been approved by the Institutional Review Board of the Oregon Health & Science University. The respondents included 85.0% with ankylosing spondylitis and others with additional forms of spondyloarthroarthritis such as psoriatic spondyloarthritis. Of those patients who knew results of human leukocyte antigen …
Phosphodiesterase 3A and Arterial Hypertension
Authors: Maria Ercu, Lajos Markó, Carolin Schächterle, Dmitry Tsvetkov, Yingqiu Cui, Sara Maghsodi, Theda U.P. Bartolomaeus, Philipp G. Maass, Kerstin Zühlke, Nerine Gregersen, Norbert Hübner, Russell Hodge, Astrid Mühl, Bärbel Pohl, Rosana Molé Illas, Andrea Geelhaar, Stephan Walter, Hanna Napieczynska, Stefanie Schelenz, Martin Taube, Arnd Heuser, Yoland-Marie Anistan, Fatimunnisa Qadri, Mihail Todiras, Ralph Plehm, Elena Popova, Reika Langanki, Jenny Eichhorst, Martin Lehmann, Burkhard Wiesner, Michael Russwurm, Sofia K. Forslund, Ilona Kamer, Dominik N. Müller, Maik Gollasch, Atakan Aydin, Sylvia Bähring, Michael Bader, Friedrich C. Luft, Enno Klussmann
Journal: Circulation (2020)

Background: High blood pressure is the primary risk factor for cardiovascular death worldwide. Autosomal dominant hypertension with brachydactyly clinically resembles salt-resistant essential hypertension and causes death by stroke before 50 years of age. We recently implicated the gene encoding phosphodiesterase 3A ( PDE3A ); however, in vivo modeling of the genetic defect and thus showing an involvement of mutant PDE3A is lacking. Methods: We used genetic mapping, sequencing, transgenic technology, CRISPR-Cas9 gene editing, immunoblotting, and fluorescence resonance energy transfer. We identified new patients, performed extensive animal phenotyping, and explored new signaling pathways. Results: We describe a novel mutation within a 15 base pair (bp) region of the PDE3A gene and define this segment as a mutational hotspot in hypertension with brachydactyly. The mutations cause an increase in enzyme activity. A CRISPR/Cas9-generated rat model, with a 9-bp deletion within the hotspot analogous to a human deletion, recapitulates hypertension with brachydactyly. In mice, mutant transgenic PDE3A overexpression in smooth muscle cells confirmed that mutant PDE3A causes hypertension. The mutant PDE3A enzymes display consistent changes in their phosphorylation and an increased interaction with the 14-3-3θ adaptor protein. This aberrant signaling is associated with an increase in vascular smooth muscle cell proliferation and changes in vessel morphology and function. Conclusions: The mutated PDE3A gene drives mechanisms that increase peripheral vascular resistance causing hypertension. We present 2 new animal models that will serve to elucidate the underlying mechanisms further. Our findings could facilitate the search for new antihypertensive treatments.
Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2
Authors: Elizabeth Whittaker, Alasdair Bamford, Julia Kenny, Myrsini Kaforou, Christine E. Jones, Priyen Shah, Padmanabhan Ramnarayan, Alain Fraisse, Owen Miller, Patrick Davies, Filip Kucera, Joe Brierley, Marilyn McDougall, Michael Carter, Adriana Tremoulet, Chisato Shimizu, Jethro Herberg, Jane C. Burns, Hermione Lyall, Michael Levin
Journal: JAMA (2020)

In communities with high rates of coronavirus disease 2019, reports have emerged of children with an unusual syndrome of fever and inflammation.
Micro RNA expression to predict side effects of preoperative chemoradiotherapy in rectal cancer
Authors: T. Nakao
Journal: Journal of Clinical Oncology (2009)

e22211 Background: Preoperative chemoradiotherapy (CRT) in lower rectal cancer is used to prevent from local recurrence and preserve anus by avoiding to rectal amputation. We have reported 17 micro DNAs and micro RNAs can predict effect of CRT in ASCO-GI 2009. In this study we aimed to predict side effect of CRT such as diarrhea using micro RNA2. present 16 micro RNA to predict side effect of CRT. Methods: Rectal cancer patients (n=22) who underwent preoperative CRT (40Gy radiotherapy combined with S- 1) were studied. S-1 is a novel oral fluoropyrimidine inhibitory for dihydropyrimidine dehydrogenase and has potent radiosensitizing property. RNA harvested from biopsy specimens of rectal cancer before preoperative CRT was hybridized to miRNA microarrays (821 genes). Side effect of CRT was evaluated by NCI-CTC. Groups were classified as side effect group (grade 3 or over) or non side effect group (group 0, 1, 2), respectively. Results: Fifteen patients had well differentiated adenocarcinoma and 7 patients had poorly differentiated adenocarcinoma. Before CRT, 3 patients are stage I, 1 patient is stage IIA, 7 patients are stage IIIB, 8 patients are stage lllC, 3 patients are stage lV in TMN classification. After CRT, 14 patients had PR (RR 63.6%) in RECIST and 15 patient had down staging in TMN classification. Four patients had side effect. One patient had diarrhea and cytopenia, 2 patients had diarrhea, 1 patient had dermatitis. All of them were grade 3. Sixteen miRNAs(micro RNA23a, 27a, 142–3p, 142–5p, 155, 185, 196a, 221, 223, 224, 374a, 374b, 376a, 378, 424, 452) were significantly lower expressed in side effect group than no side effect group. Conclusions: Sixteen micro RNAs were down-regulated in side effect group. Therefore, profile of micro RNA expression may predict the side effect of CRT. No significant financial relationships to disclose.
AB0503 USE OF BIOLOGICAL THERAPY IN A COHORT OF PATIENTS WITH TAKAYASU ARTERITIS IN A THIRD LEVEL HOSPITAL.
Authors: R. J. Gil Velez, E. Rubio Romero, I. Madroñal García
Journal: Annals of the Rheumatic Diseases (2020)

Background: Takayasu arteritis is a granulomatous vasculitis that affects large vassels, specially aorta and its main ramifications. It is a rare disease with an incidence between 0.3 and 1.2 per million inhabitants in Europe. It is more common in women (80%) and it usually occurs before age 40. Objectives: Describe the characteristics and the use of biological therapy in a cohort of patients with Takayasu arteritis in our Hospital. Methods: Retrospective descriptive study of patients diagnosed with Takayasu arteritis treated in the Rheumatology and Internal Medicine service in our hospital during 2019. Data have been obtained by reviewing medical records. Results: 39 patients with takayasu arteritis were included, 33 women (84.4%) and 6 men, withan average age of 48 ±12 years. About treatment, 35 patients received glucocorticoid treatment, of these, 23 patients (65.7%) received treatment with DMARDs. Methotrexato (47.8%) and Ciclophosphamide (43.5%) are the most used. 12.8% (5) of patients received treatment with biological therapy 2 patients received treatment with Rituximab (already retired) and 3 patients maintained the treatment with Tocilizumab. (The characteristics of the patients are in table 1). About the course of disease, 47.8% of patients have achieved clinical remission, 43.6% have a chronic course, and only 3 patients have presented relapse of disease. Conclusion: The results of our study are consistent with what is published in the literature. The average age of presentation is higher than in other series (48 ±12 years), this is because all patients are European and Caucasian. There is still not much experience on biological treatment in patients diagnosed with sarcoidosis, however the use of Rituximab, AntiTNFs and Tocilizumab has been described, presenting a good clinical response and with few adverse effects, as has been observed in our patients. Disclosure of Interests: None declared
Glucosamine-NISV delivers antibody across the blood-brain barrier: Optimization for treatment of encephalitic viruses
Authors: Stuart Woods, Lyn M. O'Brien, Wendy Butcher, Jane E. Preston, Ana R. Georgian, E. Diane Williamson, F. Javier Salguero, Francesca Modino, N. Joan Abbott, Craig W. Roberts, Riccardo V. D'Elia
Journal: Journal of Controlled Release (2020)
Abstract IA26: Multiplexed functional cancer genomics
Authors: Hongchen Cai, Chuan Li, Su Kit Chew, Maryam Yousefi, Giorgia Foggetti, Wen-Yang Lin, Zoë N. Rogers, Ian P. Winters, Christopher D. McFarland, Katherina Politi, Charlie Swanton, Dmitri A. Petrov, Monte M. Winslow
Journal: Cancer Research (2020)

Abstract Extensive cancer genotyping has identified a large number of putative tumor-suppressor genes. However, genome sequencing data alone are insufficient to uncover the importance and role of these genes during carcinogenesis. Moreover, whether tumor suppressors restrict the rate of tumor growth, decrease the probability of incipient tumorigenesis, or limit the emergence of particularly fast-growing clones remains unknown for even the most well-studied tumor suppressors. I will discuss the development and use of multiplexed autochthonous mouse models of human lung adenocarcinoma that integrate tumor barcoding, CRISPR/Cas9-based genome editing, and high-throughput barcode sequencing (Tuba-seq). Using these methods, the impact of large panels of putative tumor suppressor genes can be quantified in parallel. We find that many previously understudied genes have strong effects on multiple aspects of tumor growth in vivo. While some functional tumor-suppressor genes have particularly strong effects only during some but not other phases of tumorigenesis, many genes impacted multiple facets of cancer development. Tuba-seq-based studies across oncogenic contexts and with combinatorial tumor suppressor gene inactivation further highlight the context dependency of gene function during carcinogenesis. These cause-and-effect analyses uncover an unexpectedly complex taxonomy of tumor suppression. We have further employed these multiplexed and quantitative in vivo models to assess the relationship between tumor genotype and therapeutic responses at scale. We coupled Tuba-seq with robust statistical methods to enable the generation of a pharmacogenomic map of lung cancer treatment responses in vivo. We uncover a surprisingly informative map of genotype-specific therapeutic responses, which highlights the importance of tumor-suppressor genotype in driving precision treatment approaches. These blueprints of the multifaceted nature of carcinogenesis have implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches for precision cancer treatment. Citation Format: Hongchen Cai, Chuan Li, Su Kit Chew, Maryam Yousefi, Giorgia Foggetti, Wen-Yang Lin, Zoë N. Rogers, Ian P. Winters, Christopher D. McFarland, Katherina Politi, Charlie Swanton, Dmitri A. Petrov, Monte M. Winslow. Multiplexed functional cancer genomics [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA26.
Evaluation of the Safety and Tolerability of Rapid Infusion of Biosimilar Rituximab Truxima® — the University College London Hospitals (UCLH) Experience
Authors: Raakhee Shah, Simon Cheesman, Kirit M Ardeshna, Kate Cwynarski, David C. Linch, Andres E. Virchis, Jonathan Richard Lambert, Christopher Mcnamara, William Townsend
Journal: Blood (2017)
Clinical impact of COVID-19 on patients with cancer: Data from the COVID-19 and Cancer Consortium (CCC19).
Authors: Jeremy Lyle Warner, Sam Rubinstein, Petros Grivas, Toni K. Choueiri, Nicole Maria Kuderer, Dimpy Shah, Donna R Rivera, Shilpa Gupta, Mehmet Asim Bilen, Thorvardur Ragnar Halfdanarson, Deborah Blythe Doroshow, Firas Wehbe, Sumit Shah, Yu Shyr, Gilberto Lopes, Corrie Painter, Gary H. Lyman, Michael A. Thompson, Solange Peters, Brian I. Rini
Journal: Journal of Clinical Oncology (2020)

LBA110 Background: There are limited data on COVID-19 in patients with cancer. We characterize the outcomes of patients with cancer and COVID-19 and identify potential prognostic factors. Methods: The COVID-19 and Cancer Consortium (CCC19) cohort study includes patients with active or prior hematologic or invasive solid malignancies reported across academic and community sites. Results: We included 1,018 cases accrued March-April 2020. Median age was 66 years (range, 18-90). Breast (20%) and prostate (16%) cancers were most prevalent; 43% of patients were on active anti-cancer treatment. At time of data analysis, 106 patients (10.4%) have died and 26% met the composite outcome of death, severe illness requiring hospitalization, and/or mechanical ventilation. In multivariable logistic regression analysis, independent factors associated with increased 30-day mortality were age, male sex, former smoking, ECOG performance status (2 versus 0/1: partially adjusted odds ratio (pAOR) 2.74, 95% CI 1.31-5.7; 3/4 versus 0/1: pAOR 5.34, 95% CI 2.44-11.69), active malignancy (stable/responding, pAOR 1.93, 95% CI 1.06-3.5; progressing, pAOR 3.79, 95% CI 1.78-8.08), and receipt of azithromycin and hydroxychloroquine. Tumor type, race/ethnicity, obesity, number of comorbidities, recent surgery, and type of active cancer therapy were not significant factors for mortality. Conclusions: All-cause 30-day mortality and severe illness in this cohort were significantly higher than previously reported for the general population and were associated with general risk factors as well as those unique to patients with cancer. Cancer type and treatment were not independently associated with increased 30-day mortality. Longer follow-up is needed to better understand the impact of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments.
The INPP4B Tumor Suppressor Modulates EGFR Trafficking and Promotes Triple-Negative Breast Cancer
Authors: Hui Liu, Marcia N. Paddock, Haibin Wang, Charles J. Murphy, Renee C. Geck, Adrija J. Navarro, Gerburg M. Wulf, Olivier Elemento, Volker Haucke, Lewis C. Cantley, Alex Toker
Journal: Cancer Discovery (2020)

Inactivation of the tumor suppressor lipid phosphatase INPP4B is common in triple-negative breast cancer (TNBC). We generated a genetically engineered TNBC mouse model deficient in INPP4B. We found a dose-dependent increase in tumor incidence in INPP4B homozygous and heterozygous knockout mice compared with wild-type (WT), supporting a role for INPP4B as a tumor suppressor in TNBC. Tumors derived from INPP4B knockout mice are enriched for AKT and MEK gene signatures. Consequently, mice with INPP4B deficiency are more sensitive to PI3K or MEK inhibitors compared with WT mice. Mechanistically, we found that INPP4B deficiency increases PI(3,4)P2 levels in endocytic vesicles but not at the plasma membrane. Moreover, INPP4B loss delays degradation of EGFR and MET, while promoting recycling of receptor tyrosine kinases (RTK), thus enhancing the duration and amplitude of signaling output upon growth factor stimulation. Therefore, INPP4B inactivation in TNBC promotes tumorigenesis by modulating RTK recycling and signaling duration. SIGNIFICANCE: Inactivation of the lipid phosphatase INPP4B is frequent in TNBC. Using a genetically engineered mouse model, we show that INPP4B functions as a tumor suppressor in TNBC. INPP4B regulates RTK trafficking and degradation, such that loss of INPP4B prolongs both PI3K and ERK activation.This article is highlighted in the In This Issue feature, p. 1079.
A Long Noncoding RNA from the HBS1L-MYB Intergenic Region on Chr6q23 Regulates Human Fetal Hemoglobin Expression
Authors: Tasha A. Morrison, Ibifiri Wilcox, Hong-Yuan Luo, John Farrell, Ryo Kurita, Yukio Nakamura, George J Murphy, Shuaiying Cui, Martin H. Steinberg, David H.K. Chui
Journal: Blood (2017)
Abstract A13: <i>ASCL1</i> confers tolerance to tyrosine kinase inhibitors in <i>EGFR</i> mutant lung cancer
Authors: Bomiao Hu, Fernando J. de Miguel, Zongzhi Liu, Lok-Hei Chan, Mary Ann Melnick, Qin Yan, Don Nguyen, Rong Fan, Katerina Politi
Journal: Cancer Research (2020)

Abstract The majority of EGFR mutant lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors (TKIs). However, the majority of these responses are partial, with drug-tolerant residual disease remaining even at the time of maximal response. This residual disease serves as a reservoir for the emergence of acquired resistance and tumor relapse, which inevitably occurs in patients treated with TKIs. It is thus critical to understand the biology of residual tumor cells and find out the mechanisms that underlie drug tolerance. Knowledge of such mechanisms could lead to the identification of potential strategies to forestall the emergence of drug resistance. Studies of residual disease have been hampered by the difficulty of studying these persister cells in patient specimens, and most studies to date have relied on analysis of established cell lines in culture. To investigate the cellular and molecular properties of residual tumor cells in vivo, we leveraged patient-derived models of EGFR mutant lung cancer. Three EGFR mutant PDXs were treated with the 3rd-generation TKI osimertinib. Tumors regressed in all cases, but measurable residual tumor remained in 2 out of the 3 PDXs even after 6 weeks of osimertinib treatment. Whole-exome sequencing (WES) of the untreated PDXs compared to the residual tumors revealed an unchanged mutational landscape between the samples, indicating that genetic mechanisms did not account for drug tolerance. Bulk RNA-sequencing, however, revealed extensive transcriptional changes between the untreated PDX and residual disease. In one of the PDXs, we identified upregulation of neuroendocrine lineage transcription factor ASCL1 in residual disease compared to untreated tumors. Using single-cell RNA-sequencing, we found a pre-existing ASCL1hi tumor cell population in untreated tumors, suggesting that these cells, which possessed drug-tolerant properties, were selected for during drug treatment. Depending on the cell line examined, expression of ASCL1 in human mutant EGFR lung cancer cell lines increased the number of persister clones following osimertinib treatment, indicating that the cellular context contributed to ASCL1’s role in conferring drug tolerance. Our studies provide insights into the role of neuroendocrine factor ASCL1 as a potential driver of drug tolerance in mutant EGFR lung cancer, and ongoing work is focused on identifying the mechanistic underpinnings of these findings. Citation Format: Bomiao Hu, Fernando J. de Miguel, Zongzhi Liu, Lok-Hei Chan, Mary Ann Melnick, Qin Yan, Don Nguyen, Rong Fan, Katerina Politi. ASCL1 confers tolerance to tyrosine kinase inhibitors in EGFR mutant lung cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A13.