tbuckley/cabot-search huggingface dataset:
Chromatin Accessibility Identifies Regulatory Elements Predictive of Gene Expression and Disease Outcome in Multiple Myeloma
Authors: Benjamin G. Barwick, Vikas A. Gupta, Shannon M. Matulis, Jonathan C. Patton, Doris R. Powell, Yanyan Gu, David L. Jaye, Karen N. Conneely, Yin C. Lin, Craig C. Hofmeister, Ajay K. Nooka, Jonathan J. Keats, Sagar Lonial, Paula M. Vertino, Lawrence H. Boise
Journal: Clinical Cancer Research (2021)

Multiple myeloma is a malignancy of plasma cells. Extensive genetic and transcriptional characterization of myeloma has identified subtypes with prognostic and therapeutic implications. In contrast, relatively little is known about the myeloma epigenome.CD138+CD38+ myeloma cells were isolated from fresh bone marrow aspirate or the same aspirate after freezing for 1-6 months. Gene expression and chromatin accessibility were compared between fresh and frozen samples by RNA sequencing (RNA-seq) and assay for transpose accessible chromatin sequencing (ATAC-seq). Chromatin accessible regions were used to identify regulatory RNA expression in more than 700 samples from newly diagnosed patients in the Multiple Myeloma Research Foundation CoMMpass trial (NCT01454297).Gene expression and chromatin accessibility of cryopreserved myeloma recapitulated that of freshly isolated samples. ATAC-seq performed on a series of biobanked specimens identified thousands of chromatin accessible regions with hundreds being highly coordinated with gene expression. More than 4,700 of these chromatin accessible regions were transcribed in newly diagnosed myelomas from the CoMMpass trial. Regulatory element activity alone recapitulated myeloma gene expression subtypes, and in particular myeloma subtypes with immunoglobulin heavy chain translocations were defined by transcription of distal regulatory elements. Moreover, enhancer activity predicted oncogene expression implicating gene regulatory mechanisms in aggressive myeloma.These data demonstrate the feasibility of using biobanked specimens for retrospective studies of the myeloma epigenome and illustrate the unique enhancer landscapes of myeloma subtypes that are coupled to gene expression and disease progression.
P21.07 Immune-Related Adverse Events with Durvalumab Consolidation in a Real-World Cohort of Patients with Non–Small Cell Lung Cancer (NSCLC)
Authors: G. Bravo Montenegro, M. Serzan, A. Belouali, P. Sackstein, K. Chen, S. Rao, I. Veytsman, S. Madhavan, S. Liu, C. Kim
Journal: Journal of Thoracic Oncology (2021)
Antibody Responses after a Single Dose of SARS-CoV-2 mRNA Vaccine
Authors: Todd Bradley, Elin Grundberg, Rangaraj Selvarangan, Cas LeMaster, Elizabeth Fraley, Dithi Banerjee, Bradley Belden, Daniel Louiselle, Nick Nolte, Rebecca Biswell, Tomi Pastinen, Angela Myers, Jennifer Schuster
Journal: New England Journal of Medicine (2021)

Antibody Responses after a Single Dose of SARS-CoV-2 mRNA VaccineTo the Editor: Currently, two vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that involve messenger RNA (mRNA) platform technology have been approved for emergency use by the Food and Drug Administration (FDA) (mRNA-1273, Moderna; and BNT162b2, Pfizer). 1,2Phase 3 trials of these vaccines showed greater than 90% efficacy at preventing symptomatic infection after two doses administered 3 to 4 weeks apart.These trials primarily involved participants without previous SARS-CoV-2 infection.More than 26 million cases of coronavirus disease 2019 (Covid-19) have been documented in the United States, and high rates of seropositivity have been observed in recent studies. 3Thus, the immune response to vaccination in persons with previous SARS-CoV-2 infection needs to be defined.In this study, we determined antibody levels at baseline and 3 weeks after the first dose of the BNT162b2 SARS-CoV-2 mRNA vaccine in 36 health care workers who received laboratory confirmation of SARS-CoV-2 infection 30 to 60 days before they received the vaccine and 152 health care workers without a history of SARS-CoV-2 infection (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).The biospecimens from vaccine recipients were obtained in the context of a clinical study at Children's Mercy Kansas City, and their use was reviewed and approved by the Children's Mercy institutional review board.The requirement for written informed consent was waived, given that participants self-enrolled after they had reviewed a study information letter and were given the opportunity to ask questions.Using a multiplex bead-binding assay (Milliplex
Endoscopic management of ampullary tumors: European Society of Gastrointestinal Endoscopy (ESGE) Guideline
Authors: Geoffroy Vanbiervliet, Marin Strijker, Marianna Arvanitakis, Arthur Aelvoet, Urban Arnelo, Torsten Beyna, Olivier Busch, Pierre H. Deprez, Lumir Kunovsky, Alberto Larghi, Gianpiero Manes, Alan Moss, Bertrand Napoleon, Manu Nayar, Enrique Pérez-Cuadrado-Robles, Stefan Seewald, Marc Barthet, Jeanin E. van Hooft
Journal: Endoscopy (2021)

Main Recommendations 1 ESGE recommends against diagnostic/therapeutic papillectomy when adenoma is not proven. Strong recommendation, low quality evidence. 2 ESGE recommends endoscopic ultrasound and abdominal magnetic resonance cholangiopancreatography (MRCP) for staging of ampullary tumors. Strong recommendation, low quality evidence. 3 ESGE recommends endoscopic papillectomy in patients with ampullary adenoma without intraductal extension, because of good results regarding outcome (technical and clinical success, morbidity, and recurrence).Strong recommendation, moderate quality evidence. 4 ESGE recommends en bloc resection of ampullary adenomas up to 20–30 mm in diameter to achieve R0 resection, for optimizing the complete resection rate, providing optimal histopathology, and reduction of the recurrence rate after endoscopic papillectomy. Strong recommendation, low quality evidence. 5 ESGE suggests considering surgical treatment of ampullary adenomas when endoscopic resection is not feasible for technical reasons (e. g. diverticulum, size &gt; 4 cm), and in the case of intraductal involvement (of &gt; 20 mm). Surveillance thereafter is still mandatory. Weak recommendation, low quality evidence. 6 ESGE recommends direct snare resection without submucosal injection for endoscopic papillectomy.Strong recommendation, moderate quality evidence. 7 ESGE recommends prophylactic pancreatic duct stenting to reduce the risk of pancreatitis after endoscopic papillectomy. Strong recommendation, moderate quality evidence. 8 ESGE recommends long-term monitoring of patients after endoscopic papillectomy or surgical ampullectomy, based on duodenoscopy with biopsies of the scar and of any abnormal area, within the first 3 months, at 6 and 12 months, and thereafter yearly for at least 5 years. Strong recommendation, low quality evidence.
Effectiveness of a digital therapeutic as adjunct to treatment with medication in pediatric ADHD
Authors: Scott H. Kollins, Ann Childress, Andrew C. Heusser, Jacqueline Lutz
Journal: npj Digital Medicine (2021)

Abstract STARS-Adjunct was a multicenter, open-label effectiveness study of AKL-T01, an app and video-game-based treatment for inattention, as an adjunct to pharmacotherapy in 8–14-year-old children with attention-deficit/hyperactivity disorder (ADHD) on stimulant medication ( n = 130) or not on any ADHD medication ( n = 76). Children used AKL-T01 for 4 weeks, followed by a 4-week pause and another 4-week treatment. The primary outcome was change in ADHD-related impairment (Impairment Rating Scale (IRS)) after 4 weeks. Secondary outcomes included changes in IRS, ADHD Rating Scale (ADHD-RS). and Clinical Global Impressions Scale—Improvement (CGI-I) on days 28, 56, and 84. IRS significantly improved in both cohorts (On Stimulants: −0.7, p &lt; 0.001; No Stimulants: −0.5, p &lt; 0.001) after 4 weeks. IRS, ADHD-RS, and CGI-I remained stable during the pause and improved with a second treatment period. The treatment was well-tolerated with no serious adverse events. STARS-Adjunct extends AKL-T01’s body of evidence to a medication-treated pediatric ADHD population, and suggests additional treatment benefit.
Dose/schedule-adjusted Rd-R vs continuous Rd for elderly, intermediate-fit patients with newly diagnosed multiple myeloma
Authors: Alessandra Larocca, Francesca Bonello, Gianluca Gaidano, Mattia D’Agostino, Massimo Offidani, Nicola Cascavilla, Andrea Capra, Giulia Benevolo, Patrizia Tosi, Monica Galli, Roberto Marasca, Nicola Giuliani, Annalisa Bernardini, Elisabetta Antonioli, Delia Rota-Scalabrini, Claudia Cellini, Alessandra Pompa, Federico Monaco, Francesca Patriarca, Tommaso Caravita di Toritto, Paolo Corradini, Paola Tacchetti, Mario Boccadoro, Sara Bringhen
Journal: Blood (2021)
MA13.04 Harnessing Natural Killer Cells to Treat Metastatic Small Cell Lung Cancer
Authors: S. Best, J. Hess, F. Souza-Fonseca Guimaraes, A. Kersbergen, S. Hyslop, J. Rautela, N. Huntington, K. Sutherland
Journal: Journal of Thoracic Oncology (2021)
Recent progress of surface-enhanced Raman spectroscopy for subcellular compartment analysis
Authors: Yanting Shen, Jing Yue, Weiqing Xu, Shuping Xu
Journal: Theranostics (2021)

Organelles are involved in many cell life activities, and their metabolic or functional disorders are closely related to apoptosis, neurodegenerative diseases, cardiovascular diseases, and the development and metastasis of cancers. The explorations of subcellular structures, microenvironments, and their abnormal conditions are conducive to a deeper understanding of many pathological mechanisms, which are expected to achieve the early diagnosis and the effective therapy of diseases. Organelles are also the targeted locations of drugs, and they play significant roles in many targeting therapeutic strategies. Surface-enhanced Raman spectroscopy (SERS) is a powerful analytical tool that can provide the molecular fingerprint information of subcellular compartments and the real-time cellular dynamics in a non-invasive and non-destructive way. This review aims to summarize the recent advances of SERS studies on subcellular compartments, including five parts. The introductions of SERS and subcellular compartments are given. SERS is promising in subcellular compartment studies due to its molecular specificity and high sensitivity, and both of which highly match the high demands of cellular/subcellular investigations. Intracellular SERS is mainly cataloged as the labeling and label-free methods. For subcellular targeted detections and therapies, how to internalize plasmonic nanoparticles or nanostructure in the target locations is a key point. The subcellular compartment SERS detections, SERS measurements of isolated organelles, investigations of therapeutic mechanisms from subcellular compartments and microenvironments, and integration of SERS diagnosis and treatment are sequentially presented. A perspective view of the subcellular SERS studies is discussed from six aspects. This review provides a comprehensive overview of SERS applications in subcellular compartment researches, which will be a useful reference for designing the SERS-involved therapeutic systems.
P52.08 Thoracic Tumors Registry (RTT): Analysis of Clinical Features and Survival in Patients with mNSCLC in Spain.
Authors: F. Franco, E. Carcereny, D. Rodríguez-Abreu, R. Lopez Castro, M. Cobo Dols, M. Guirado, B. Massuti, A.L. Ortega Granados, J. Mosquera, O. Juan, F. Aparisi, E. Del Barco, M. Dómine Gómez, A. Padilla, C. Garcia Benito, J. Calzas, R. Blanco, S. Cerezo, X. Cardenas, M. Provencio
Journal: Journal of Thoracic Oncology (2021)
Antilymphangiogenic and antihemangiogenic properties of the novel immunosuppressant FTY 720
Authors: Mareile Joka, Gerald Schmid, Markus Guba, Christiane Bruns, Karl-Walter Jauch, Christopher Heeschen, Christian Graeb
Journal: Cancer Research (2007)

3004  One known complication of patients under chronic immunosuppression after transplantation is the recurrence of tumors or de novo malignancies. FTY720 is an immunosuppressant that reduces the number of lymphocytes in peripheral blood via agonistic action on sphingosine-1 phosphate receptor 1 (S1P1). Importantly, FTY720 was recently shown to prevent tumor growth and metastasis. Here, we examined effects of FTY720 on lymph- and hem-angiogenesis.  Methods: To evaluate the anti-proliferative and anti-angiogenic properties of FTY720 we employed an MTT proliferation/viability assay and a spheroid model using human umbilical vein endothelial cells (HUVECs) and lymph endothelial cells (LECs). To substantiate our in vitro findings, the effect of FTY720 on tumor growth was illustrated in a Lewis Lung Carcinoma (LLC1) model for hem-angiogenesis and in a B16 melanoma model for lymphogenic metastasis. Both cell types were injected subcutaneously into the back of syngeneic C57BL/6 mice. Animals were treated with FTY720 or saline as control, tumor size was measured periodically. 8 (local tumor) or 15 (lung and lymph node metastases) days after injection, tumors were harvested and analyzed histologically.  Results: FTY720 showed a strong in vitro growth-suppressive as well as anti-hem-angiogenic and anti-lymph-angiogenic effect. The vascular sprouting of VEGF-A stimulated HUVEC spheroids and VEGF-C stimulated LEC spheroids, respectively, was significantly inhibited at nanomolar concentrations. Interestingly, in a coculture model using HUVECs and smooth muscle cells (SMCs), micromolar concentrations of FTY720 were needed to accomplish the same effect, indicating the stabilizing properties of SMCs towards the endothelial cells. Consequently, FTY720 significantly inhibited subcutaneous tumor growth in both models. Additionally, the microvessel density of the tumors was reduced significantly in the FTY720-treated mice as compared to saline treated control mice. In the B16 lymphogenic tumor metastasis model, the number of lung and lymph node metastases was reduced dose-dependently in FTY720-treated animals. In preliminary results CXCR4 seemed to be involved in metastatic spread.  Conclusion: FTY720 demonstrates a strong anti-angiogenic activity in vitro translating into a substantial anti-tumor and anti-lymph-metastatic effect in vivo. Therefore, following organ transplantation, a treatment regimen using FTY720 in combination with other anti-tumorigenic immunosuppressants may proof to be beneficial in preventing tumor development and progression in high-risk patients.
P65.04 Tracking circRNAs in Lung Adenocarcinoma Samples as Promising Biomarkers for Cancer Detection using the NanoString nCounter®
Authors: C. Pedraz-Valdunciel, C. Huang, M. Ito, J. Bracht, A. Giménez-Capitán, E. Aldeguer, M. Filipska, W. Xu, M.A. Molina-Vila, R. Rosell
Journal: Journal of Thoracic Oncology (2021)
Antibody Response After SARS-CoV-2 Infection and Implications for Immunity
Authors: Irina Arkhipova-Jenkins, Mark Helfand, Charlotte Armstrong, Emily Gean, Joanna Anderson, Robin A. Paynter, Katherine Mackey
Journal: Annals of Internal Medicine (2021)

The clinical significance of the antibody response after SARS-CoV-2 infection remains unclear.To synthesize evidence on the prevalence, levels, and durability of detectable antibodies after SARS-CoV-2 infection and whether antibodies to SARS-CoV-2 confer natural immunity.MEDLINE (Ovid), Embase, CINAHL, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, World Health Organization global literature database, and Covid19reviews.org from 1 January through 15 December 2020, limited to peer-reviewed publications available in English.Primary studies characterizing the prevalence, levels, and duration of antibodies in adults with SARS-CoV-2 infection confirmed by reverse transcriptase polymerase chain reaction (RT-PCR); reinfection incidence; and unintended consequences of antibody testing.Two investigators sequentially extracted study data and rated quality.Moderate-strength evidence suggests that most adults develop detectable levels of IgM and IgG antibodies after infection with SARS-CoV-2 and that IgG levels peak approximately 25 days after symptom onset and may remain detectable for at least 120 days. Moderate-strength evidence suggests that IgM levels peak at approximately 20 days and then decline. Low-strength evidence suggests that most adults generate neutralizing antibodies, which may persist for several months like IgG. Low-strength evidence also suggests that older age, greater disease severity, and presence of symptoms may be associated with higher antibody levels. Some adults do not develop antibodies after SARS-CoV-2 infection for reasons that are unclear.Most studies were small and had methodological limitations; studies used immunoassays of variable accuracy.Most adults with SARS-CoV-2 infection confirmed by RT-PCR develop antibodies. Levels of IgM peak early in the disease course and then decline, whereas IgG peaks later and may remain detectable for at least 120 days.Agency for Healthcare Research and Quality. (PROSPERO: CRD42020207098).
c-MYC-directed NRF2 drives malignant progression of head and neck cancer via glucose-6-phosphate dehydrogenase and transketolase activation
Authors: Ya-Chu Tang, Jenn-Ren Hsiao, Shih-Sheng Jiang, Jang-Yang Chang, Pei-Yi Chu, Ko-Jiunn Liu, Hsun-Lang Fang, Li-Mei Lin, Huang-Hui Chen, Yen-Wen Huang, Yu-Tsen Chen, Fang-Yu Tsai, Su-Fang Lin, Yung-Jen Chuang, Ching-Chuan Kuo
Journal: Theranostics (2021)

Rationale: NRF2, a redox sensitive transcription factor, is up-regulated in head and neck squamous cell carcinoma (HNSCC), however, the associated impact and regulatory mechanisms remain unclear. Methods: The protein expression of NRF2 in HNSCC specimens was examined by IHC. The regulatory effect of c-MYC on NRF2 was validated by ChIP-qPCR, RT-qPCR and western blot. The impacts of NRF2 on malignant progression of HNSCC were determined through genetic manipulation and pharmacological inhibition in vitro and in vivo. The gene-set enrichment analysis (GSEA) on expression data of cDNA microarray combined with ChIP-qPCR, RT-qPCR, western blot, transwell migration/ invasion, cell proliferation and soft agar colony formation assays were used to investigate the regulatory mechanisms of NRF2. Results: NRF2 expression is positively correlated with malignant features of HNSCC. In addition, carcinogens, such as nicotine and arecoline, trigger c-MYC-directed NRF2 activation in HNSCC cells. NRF2 reprograms a wide range of cancer metabolic pathways and the most notable is the pentose phosphate pathway (PPP). Furthermore, glucose-6-phosphate dehydrogenase (G6PD) and transketolase (TKT) are critical downstream effectors of NRF2 that drive malignant progression of HNSCC; the coherently expressed signature NRF2/G6PD/TKT gene set is a potential prognostic biomarker for prediction of patient overall survival. Notably, G6PD- and TKT-regulated nucleotide biosynthesis is more important than redox regulation in determining malignant progression of HNSCC. Conclusions: Carcinogens trigger c-MYC-directed NRF2 activation. Over-activation of NRF2 promotes malignant progression of HNSCC through reprogramming G6PD- and TKT-mediated nucleotide biosynthesis. Targeting NRF2-directed cellular metabolism is an effective strategy for development of novel treatments for head and neck cancer.
Patient who sued trust for £5.7m is sentenced to six months in jail for faking disabilities
Authors: Clare Dyer
Journal: BMJ (2021)

A patient who sued a hospital trust for more than £5.7m (€6.6m; $7.9m) for not diagnosing her cauda equina syndrome quickly enough has been handed a six month jail sentence for contempt of court after exaggerating her disabilities.1

Linda Metcalf, 37, claimed a total of £5 712 773 from Calderdale & Huddersfield NHS Foundation Trust after lying about her disabilities when she was assessed by a range of experts. The trust admitted a day’s delay in diagnosing the syndrome and performing an operation in 2012.

Metcalf maintained her story for more than three years, her exaggerations “amounting at times to outright invention,” said Mr Justice Griffiths. She “dishonestly and falsely” claimed that she could not walk unaided …
Leukocyte Heterogeneity in Pancreatic Ductal Adenocarcinoma: Phenotypic and Spatial Features Associated with Clinical Outcome
Authors: Shannon M. Liudahl, Courtney B. Betts, Shamilene Sivagnanam, Vicente Morales-Oyarvide, Annacarolina da Silva, Chen Yuan, Samuel Hwang, Alison Grossblatt-Wait, Kenna R. Leis, William Larson, Meghan B. Lavoie, Padraic Robinson, Andressa Dias Costa, Sara A. Väyrynen, Thomas E. Clancy, Douglas A. Rubinson, Jason Link, Dove Keith, Wesley Horton, Margaret A. Tempero, Robert H. Vonderheide, Elizabeth M. Jaffee, Brett Sheppard, Jeremy Goecks, Rosalie C. Sears, Byung S. Park, Motomi Mori, Jonathan A. Nowak, Brian M. Wolpin, Lisa M. Coussens
Journal: Cancer Discovery (2021)

Immunotherapies targeting aspects of T cell functionality are efficacious in many solid tumors, but pancreatic ductal adenocarcinoma (PDAC) remains refractory to these treatments. Deeper understanding of the PDAC immune ecosystem is needed to identify additional therapeutic targets and predictive biomarkers for therapeutic response and resistance monitoring. To address these needs, we quantitatively evaluated leukocyte contexture in 135 human PDACs at single-cell resolution by profiling density and spatial distribution of myeloid and lymphoid cells within histopathologically defined regions of surgical resections from treatment-naive and presurgically (neoadjuvant)-treated patients and biopsy specimens from metastatic PDAC. Resultant data establish an immune atlas of PDAC heterogeneity, identify leukocyte features correlating with clinical outcomes, and, through an in silico study, provide guidance for use of PDAC tissue microarrays to optimally measure intratumoral immune heterogeneity. Atlas data have direct applicability as a reference for evaluating immune responses to investigational neoadjuvant PDAC therapeutics where pretherapy baseline specimens are not available. SIGNIFICANCE: We provide a phenotypic and spatial immune atlas of human PDAC identifying leukocyte composition at steady state and following standard neoadjuvant therapies. These data have broad utility as a resource that can inform on leukocyte responses to emerging therapies where baseline tissues were not acquired.This article is highlighted in the In This Issue feature, p. 1861.
One‐Step All‐Aqueous Interfacial Assembly of Robust Membranes for Long‐Term Encapsulation and Culture of Adherent Stem/Stromal Cells
Authors: Sara Vilabril, Sara Nadine, Catarina M. S. S. Neves, Clara R. Correia, Mara G. Freire, João A. P. Coutinho, Mariana B. Oliveira, João F. Mano
Journal: Advanced Healthcare Materials (2021)

Abstract The therapeutic effectiveness and biological relevance of technologies based on adherent cells depend on platforms that enable long‐term culture in controlled environments. Liquid‐core capsules have been suggested as semipermeable moieties with spatial homogeneity due to the high mobility of all components in their core. The lack of cell‐adhesive sites in liquid‐core structures often hampers their use as platforms for stem cell‐based technologies for long‐term survival and cell‐directed self‐organization. Here, the one‐step fast formation of robust polymeric capsules formed by interfacial complexation of oppositely charged polyelectrolytes in an all‐aqueous environment, compatible with the simultaneous encapsulation of mesenchymal stem/stromal cells (MSCs) and microcarriers, is described. The adhesion of umbilical cord MSCs to polymeric microcarriers enables their aggregation and culture for more than 21 days in capsules prepared either manually by dropwise addition, or by scalable electrohydrodynamic atomization, generating robust and stable capsules. Cell aggregation and secretion overtime can be tailored by providing cells with static or dynamic (bioreactor) environments.