tbuckley/cabot-search huggingface dataset:
CUE-101, a Novel E7-pHLA-IL2-Fc Fusion Protein, Enhances Tumor Antigen-Specific T-Cell Activation for the Treatment of HPV16-Driven Malignancies
Authors: Steven N. Quayle, Natasha Girgis, Dharma R. Thapa, Zohra Merazga, Melissa M. Kemp, Alex Histed, Fan Zhao, Miguel Moreta, Paige Ruthardt, Sandrine Hulot, Alyssa Nelson, Lauren D. Kraemer, Dominic R. Beal, Luke Witt, Jessica Ryabin, Jonathan Soriano, Mark Haydock, Emily Spaulding, John F. Ross, Peter A. Kiener, Steven Almo, Rodolfo Chaparro, Ronald Seidel, Anish Suri, Saso Cemerski, Kenneth J. Pienta, Mary Ellen Simcox
Journal: Clinical Cancer Research (2020)

Abstract Purpose: To assess the potential for CUE-101, a novel therapeutic fusion protein, to selectively activate and expand HPV16 E711-20-specific CD8+ T cells as an off-the shelf therapy for the treatment of HPV16-driven tumors, including head and neck squamous cell carcinoma (HNSCC), cervical, and anal cancers. Experimental Design: CUE-101 is an Fc fusion protein composed of a human leukocyte antigen (HLA) complex, an HPV16 E7 peptide epitope, reduced affinity human IL2 molecules, and an effector attenuated human IgG1 Fc domain. Human E7-specific T cells and human peripheral blood mononuclear cells (PBMC) were tested to demonstrate cellular activity and specificity of CUE-101, whereas in vivo activity of CUE-101 was assessed in HLA-A2 transgenic mice. Antitumor efficacy with a murine surrogate (mCUE-101) was tested in the TC-1 syngeneic tumor model. Results: CUE-101 demonstrates selective binding, activation, and expansion of HPV16 E711-20-specific CD8+ T cells from PBMCs relative to nontarget cells. Intravenous administration of CUE-101 induced selective expansion of HPV16 E711-20-specific CD8+ T cells in HLA-A2 (AAD) transgenic mice, and anticancer efficacy and immunologic memory was demonstrated in TC-1 tumor-bearing mice treated with mCUE-101. Combination therapy with anti-PD-1 checkpoint blockade further enhanced the observed efficacy. Conclusions: Consistent with its design, CUE-101 demonstrates selective expansion of an HPV16 E711-20-specific population of cytotoxic CD8+ T cells, a favorable safety profile, and in vitro and in vivo evidence supporting its potential for clinical efficacy in an ongoing phase I trial (NCT03978689).
When things don't add up ‐ methotrexate unexpectedly revealed as the cause of pancytopenia
Authors: Rory Bennett, Anna Ruskova, Clinton Lewis, Imogen Caldwell, Barbara Bain
Journal: American Journal of Hematology (2020)

A 24-year-old woman presented with acute onset of pancytopenia and infectious complications, including Staphylococcus aureus bacteremia. Iatrogenic myelosuppression from lamotrigine, prescribed for bipolar affective disorder, was suspected. Her counts normalized upon cessation of lamotrigine together with filgrastim (G-CSF) therapy. However, she presented again 6 weeks later with a neutropenic fever and mouth ulcers. Blood counts on admission showed agranulocytosis (neutrophils 0.0 × 109/L) with a hemoglobin concentration of 89 g/L and platelet count of 226 × 109/L. There was no improvement following G-CSF. Vitamin B12 (305 pmol/L) and serum folate (>45 nmol/L) values were normal, and tests for autoimmune disease and viral infection were negative. Bone marrow examination revealed striking megaloblastosis with trilineage dysplasia (Images ×100 objective). Neutrophils demonstrated hypergranularity, prominent Döhle bodies and nuclear fragments, as well as macropolycytes and giant metamyelocytes. Erythropoiesis was frankly megaloblastic with prominent nuclear fragments and nuclear dysmorphism. Megakaryocytes were generally small and hypolobated. Cytogenetic analysis showed a normal karyotype. Some of the granulocytic changes were considered consistent with G-CSF therapy, but this did not explain the megaloblastosis. The rapid onset of pancytopenia and spontaneous platelet count recovery were clearly atypical for a myelodysplastic syndrome. Thus, a toxic effect was suspected. Elevated serum methotrexate levels (up to 0.57 mmol/L) were identified on current and retrospective testing of stored samples. Chronic surreptitious methotrexate ingestion was confirmed on direct questioning, the drug having been obtained from a friend's prescribed supply. The patient's care was transferred to psychiatric services upon resolution of neutropenia. This is a case of drug-induced cytopenias with megaloblastosis, morphologically mimicking a myelodysplastic syndrome. It emphasizes the value of bone marrow morphology and recognition of different patterns of dysplasia, as well as the importance of clinicopathologic correlation. None.
An MD Made in America
Authors: Inginia Genao
Journal: Annals of Internal Medicine (2020)

On Being a Doctor21 January 2020An MD Made in AmericaInginia Genao, MDInginia Genao, MDYale University School of Medicine, New Haven, Connecticut (I.G.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M19-1935 Audio Reading - “An MD Made in America” Audio. Virginia Hood, MD, reads “An MD Made in America” by Inginia Genao, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail I come from poverty.It's not easy for me to share this with you, my colleagues. In becoming a physician, I have endured struggles that I have long kept secret because of fear. The fear of being looked down on, the fear of being made to feel less qualified as a physician, and the fear of hearing comments that would reinforce how I have felt too many times: lost, invisible, inferior, and without a sense of belonging. I'm sharing my story to encourage other immigrants not to give up on their dreams, because in this nation most people originate from ... Author, Article, and Disclosure InformationAffiliations: Yale University School of Medicine, New Haven, Connecticut (I.G.)Corresponding Author: Inginia Genao, MD, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06820; e-mail, inginia.[email protected]edu. PreviousarticleNextarticle Advertisement Audio Reading - “An MD Made in America” Audio. Virginia Hood, MD, reads “An MD Made in America” by Inginia Genao, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 21 January 2020Volume 172, Issue 2Page: 157-158KeywordsChildrenComputed axial tomographyFearHealth insuranceHearingHipKneesMeaslesResidencySmell ePublished: 21 January 2020 Issue Published: 21 January 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Transmission of Rat Hepatitis E Virus Infection to Humans in Hong Kong: A Clinical and Epidemiological Analysis
Authors: Siddharth Sridhar, Cyril Chik‐Yan Yip, Shusheng Wu, Nicholas Foo‐Siong Chew, Kit‐Hang Leung, Jasper Fuk‐Woo Chan, Pyrear Suhui Zhao, Wan‐Mui Chan, Rosana Wing‐Shan Poon, Hoi‐Wah Tsoi, Jian‐Piao Cai, Helen Shuk‐Ying Chan, Anthony Wai‐Shing Leung, Cindy Wing‐Sze Tse, Jonpaul Sze‐Tsing Zee, Owen Tak‐Yin Tsang, Vincent Chi‐Chung Cheng, Susanna Kar‐Pui Lau, Patrick Chiu‐Yat Woo, Dominic Ngai‐Chong Tsang, Kwok‐Yung Yuen
Journal: Hepatology (2020)

Hepatitis E virus (HEV) variants causing human infection predominantly belong to HEV species A (HEV-A). HEV species C genotype 1 (HEV-C1) circulates in rats and is highly divergent from HEV-A. It was previously considered unable to infect humans, but the first case of human HEV-C1 infection was recently discovered in Hong Kong. The aim of this study is to further describe the features of this zoonosis in Hong Kong.We conducted a territory-wide prospective screening study for HEV-C1 infection over a 31-month period. Blood samples from 2,860 patients with abnormal liver function (n = 2,201) or immunosuppressive conditions (n = 659) were screened for HEV-C1 RNA. In addition, 186 captured commensal rats were screened for HEV-C1 RNA. Sequences of human-derived and rat-derived HEV-C1 isolates were compared. Epidemiological and clinical features of HEV-C1 infection were analyzed. HEV-C1 RNA was detected in 6/2,201 (0.27%) patients with hepatitis and 1/659 (0.15%) immunocompromised persons. Including the previously reported case, eight HEV-C1 infections were identified, including five in patients who were immunosuppressed. Three patients had acute hepatitis, four had persistent hepatitis, and one had subclinical infection without hepatitis. One patient died of meningoencephalitis, and HEV-C1 was detected in cerebrospinal fluid. HEV-C1 hepatitis was generally milder than HEV-A hepatitis. HEV-C1 RNA was detected in 7/186 (3.76%) rats. One HEV-C1 isolate obtained from a rat captured near the residences of patients was closely related to the major outbreak strain.HEV-C1 is a cause of hepatitis E in humans in Hong Kong. Immunosuppressed individuals are susceptible to persistent HEV-C1 infection and extrahepatic manifestations. Subclinical HEV-C1 infection threatens blood safety. Tests for HEV-C1 are required in clinical laboratories.
An Electroencephalography Connectomic Profile of Posttraumatic Stress Disorder
Authors: Russell T. Toll, Wei Wu, Sharon Naparstek, Yu Zhang, Manjari Narayan, Brian Patenaude, Carlo De Los Angeles, Kasra Sarhadi, Nicole Anicetti, Parker Longwell, Emmanuel Shpigel, Rachael Wright, Jennifer Newman, Bryan Gonzalez, Roland Hart, Silas Mann, Duna Abu-Amara, Kamron Sarhadi, Carena Cornelssen, Charles Marmar, Amit Etkin
Journal: American Journal of Psychiatry (2020)

The authors sought to identify brain regions whose frequency-specific, orthogonalized resting-state EEG power envelope connectivity differs between combat veterans with posttraumatic stress disorder (PTSD) and healthy combat-exposed veterans, and to determine the behavioral correlates of connectomic differences.The authors first conducted a connectivity method validation study in healthy control subjects (N=36). They then conducted a two-site case-control study of veterans with and without PTSD who were deployed to Iraq and/or Afghanistan. Healthy individuals (N=95) and those meeting full or subthreshold criteria for PTSD (N=106) underwent 64-channel resting EEG (eyes open and closed), which was then source-localized and orthogonalized to mitigate effects of volume conduction. Correlation coefficients between band-limited source-space power envelopes of different regions of interest were then calculated and corrected for multiple comparisons. Post hoc correlations of connectomic abnormalities with clinical features and performance on cognitive tasks were conducted to investigate the relevance of the dysconnectivity findings.Seventy-four brain region connections were significantly reduced in PTSD (all in the eyes-open condition and predominantly using the theta carrier frequency). Underconnectivity of the orbital and anterior middle frontal gyri were most prominent. Performance differences in the digit span task mapped onto connectivity between 25 of the 74 brain region pairs, including within-network connections in the dorsal attention, frontoparietal control, and ventral attention networks.Robust PTSD-related abnormalities were evident in theta-band source-space orthogonalized power envelope connectivity, which furthermore related to cognitive deficits in these patients. These findings establish a clinically relevant connectomic profile of PTSD using a tool that facilitates the lower-cost clinical translation of network connectivity research.
Abstract 472: Organizations Unite in “Call-Push-Shock” Movement to Impact Public Understanding That Drives Action
Authors: Mary M Newman, Martha E Lopez-Anderson, Jennifer F Chap, Carissa B Caramanis, Maureen Legg, Margaret Graham
Journal: Circulation (2019)

Introduction: The incidence of OHCA in the U.S. is high (&gt;350,000); the survival rate is low, about 1 in 10. Less than half of victims receive bystander CPR (39%) or treatment with an AED (6%) before EMS arrival. Consumer research indicates the public’s motivation to learn CPR/AED skills and help in emergencies increases with understanding of CA and the impact of bystander action. Two tested messages resonate most with the public: CPR/AED use can double or triple the chance of survival, and CA can happen to a loved one. Hypothesis: An inclusive national movement of organizations using unified, co-branded and tested messaging in a coordinated, multi-channel social media campaign could improve targeted reach and, over time, public understanding of CA and the importance of bystander action. Creating a gold standard for educational content on CA could improve message retention and motivation to act over time. Methods: We created a movement through consistent messaging in a user-friendly toolkit. We built a landing page (CallPushShock.org) and co-sponsored a social media campaign on CA and the importance of bystander action. We launched the campaign during CPR-AED Awareness Week (June 2018). We invited other organizations to join for SCA Awareness Month (Oct 2018), providing co-branded social media assets (Facebook/Twitter posts, videos, infographic) and posting schedules to all partners. Social media analytics were used to measure the reach of the campaign. Results: The campaign launched in June, attracting 20 partners by October. Combined co-sponsor results for June were: News release: 548,464 headline impressions (PR Web); hashtag (#callpushshock) impressions: 243,345 (Keyhole); FB reach: 86,134; Twitter impressions: 25,107; YouTube views: 351; e-news opens: 4,226 (MailChimp, Constant Contact); landing page: 1,291 users (Google). [ Oct 2018 and June 2019 results in development, reflecting extended partner reach.] Conclusion: A social media campaign, leveraging consumer-tested messaging used by multiple organizations in a unified, consistent movement can be effective in improving targeted reach and educational outcomes. A sustained effort is needed to determine campaign impact in improving public understanding of CA and bystander action over time.
Outcomes of rare patients with a primary cutaneous CD30+ lymphoproliferative disorder developing extracutaneous disease
Authors: Rutger C. Melchers, Rein Willemze, Joost S. P. Vermaat, Patty M. Jansen, Laurien A. Daniëls, Hein Putter, Marcel W. Bekkenk, Ellen R. M. de Haas, Barbara Horvath, Michelle M. van Rossum, Cornelus J. G. Sanders, Joep C. J. M. Veraart, Maarten H. Vermeer, Koen D. Quint
Journal: Blood (2020)
Gene Polymorphisms of Costimulatory Molecules: CTLA-4/CD28/ICOS Are Associated with B-Cell Chronic Lymphocytic Leukemia (B-CLL).
Authors: Irena Frydecka, Katarzyna Suwalska, Edyta Pawlak, Lidia Karabon, Anna Tomkiewicz, Tadeusz Dobosz, Donata Urbaniak-Kujda, Kazimierz Kuliczkowski, Dariusz Wolowiec
Journal: Blood (2007)
Directing Traffic: How to Effectively Drive T Cells into Tumors
Authors: Annabelle J. Anandappa, Catherine J. Wu, Patrick A. Ott
Journal: Cancer Discovery (2020)

Although immune checkpoint inhibitors (ICI) have demonstrated clinical activity in multiple tumor types, the majority of patients do not respond to ICI monotherapy. Mounting evidence suggests that ICI-mediated clinical responses rely upon tumor infiltration by T cells that are able to recognize and kill cancer cells. Here, we review therapeutic modalities that have been shown to promote T-cell infiltration into human tumors in studies to date, and discuss emerging data guiding how these modalities can be sequenced in order to optimize T-cell effector function and memory T-cell generation, while minimizing overactivation and potential toxicity. SIGNIFICANCE: The lack of preexisting T-cell inflammation in tumors is a major barrier to effective cancer immunity. A deep understanding of the mechanisms that prevent T cells from trafficking into the tumor in a given individual will be critical for tailoring immunotherapy combinations that can overcome resistance to ICI in patients with cancer.
A17 Inhibition of RUVBL1/2 ATPase Activity Drives Immune Infiltration and Radiosensitizes Non-Small Cell Lung Cancer
Authors: P. Yenerall, A.K. Das, S. Wang, R.K. Kollipara, H. Li, L. Shan Li, P. Villalobos, J. Flaming, K. Huffman, B.C. Timmons, C. Gilbreath, R. Sonavane, J. Rodriguez-Canales, C. Moran, C. Behrens, M. Hirasawa, T. Takata, R. Murakami, K. Iwanaga, G.V. Raj, I.I. Wistuba, J.D. Minna, R. Kittler
Journal: Journal of Thoracic Oncology (2020)
Cumulative Exposure (EXP) to Bevacizumab (BV) Maintenance after Induction Therapy and Survival in Advanced Non-Small Cell Lung Cancer (NSCLC): A Time-Dependent Analysis from the Sail (MO19390) Study
Authors: N. Thatcher, P. Garrido Lopez, N. Pavlakis, J. Laskin, E. Dansin, F. Griesinger, L. Leon, D. Dalal, P. Perez-Moreno, L. Crino
Journal: Annals of Oncology (2012)
Clinical evaluation of modifications to a human papillomavirus assay to optimise its utility for cervical cancer screening in low-resource settings: a diagnostic accuracy study
Authors: Louise Kuhn, Rakiya Saidu, Rosalind Boa, Ana Tergas, Jennifer Moodley, David Persing, Scott Campbell, Wei-Yann Tsai, Thomas C Wright, Lynette Denny
Journal: The Lancet Global Health (2020)

HPV-based screen and treat is the recommended approach for cervical cancer screening in low-resource settings, but quite low specificity of human papillomavirus (HPV) testing, particularly in women living with HIV, leads to overtreatment. We evaluated whether HPV type restriction and more stringent cutoffs on Xpert HPV optimise performance characteristics of this assay for screen and treat.We recruited HIV-negative and HIV-positive women aged 30-65 years from a primary care facility and a referral colposcopy clinic in Cape Town, South Africa. Women included had no history of any anogenital cancer or treatment for cervical dysplasia, had no hysterectomy, and were not pregnancy at the time of recruitment. All women had cervical samples collected for Xpert HPV (an assay that detects high-risk HPV types in five channels: HPV type 16; HPV types 18 or 45, or both; HPV types 31, 33, 35, 52, or 58, or more than one of these types; HPV types 51 or 59, or both; and HPV types 39, 56, 66, or 68, or more than one of these types) and underwent colposcopy and histological sampling with consensus pathology review. Logistic regression and receiver operating characteristic curves were used to evaluate improvements in specificity attained by modifying cycle threshold cutoffs to define screen-positive results.We recruited 1121 women aged 30-65 years, 586 of whom were HIV-negative and 535 HIV-positive. Sensitivity of detecting cervical intraepithelial neoplasia grade 2 or greater in HIV-negative women using manufacturer-defined cycle threshold cutoffs for all channels was 88·7% (95% CI 83·1-94·3), and specificity was 86·9% (83·4-90·4). Sensitivity was 93·6% (90·0-97·3) and specificity 59·9% (54·1-65·7) in HIV-positive women. Cycle threshold values from channels detecting HPV type 16, HPV types 18 or 45 (or both), and HPV types 31, 33, 35, 52, or 58 (or more than one of these types) were informative to predict cervical intraepithelial neoplasia grade 2 or greater. Shifting cycle threshold cutoffs on these three channels allowing sensitivity to decline to 75-85%, led to specificities of 91·3-95·3% in HIV-negative women and 77·0-85·8% in HIV-positive women.More stringent cycle threshold cutoffs on selected channels in Xpert HPV improve specificity with only modest losses in sensitivity, making this assay an optimal choice for HPV-based screen and treat in settings with a high prevalence of HIV. These modifications can be made from standard output with no need for new engineering. Decision making about performance characteristics of HPV testing can be shifted to programme implementers and cutoffs selected according to resource availability and community preferences.Supported by the National Cancer Institute UH2/3 CA189908.
Good News and Bad News — 4CMenB Vaccine for Group B <i>Neisseria meningitidis</i>
Authors: Lee H. Harrison, David S. Stephens
Journal: New England Journal of Medicine (2020)

Neisseria meningitidis remains a major cause of meningitis, sepsis, and other serious infections globally. Almost all meningococcal infections are caused by one of six capsular groups (A, B, C, W, X, and Y) that are distinguished by different biochemical compositions of the polysaccharide capsules. Over the past two decades, the use of meningococcal capsular polysaccharide–protein conjugate vaccines has led to major successes in the prevention of invasive meningococcal disease. For example, the introduction of monovalent meningococcal capsular group A conjugate vaccine in the "African meningitis belt" (from Senegal to Ethiopia) and meningococcal group C conjugate vaccine in the United Kingdom . . .
B04 Activity of Larotrectinib in Tropomyosin Receptor Kinase Fusion Lung Cancer
Authors: A.F. Farago, S. Kummar, V. Moreno, J. Patel, U. Lassen, L. Rosen, B.H. Childs, D.M. Hyman, A. Drilon
Journal: Journal of Thoracic Oncology (2020)
A Prospective Analysis of Circulating Plasma Metabolites Associated with Ovarian Cancer Risk
Authors: Oana A. Zeleznik, A. Heather Eliassen, Peter Kraft, Elizabeth M. Poole, Bernard A. Rosner, Sarah Jeanfavre, Amy A. Deik, Kevin Bullock, Daniel S. Hitchcock, Julian Avila-Pacheco, Clary B. Clish, Shelley S. Tworoger
Journal: Cancer Research (2020)

Ovarian cancer has few known risk factors, hampering identification of high-risk women. We assessed the association of prediagnostic plasma metabolites (N = 420) with risk of epithelial ovarian cancer, including both borderline and invasive tumors. A total of 252 cases and 252 matched controls from the Nurses' Health Studies were included. Multivariable logistic regression was used to estimate ORs and 95% confidence intervals (CI), comparing the 90th-10th percentile in metabolite levels, using the permutation-based Westfall and Young approach to account for testing multiple correlated hypotheses. Weighted gene coexpression network analysis (WGCNA; n = 10 metabolite modules) and metabolite set enrichment analysis (n = 23 metabolite classes) were also evaluated. An increase in pseudouridine levels from the 10th to the 90th percentile was associated with a 2.5-fold increased risk of overall ovarian cancer (OR = 2.56; 95% CI, 1.48-4.45; P = 0.001/adjusted P = 0.15); a similar risk estimate was observed for serous/poorly differentiated tumors (n = 176 cases; comparable OR = 2.38; 95% CI, 1.33-4.32; P = 0.004/adjusted P = 0.55). For nonserous tumors (n = 34 cases), pseudouridine and C36:2 phosphatidylcholine plasmalogen had the strongest statistical associations (OR = 9.84; 95% CI, 2.89-37.82; P < 0.001/adjusted P = 0.07; and OR = 0.11; 95% CI, 0.03-0.35; P < 0.001/adjusted P = 0.06, respectively). Five WGCNA modules and 9 classes were associated with risk overall at FDR ≤ 0.20. Triacylglycerols (TAG) showed heterogeneity by tumor aggressiveness (case-only heterogeneity P < 0.0001). The TAG association with risk overall and serous tumors differed by acyl carbon content and saturation. In summary, this study suggests that pseudouridine may be a novel risk factor for ovarian cancer and that TAGs may also be important, particularly for rapidly fatal tumors, with associations differing by structural features. SIGNIFICANCE: Pseudouridine represents a potential novel risk factor for ovarian cancer and triglycerides may be important particularly in rapidly fatal ovarian tumors.