tbuckley/cabot-search huggingface dataset:
Soundings: Compassionate care
Authors: George Dunea
Journal: BMJ (2005)

An 87 year old woman is brought to the emergency room of a small Chicago hospital. She has had a stroke. She is unresponsive, stops breathing, and is intubated and connected to a ventilator.

Later it turns out that she has not had a stroke at all. She was brought by her daughter from another state and has been demented for seven years. She has no papers, no visa, no insurance. She came to the US 20 years ago as a visitor and stayed on. One of her daughters collects public assistance for her two children. She also had no visa and was to be deported, but the order was vacated on grounds that she had not had adequate legal representation. She then married an American to obtain a green card and soon after that divorced him. The other daughter has a visitor's visa and visits her native country three times a year to maintain her visitor's status.

Six months go by, or more. The little hospital, always teetering on the brink of bankruptcy, has run up a bill of almost $2m (£1.1m; €1.6m). The woman is still on a ventilator. She needs special nursing, frequent turning, skin care, tube feeding. Administrators, lawyers, and ethics committees are deeply involved. The finance officer is tearing his hair out. The daughters want everything done and believe she will recover if given massive doses of antibiotics. They at last agree to have her transferred to a nursing home, but only provided that the hospital pays for her care. An announcement goes out that the woman has left. Many predict that she will be back soon.

She is one of thousands of “undocumented” patients receiving care in America (it is politically incorrect to call them illegal aliens). They come for open heart surgery, chronic dialysis, cancer treatment, hypertension, or diabetes. They come across the long Mexican border, by boat from the Caribbean, as visitors from Africa, Asia, eastern Europe. They are directed, as by a hidden hand, to hospitals that it is known will not refuse them. They sometimes arrive there directly from the airport. They often bring their doctors' reports, x rays. Renal patients come with functioning catheters ready to have dialysis. Others go straight to the cardiac lab. They all receive care. They never leave. They cost taxpayers billions of dollars. Who says that the American healthcare system is not compassionate?
Transcription factors as drivers of distinct pancreatic ductal adenocarcinoma (PDAC) programmes: a role for HNF4A
Authors: Giuseppe Riccardo Diaferia, Gioacchino Natoli
Journal: Gut (2020)

In the last decade, many efforts have been dedicated to study pancreatic ductal adenocarcinoma (PDAC) biology to better understand the molecular bases of the aggressive clinical course and the therapeutic challenges posed by this nearly invariably lethal disease. Genetic and transcriptional studies have revealed an extensive heterogeneity that ultimately resulted in a new clinically applicable molecular taxonomy for PDAC.1 Defining PDAC subgroups with distinct subtype-specific vulnerabilities represents one of the most urgent needs required to implement tumour-targeted therapeutic strategies that may improve disease outcome.

How transcriptional heterogeneity in PDAC is determined or regulated remains unknown to a large extent, and the relative role of intrinsic and microenvironment-derived cues is unclear. At this time, PDACs can be classified into two or more major subtypes among which the ‘classical/pancreatic progenitor’ and ‘basal-like/squamous’ subtypes were validated across different platforms by integrating mutational and transcriptional profiles together with tumour purity estimates.2 These subtypes greatly overlap with histological tumour grading in that the ‘classical’ subtype corresponds to low-grade (namely, well-differentiated) tumour areas and the ‘basal-like’ to high-grade (namely, poorly differentiated) regions with squamoid features. It is important to stress that the extent to which these two differentiation grades coexist in PDACs is still unclear, suggesting that genomic …
Abstract A07: Activating mutations in uveal melanoma convey sensitivity to g-alpha q inhibition
Authors: Tyler D. Hitchman, Emilie Ceraudo, Amanda R. Moore, Alexander N. Shoushtari, Jasmine H. Francis, Youxin Guan, Juliet Chen, Matthew T. Chang, Barry S. Taylor, Thomas P. Sakmar, Thomas Huber, Ping Chi, Yu Chen
Journal: Cancer Research (2020)

Abstract Uveal melanoma (UVM) is the most common intraocular malignancy, which represents about 5% of all melanoma cases per year in the United States. Half of all patients eventually develop metastatic disease, resulting in an average survival rate of six months and a five-year survival rate of ~15%. Recent studies have revealed the underlying genetic landscape of uveal melanoma but have not resulted in any therapeutic options to effectively treat UVM. UVMs harbor mutually exclusive activating mutations in GPCR signaling: ~90% in G-protein alpha q (Gq) subunits GNAQ/GNA11, ~5% in the GPCR CYSLTR2, and ~4% in a downstream effector. These mutations aberrantly activate canonical PLCβ signaling: cleavage of PIP2 into DAG and IP3, both of which lead to PKC activation. In addition to uveal melanoma, recent studies have shown this exact pathway to be activated in a subset of cutaneous and mucosal melanomas as well as other diseases like blue nevi, leptomeningeal melanocytic neoplasms (LMNs), and Sturge-Weber syndrome. My project focuses on understanding how Gq signals in UVM tumorigenesis and if Gq inhibition has therapeutic potential in UVM by addressing the following aims: 1) Using a highly specific Gq inhibitor, I will ask how Gq inhibition effects different activating mutations in UVM using representative in vitro models. I have generated melanocytes dependent on different mutations in the PLCβ pathway to study pathway inhibition and therapeutic efficacy. Based on my preliminary data I will also interrogate the mechanistic basis for Gq inhibition sensitivity in GNAQQ209L driven melanocytes. 2) Determining clinical potential of this drug by testing its pharmacologic properties in vivo. Using the melanocytes I have generated along with UVM cell lines and our GEMM, we will be able to thoroughly test the drug’s efficacy against a variety of xenografts. 3) Taking advantage of the ability to inhibit active Gq, I will aim to identify other pathways activated downstream of Gq using proteomic and transcriptomic approaches. This may provide alternative therapeutic strategies to target this recalcitrant disease. The outcome of this research will indicate the effectiveness of Gq inhibition in UVM as well as elucidate currently unknown signaling pathways essential for UVM tumorigenesis. Citation Format: Tyler D. Hitchman, Emilie Ceraudo, Amanda R. Moore, Alexander N. Shoushtari, Jasmine H. Francis, Youxin Guan, Juliet Chen, Matthew T. Chang, Barry S. Taylor, Thomas P. Sakmar, Thomas Huber, Ping Chi, Yu Chen. Activating mutations in uveal melanoma convey sensitivity to g-alpha q inhibition [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A07.
Crowding and the shape of COVID-19 epidemics
Authors: Benjamin Rader, Samuel V. Scarpino, Anjalika Nande, Alison L. Hill, Ben Adlam, Robert C. Reiner, David M. Pigott, Bernardo Gutierrez, Alexander E. Zarebski, Munik Shrestha, John S. Brownstein, Marcia C. Castro, Christopher Dye, Huaiyu Tian, Oliver G. Pybus, Moritz U. G. Kraemer
Journal: Nature Medicine (2020)
<i>Paenibacillus</i>infection with frequent viral coinfection contributes to postinfectious hydrocephalus in Ugandan infants
Authors: Joseph N. Paulson, Brent L. Williams, Christine Hehnly, Nischay Mishra, Shamim A. Sinnar, Lijun Zhang, Paddy Ssentongo, Edith Mbabazi-Kabachelor, Dona S. S. Wijetunge, Benjamin von Bredow, Ronnie Mulondo, Julius Kiwanuka, Francis Bajunirwe, Joel Bazira, Lisa M. Bebell, Kathy Burgoine, Mara Couto-Rodriguez, Jessica E. Ericson, Tim Erickson, Matthew Ferrari, Melissa Gladstone, Cheng Guo, Murali Haran, Mady Hornig, Albert M. Isaacs, Brian Nsubuga Kaaya, Sheila M. Kangere, Abhaya V. Kulkarni, Elias Kumbakumba, Xiaoxiao Li, David D. Limbrick, Joshua Magombe, Sarah U. Morton, John Mugamba, James Ng, Peter Olupot-Olupot, Justin Onen, Mallory R. Peterson, Farrah Roy, Kathryn Sheldon, Reid Townsend, Andrew D. Weeks, Andrew J. Whalen, John Quackenbush, Peter Ssenyonga, Michael Y. Galperin, Mathieu Almeida, Hannah Atkins, Benjamin C. Warf, W. Ian Lipkin, James R. Broach, Steven J. Schiff
Journal: Science Translational Medicine (2020)

A new strain of the bacterium Paenibacillus contributes to postinfectious hydrocephalus in Ugandan infants.
Norlichexanthone purified from plant endophyte prevents postmenopausal osteoporosis by targeting ER to inhibit RANKL signaling
Authors: Keqi Wang, Yongyan Chen, Shuo Gao, Maosi Wang, Mengmeng Ge, Qian Yang, Mingkai Liao, Lin Xu, Junjie Chen, Zhiping Zeng, Haifeng Chen, Xiao-kun Zhang, Ting Lin, Hu Zhou
Journal: Acta Pharmaceutica Sinica B (2020)

Although different types of drugs are available for postmenopausal osteoporosis, the limitations of the current therapies including drug resistances and adverse effects require identification of novel anti-osteoporosis agents. Here, we defined that norlichexanthone (NOR), a natural product, is a ligand of estrogen receptor-alpha (ERα) and revealed its therapeutic potential for postmenopausal osteoporosis. We used mammalian-one hybrid assay to screen for ERα modulators from crude extracts of several plant endophytes. As a result, NOR purified from the extract of endophyte ARL-13 was identified as a selective ERα modulator. NOR directly bound to ERα with an affinity in nanomolar range, revealing that it is a natural ligand of ERα. NOR induced osteoblast formation in MC3T3-E1 precursor cells. Conversely, NOR inhibited receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast formation in both RAW264.7 macrophages and mouse primary monocytes. Mechanistically, NOR inhibited RANKL-induced association of ERα and TRAF6 to prevent ERα-mediated TRAF6 activation via Lys63-linked ubiquitination. Importantly, NOR exhibited potent anti-osteoporosis efficacy in an ovariectomized mouse model. Comparing to estrogen, NOR was of much less capability in stimulating endometrial hyperplasia and promoting mammalian cancer cell proliferation. Taken together, our study identified NOR as a natural and high affinity ligand of ERα with substantial anti-osteoporosis but less estrogenic activity.
A global review of publicly available datasets for ophthalmological imaging: barriers to access, usability, and generalisability
Authors: Saad M Khan, Xiaoxuan Liu, Siddharth Nath, Edward Korot, Livia Faes, Siegfried K Wagner, Pearse A Keane, Neil J Sebire, Matthew J Burton, Alastair K Denniston
Journal: The Lancet Digital Health (2020)

Health data that are publicly available are valuable resources for digital health research. Several public datasets containing ophthalmological imaging have been frequently used in machine learning research; however, the total number of datasets containing ophthalmological health information and their respective content is unclear. This Review aimed to identify all publicly available ophthalmological imaging datasets, detail their accessibility, describe which diseases and populations are represented, and report on the completeness of the associated metadata. With the use of MEDLINE, Google's search engine, and Google Dataset Search, we identified 94 open access datasets containing 507 724 images and 125 videos from 122 364 patients. Most datasets originated from Asia, North America, and Europe. Disease populations were unevenly represented, with glaucoma, diabetic retinopathy, and age-related macular degeneration disproportionately overrepresented in comparison with other eye diseases. The reporting of basic demographic characteristics such as age, sex, and ethnicity was poor, even at the aggregate level. This Review provides greater visibility for ophthalmological datasets that are publicly available as powerful resources for research. Our paper also exposes an increasing divide in the representation of different population and disease groups in health data repositories. The improved reporting of metadata would enable researchers to access the most appropriate datasets for their needs and maximise the potential of such resources.
Host genetics and tumor environment determine the functional impact of neutrophils in mouse tumor models
Authors: Marit van Elsas, Jan Willem Kleinovink, Matthijs Moerland, Gary Feiss, Guillaume Beyrend, Ramon Arens, Hailiang Mei, Peter H Nibbering, Silvana M Jirka, Thorbald van Hall, Sjoerd H van der Burg
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Neutrophils have been reported to have protumor, antitumor or neutral effects in cancer progression. The underlying causes for this functional variability are not clear. Methods We studied the role of neutrophils in six different mouse tumor models by intratumoral injection of antimicrobial peptides or vaccination. Changes in systemic and intratumoral immune cells were analyzed by flow-cytometry and mass-cytometry. The role of neutrophils was studied by antibody-mediated neutrophil depletion. Neutrophils from different mouse strains were compared by RNA sequencing. Results The antimicrobial peptide Omiganan reduced the growth of TC-1 tumors in BL/6 mice and CT26 tumors in BALB/c mice. No significant effects were observed in B16F10, MC38 and 4T1 tumors. Growth delay was associated with increased abundance of neutrophils in TC-1 but not CT26 tumors. Systemic neutrophil depletion abrogated Omiganan efficacy in TC-1 but further reduced growth of CT26, indicating that neutrophils were required for the antitumor effect in TC-1 but suppressed tumor control in CT26. Neutrophils were also required for a therapeutic vaccine-induced T-cell mediated control of RMA tumors in BL/6 mice. Clearly, the circulating and intratumoral neutrophils differed in the expression of Ly6G and CD62L, between TC-1 and CT26 and between blood neutrophils of tumor-naïve BL/6 and BALB/c mice. RNA-sequencing revealed that neutrophils from BL/6 mice but not BALB/c mice displayed a robust profile of immune activation, matching their opposing roles in TC-1 and RMA versus CT26. Conclusions Neutrophil functionality differs strongly between mouse strains and tumor types, with consequences for tumor progression and therapy.
Abstract IA14: Immunosensitivity and resistance in advanced uveal melanoma
Authors: Richard D. Carvajal
Journal: Cancer Research (2020)

Abstract Despite the ability to effectively achieve control of uveal melanoma at the site of origin, patient outcomes have remained suboptimal due to the ultimate development of recurrent distant disease in a significant proportion of those diagnosed, together with the limited efficacy of currently available therapies in this setting. Initial insights into the tumorigenic effects of the functionally activating, mutually exclusive, early event mutations in GNAQ, GNA11, PLCB4, and CYSLTR2 led to the development of a generation of trials evaluating the effects of inhibition of single or multiple downstream pathways including the MAPK and PI3K pathways. Given the dramatic efficacy of targeted therapy in cutaneous melanoma harboring a BRAF mutation, there was initial hope that a similar strategy might demonstrate comparable effects in uveal melanoma. Unfortunately, the completed and reported clinical trials targeting these pathways have demonstrated minimal, if any, efficacy. Likewise, despite the initial enthusiasm for immunologic checkpoint blockade for the treatment of metastatic uveal melanoma given the durable antitumor responses and cures achieved in cutaneous melanoma, the activity observed thus far has been limited. Nevertheless, with the critical and clinically significant advances made over that past 10 years in precision oncology and immuno-oncology, coupled with rapidly developing advances in our understanding of the biology of uveal melanoma, there is now a new cause for hope for our patients. Trials evaluating the inhibition of alternative nodes in activated pathways alone or in preclinically synergistic combinations are ongoing, new epigenetic strategies are being explored, and preliminary promising data from novel immunologic treatment strategies including adoptive cellular therapy and T-cell redirection all provide new optimism that these innovative treatment options may meaningfully impact the course of the disease. Citation Format: Richard D. Carvajal. Immunosensitivity and resistance in advanced uveal melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA14.
Allele‐Specific Quantification of HLA–DRB1 Transcripts Reveals Imbalanced Allelic Expression That Modifies the Amino Acid Effects in HLA–DRβ1
Authors: Sehwan Chun, So‐Young Bang, Eunji Ha, Jing Cui, Ki‐Nam Gu, Hye‐Soon Lee, Kwangwoo Kim, Sang‐Cheol Bae
Journal: Arthritis & Rheumatology (2020)

Objective HLA association fine‐mapping studies have shown the effects of missense variants in HLA–DRB1 on rheumatoid arthritis (RA) susceptibility, prognosis, and autoantibody production. However, the phenotypic effects of expression changes in HLA–DRB1 remain poorly understood. Therefore, we investigated the allele‐specific expression of HLA–DRB1 and its effect on an HLA–DRβ1 structure–associated trait in RA. Methods We quantified the allele‐specific expression of each HLA–DRB1 3‐field classic allele in 48 Korean RA patients with anti–citrullinated protein antibodies (ACPAs) and 319 healthy European subjects by using both RNA sequencing and HLA–DRB1 genotype data to calculate the relative expression strength of multiple HLA–DRB1 alleles (n = 14 in Koreans and n = 25 in Europeans) in each population. The known association between ACPA level and alanine at position 74 of HLA–DRβ1 in ACPA‐positive RA was revisited to understand the phenotypic effect of allele‐specific expression of HLA–DRB1 by modeling multivariate logistic regression with the genomic dosage or relative expression dosage of Ala‐74 in 2 independent sets of 1,723 Korean RA patients with ACPA. Results The relative expression strength was highly allele‐specific, causing imbalanced allelic expression in HLA–DRB1 heterozygotes. The association between HLA‐DRβ1 Ala‐74 and ACPA level in RA was better explained by relative expression dosage of Ala‐74 than by the genomic dosage (change in Akaike's information criterion = −6.98). Moreover, the expression variance of Ala‐74 in Ala‐74 heterozygotes with no genomic variance of Ala‐74 was significantly associated with ACPA level ( P = 2.26 × 10 −3 ). Conclusion Our findings illustrate the advantage of integrating quantitative and qualitative changes in HLA–DRB1 into a single model for understanding HLA–DRB1 associations.
Endoscopic removal of migrated esophageal stent: the “cap-assisted” method
Authors: Xubiao Nie, Chaoqiang Fan, Shiming Yang, Jianying Bai
Journal: Endoscopy (2020)

A 65-year-old man presented with symptoms of dysphagia, abdominal pain, and retrosternal pain, and was eventually diagnosed with metastatic adenocarcinoma of the cardia. The patient was treated with palliative chemotherapy and esophageal stenting to relieve symptoms. Abdominal pain and dysphagia reappeared after only 3 months and he returned to the local hospital. Painless endoscopy disclosed that the stent had migrated and was located along the great curvature of the gastric body ([Fig. 1 a]). Repeated attempts to remove the stent failed. The patient then came to our hospital for treatment. Endoscopy revealed mild stenosis in the middle and lower esophagus caused by a tumor ([Fig. 1 b]), and the standard gastroscope (9.8 mm) encountered slight resistance through the narrow section. Under direct view of the endoscope, we grasped the fixing wire of the stent with a rat-tooth forceps and pulled it back it until the proximal end of the stent was fully retracted into the transparent cap (Olympus MH-463) to reduce the size of the stent and prevent its proximal end from damaging the esophageal mucosa during the removal process ([Fig. 1 c, d]). Afterwards, the stent was gently removed through the esophageal stricture, the upper esophageal sphincter, and the throat ([Video 1]). The whole procedure was completed in fewer than 6 minutes. Repeat endoscopy revealed mild bleeding from the surface of the tumor but no lesions elsewhere ([Fig. 1 e]).
Neuregulin-1 Induces Cardiac Hypertrophy and Impairs Cardiac Performance in Post–Myocardial Infarction Rats
Authors: Magdalena Zurek, Edvin Johansson, Malin Palmer, Tamsin Albery, Karin Johansson, Katarina Rydén-Markinhutha, Qing-Dong Wang
Journal: Circulation (2020)
Ammonia-Induced Brain Oedema and Immune Dysfunction is Mediated by Toll-Like Receptor 9 (TLR9)
Authors: G.M. Vijay, C. Hu, J. Peng, I.G. Martinez, R. Hoque, X. Zhang, Y. Ma, W. Mehal, D. Shawcross, L. Wen
Journal: Journal of Hepatology (2016)
Criterion validity of ultrasound in the identification of calcium pyrophosphate crystal deposits at the knee: an OMERACT ultrasound study
Authors: Georgios Filippou, Anna Scanu, Antonella Adinolfi, Carmela Toscano, Dario Gambera, Raquel Largo, Esperanza Naredo, Emilio Calvo, Gabriel Herrero-Beaumont, Pascal Zufferey, Christel Madelaine Bonjour, Daryl K MacCarter, Stanley Makman, Zachary Weber, Fabiana Figus, Ingrid Möller, Marwin Gutierrez, Carlos Pineda, Denise Clavijo Cornejo, Hector Garcia, Victor Ilizaliturri, Jaime Mendoza Torres, Raul Pichardo, Luis Carlos Rodriguez Delgado, Emilio Filippucci, Edoardo Cipolletta, Teodora Serban, Catalin Cirstoiu, Florentin Ananu Vreju, Dan Grecu, Gaël Mouterde, Marcello Govoni, Leonardo Punzi, Nemanja S Damjanov, Helen Isobel Keen, George AW Bruyn, Lene Terslev, Maria-Antonietta D'Agostino, Carlo Alberto Scirè, Annamaria Iagnocco
Journal: Annals of the Rheumatic Diseases (2020)

Objective To evaluate the discriminatory ability of ultrasound in calcium pyrophosphate deposition disease (CPPD), using microscopic analysis of menisci and knee hyaline cartilage (HC) as reference standard. Methods Consecutive patients scheduled for knee replacement surgery, due to osteoarthritis (OA), were enrolled. Each patient underwent ultrasound examination of the menisci and HC of the knee, scoring each site for presence/absence of CPPD. Ultrasound signs of inflammation (effusion, synovial proliferation and power Doppler) were assessed semiquantitatively (0–3). The menisci and condyles, retrieved during surgery, were examined microscopically by optical light microscopy and by compensated polarised microscopy. CPPs were scored as present/absent in six different samples from the surface and from the internal part of menisci and cartilage. Ultrasound and microscopic analysis were performed by different operators, blinded to each other’s findings. Results 11 researchers from seven countries participated in the study. Of 101 enrolled patients, 68 were included in the analysis. In 38 patients, the surgical specimens were insufficient. The overall diagnostic accuracy of ultrasound for CPPD was of 75%—sensitivity of 91% (range 71%–87% in single sites) and specificity of 59% (range 68%–92%). The best sensitivity and specificity were obtained by assessing in combination by ultrasound the medial meniscus and the medial condyle HC (88% and 76%, respectively). No differences were found between patients with and without CPPD regarding ultrasound signs of inflammation. Conclusion Ultrasound demonstrated to be an accurate tool for discriminating CPPD. No differences were found between patents with OA alone and CPPD plus OA regarding inflammation.
Distinct patterns of apoptosis and its relationship with CD44 expression induced by thrombopoietin and granulocyte-colony stimulating factor during ex vivo expansion of human cord blood CD34+ cells.
Authors: JY Seoh, Sy Woo, YJ Kim, HY Park, S Lee, ES Yoo, Jy Ahn, KH Rhu, SN Lee, WS Chung, C Seong
Journal: Blood (2019)