tbuckley/cabot-search huggingface dataset:
Abstract C28: KMT2D mediates TGF-β-induced epithelial-to-mesenchymal transition to promote more aggressive pancreatic cancer
Authors: Hong S. Kim, Shuang Lu, Yubo Cao, Zhujun Yi, Sivakumar Jeyarajan, Lili Zhao, Karan Bedi, Ishwarya V. Narayanan, Michelle T. Paulsen, Mats Ljungman, Jiaqi Shi
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second leading cause of cancer-related death in the United States by 2030. Surgery is the only potential curative treatment for patients with PDAC. However, less than 20% of patients are operable due to early metastasis. The mechanism of metastasis in PDAC is not fully understood. Recent studies failed to find metastasis-specific genetic mutations in PDAC, suggesting that aberrant epigenetic regulation may be one of the crucial mechanisms. Lysine-specific histone methyltransferase 2D (KMT2D) is one of the most frequently mutated epigenetic genes in human cancers, including PDAC. TCGA database analysis showed that KMT2D mutation is associated with poor survival in PDAC patients. However, the role of KMT2D in PDAC development remains elusive. Using human pancreatic tissue microarray containing both primary and metastatic PDAC tissues, we have found that the expression of KMT2D is specifically and significantly suppressed in metastatic PDAC, suggesting an important role of KMT2D in metastasis. Furthermore, treating PDAC cells with TGF-β resulted in decrease in KMT2D expression. In order to investigate the role of KMT2D in PDAC, we knocked out KMT2D (KMT2D KO) expression using CRISPR/Cas9 system in PDAC cell lines. We performed a novel Bru-seq analysis to investigate the effect of KMT2D on global nascent RNA transcript profile. Interestingly, epithelial-to-mesenchymal transition (EMT) pathway was one of the pathways that were highly upregulated upon KMT2D loss. RNA and protein assays confirmed that KMT2D KO cells had decreased epithelial marker, E-cadherin, and increased mesenchymal markers, vimentin and Snail. KMT2D KO cells also displayed enhanced ability to migrate and invade. Orthotopic xenograft mouse model using KMT2D KO cells showed less differentiated and more mesenchymal tumor cell morphology and larger primary and metastatic tumors compared to control cells. Taken together, loss of KMT2D in PDAC cells mediates TGF-β-induced EMT and enhances tumor growth and metastatic ability. These findings link epigenetic regulation to TGF-β signaling in PDAC and lay the foundation for designing novel therapeutic strategies. Citation Format: Hong S. Kim, Shuang Lu, Yubo Cao, Zhujun Yi, Sivakumar Jeyarajan, Lili Zhao, Karan Bedi, Ishwarya V. Narayanan, Michelle T. Paulsen, Mats Ljungman, Jiaqi Shi. KMT2D mediates TGF-β-induced epithelial-to-mesenchymal transition to promote more aggressive pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C28.
Efficacy and improved tolerability of combination therapy with interleukin-1 blockade and MAPK pathway inhibitors for the treatment of Erdheim-Chester disease
Authors: Corrado Campochiaro, Giulio Cavalli, Nicola Farina, Alessandro Tomelleri, Giacomo De Luca, Lorenzo Dagna
Journal: Annals of the Rheumatic Diseases (2019)

We have read with interest the article by Cohen-Aubart et al 1 reporting the efficacy of infliximab in the treatment of Erdheim-Chester disease (ECD), a rare non-Langerhans histiocytosis. The anti-Tumor Necrosis Factor-α agent demonstrated a variable degree of efficacy, suggesting that infliximab might represent a therapeutic option for moderately severe ECD cases; similar results had been observed with anakinra.2 3 Nonetheless, following the identification of causative mutations along the mitogen-activated protein kinase(MAPK) pathway,4 severe forms of ECD are currently treated with targeted small molecule agents. Specifically, the BRAF inhibitor vemurafenib and the MAPK or extracellular-signal regulated kinase (MEK) inhibitor cobimetinib have been successfully used to treat life-threatening forms of ECD. Although life-saving, these drugs are associated with severe toxicity, which often mandates treatment discontinuation.5 …
Normative data for multiple breath washout outcomes in school-aged Caucasian children
Authors: Pinelopi Anagnostopoulou, Philipp Latzin, Renee Jensen, Mirjam Stahl, Alana Harper, Sophie Yammine, Jakob Usemann, Rachel E. Foong, Ben Spycher, Graham L. Hall, Florian Singer, Sanja Stanojevic, Marcus A. Mall, Felix Ratjen, Kathryn A. Ramsey
Journal: European Respiratory Journal (2019)

Background The multiple breath nitrogen washout (N 2 MBW) technique is increasingly used to assess the degree of ventilation inhomogeneity in school-aged children with lung disease. However, reference values for healthy children are currently not available. The aim of this study was to generate reference values for N 2 MBW outcomes in a cohort of healthy Caucasian school-aged children. Methods N 2 MBW data from healthy Caucasian school-age children between 6 and 18 years old were collected from four experienced centres. Measurements were performed using an ultrasonic flowmeter (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) and were analysed with commercial software (Spiroware version 3.2.1, Eco Medics AG). Normative values and upper limits of normal (ULN) were generated for lung clearance index (LCI) at 2.5% (LCI 2.5% ) and at 5% (LCI 5% ) of the initial nitrogen concentration and for moment ratios (M 1 /M 0 and M 2 /M 0 ). A prediction equation was generated for functional residual capacity (FRC). Results Analysis used 485 trials from 180 healthy Caucasian children aged from 6 to 18 years old. While LCI increased with age, this increase was negligible (0.04 units·year –1 for LCI 2.5% ) and therefore fixed ULN were defined for this age group. These limits were 7.91 for LCI 2.5% , 5.73 for LCI 5% , 1.75 for M 1 /M 0 and 6.15 for M 2 /M 0 , respectively. Height and weight were found to be independent predictors of FRC. Conclusion We report reference values for N 2 MBW outcomes measured on a commercially available ultrasonic flowmeter device (Exhalyzer D, Eco Medics AG) in healthy school-aged children to allow accurate interpretation of ventilation distribution outcomes and FRC in children with lung disease.
Angiotensin-(1-7) induces beige fat thermogenesis through the Mas receptor
Authors: Ariana Vargas-Castillo, Sandra Tobon-Cornejo, Leonardo Del Valle-Mondragon, Ivan Torre-Villalvazo, Alejandro Schcolnik-Cabrera, Martha Guevara-Cruz, Edgar Pichardo-Ontiveros, Rebeca Fuentes-Romero, Michael Bader, Natalia Alenina, Antonio Vidal-Puig, Enrique Hong, Nimbe Torres, Armando R. Tovar
Journal: Metabolism (2019)
Reply to Chaudhari
Authors: Mingyan Zhang, Chunqing Zhang
Journal: Endoscopy (2019)

See also:Clip-assisted endoscopic cyanoacrylate injection for gastric varices with a gastrorenal shunt: a multicenter studyEndoscopy 2019; 51(10): 936-940DOI: 10.1055/a-0977-3022See also:The fog is still not clearing!Endoscopy 2020; 52(01): 80-80DOI: 10.1055/a-1021-8676
MRI Tumor Regression Grade and Circulating Tumor DNA as Complementary Tools to Assess Response and Guide Therapy Adaptation in Rectal Cancer
Authors: Shelize Khakoo, Paul David Carter, Gina Brown, Nicola Valeri, Simona Picchia, Maria Antonietta Bali, Ridwan Shaikh, Thomas Jones, Ruwaida Begum, Isma Rana, Andrew Wotherspoon, Monica Terlizzo, Katharina von Loga, Eleftheria Kalaitzaki, Claire Saffery, David Watkins, Diana Tait, Ian Chau, Naureen Starling, Michael Hubank, David Cunningham
Journal: Clinical Cancer Research (2019)

Response to preoperative chemo-radiotherapy (CRT) varies. We assessed whether circulating tumor DNA (ctDNA) might be an early indicator of tumor response or progression to guide therapy adaptation in rectal cancer.
Transcriptomic landscape of tumour cells undergoing T-cell attack
Authors: A. Gokuldass, A. Schina, M. Lauss, K. Harbst, C.A. Chamberlain, A. Draghi, M.C. Wulff Westergaard, M. Nielsen, K. Papp, Z.M. Sztupinski, I. Casabi, I.M. Svane, Z. Szallasi, G. Jonsson, M. Donia
Journal: Annals of Oncology (2019)
Antibiotic Resistance Threat Grows
Authors: Bridget Kuehn
Journal: JAMA (2019)

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Artificial Intelligence and Surgical Decision-making
Authors: Tyler J. Loftus, Patrick J. Tighe, Amanda C. Filiberto, Philip A. Efron, Scott C. Brakenridge, Alicia M. Mohr, Parisa Rashidi, Gilbert R. Upchurch, Azra Bihorac
Journal: JAMA Surgery (2019)

Surgeons make complex, high-stakes decisions under time constraints and uncertainty, with significant effect on patient outcomes. This review describes the weaknesses of traditional clinical decision-support systems and proposes that artificial intelligence should be used to augment surgical decision-making.Surgical decision-making is dominated by hypothetical-deductive reasoning, individual judgment, and heuristics. These factors can lead to bias, error, and preventable harm. Traditional predictive analytics and clinical decision-support systems are intended to augment surgical decision-making, but their clinical utility is compromised by time-consuming manual data management and suboptimal accuracy. These challenges can be overcome by automated artificial intelligence models fed by livestreaming electronic health record data with mobile device outputs. This approach would require data standardization, advances in model interpretability, careful implementation and monitoring, attention to ethical challenges involving algorithm bias and accountability for errors, and preservation of bedside assessment and human intuition in the decision-making process.Integration of artificial intelligence with surgical decision-making has the potential to transform care by augmenting the decision to operate, informed consent process, identification and mitigation of modifiable risk factors, decisions regarding postoperative management, and shared decisions regarding resource use.
Enhanced frequency and function of follicular T cells in the tonsils of house dust mite‐sensitized children
Authors: William S. Foster, Christopher J. Grime, Hui‐Leng Tan, Geoffrey S. Williams, Matthew J. Robinson, Gianluca Carlesso, Sejal Saglani, Clare M. Lloyd, James A. Harker
Journal: Allergy (2019)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus
Authors: Sarah Reid, Andrei Alexsson, Martina Frodlund, David Morris, Johanna K Sandling, Karin Bolin, Elisabet Svenungsson, Andreas Jönsen, Christine Bengtsson, Iva Gunnarsson, Vera Illescas Rodriguez, Anders Bengtsson, Sabine Arve, Solbritt Rantapää-Dahlqvist, Maija-Leena Eloranta, Ann-Christine Syvänen, Christopher Sjöwall, Timothy James Vyse, Lars Rönnblom, Dag Leonard
Journal: Annals of the Rheumatic Diseases (2019)

Objectives To investigate associations between a high genetic disease risk and disease severity in patients with systemic lupus erythematosus (SLE). Methods Patients with SLE (n=1001, discovery cohort and n=5524, replication cohort) and healthy controls (n=2802 and n=9859) were genotyped using a 200K Immunochip single nucleotide polymorphism array. A genetic risk score (GRS) was assigned to each individual based on 57 SLE risk loci. Results SLE was more prevalent in the high, compared with the low, GRS-quartile (OR 12.32 (9.53 to 15.71), p=7.9×10 –86 and OR 7.48 (6.73 to 8.32), p=2.2×10 –304 for the discovery and the replication cohorts, respectively). In the discovery cohort, patients in the high GRS-quartile had a 6-year earlier mean disease onset (HR 1.47 (1.22 to 1.75), p=4.3×10 –5 ), displayed higher prevalence of damage accrual (OR 1.47 (1.06 to 2.04), p=2.0×10 –2 ), renal disorder (OR 2.22 (1.50 to 3.27), p=5.9×10 –5 ), anti-dsDNA (OR 1.83 (1.19 to 2.81), p=6.1×10 –3 ), end-stage renal disease (ESRD) (OR 5.58 (1.50 to 20.79), p=1.0×10 –2 ), proliferative nephritis (OR 2.42 (1.30 to 4.49), p=5.1×10 –3 ), anti-cardiolipin-IgG (OR 1.89 (1.13 to 3.18), p=1.6×10 –2 ), anti-β 2 -glycoprotein-I-IgG (OR 2.29 (1.29 to 4.06), p=4.8×10 –3 ) and positive lupus anticoagulant test (OR 2.12 (1.16 to 3.89), p=1.5×10 –2 ) compared with patients in the low GRS-quartile. Survival analysis showed earlier onset of the first organ damage (HR 1.51 (1.04 to 2.25), p=3.7×10 –2 ), first cardiovascular event (HR 1.65 (1.03 to 2.64), p=2.6×10 –2 ), nephritis (HR 2.53 (1.72 to 3.71), p=9.6×10 –7 ), ESRD (HR 6.78 (1.78 to 26.86), p=6.5×10 –3 ) and decreased overall survival (HR 1.83 (1.02 to 3.30), p=4.3×10 –2 ) in high to low quartile comparison. Conclusions A high GRS is associated with increased risk of organ damage, renal dysfunction and all-cause mortality. Our results indicate that genetic profiling may be useful for predicting outcomes in patients with SLE.
Pembrolizumab After Two or More Lines of Previous Therapy in Patients With Recurrent or Metastatic SCLC: Results From the KEYNOTE-028 and KEYNOTE-158 Studies
Authors: Hyun Cheol Chung, Sarina A. Piha-Paul, Jose Lopez-Martin, Jan H.M. Schellens, Steven Kao, Wilson H. Miller, Jean-Pierre Delord, Bo Gao, David Planchard, Maya Gottfried, Alona Zer, Shadia I. Jalal, Nicolas Penel, Janice M. Mehnert, Ignacio Matos, Jaafar Bennouna, Dong-Wan Kim, Lei Xu, Suba Krishnan, Kevin Norwood, Patrick A. Ott
Journal: Journal of Thoracic Oncology (2019)
Immunogenic cell death induced by a new photodynamic therapy based on photosens and photodithazine
Authors: Victoria D. Turubanova, Irina V. Balalaeva, Tatiana A. Mishchenko, Elena Catanzaro, Razan Alzeibak, Nina N. Peskova, Iuliia Efimova, Claus Bachert, Elena V. Mitroshina, Olga Krysko, Maria V. Vedunova, Dmitri V. Krysko
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Anti-cancer therapy is more successful when it can also induce an immunogenic form of cancer cell death (ICD). Therefore, when developing new treatment strategies, it is extremely important to choose methods that induce ICD and thereby activate anti-tumor immune response leading to the most effective destruction of tumor cells. The aim of this work was to analyze whether the clinically widely used photosensitizers, photosens (PS) and photodithazine (PD), can induce ICD when used in photodynamic therapy (PDT). <h3>Methods</h3> Cell death in murine glioma GL261 or fibrosarcoma MCA205 cells was induced by PS- or PD-PDT and cell death was analyzed by MTT or flow cytometry. Intracellular distribution of PS and PD was studied by using the laser scanning microscope. Calreticulin exposure and HMGB1 and ATP release were detected by flow cytometry, ELISA and luminescence assay, respectively. Immunogenicity in vitro was analyzed by co-culturing of dying cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of phagocytosis and maturation (CD11c<sup>+</sup>CD86<sup>+</sup>, CD11c<sup>+</sup>CD40<sup>+</sup>) of BMDCs and production of IL-6 in the supernatant were measured. In vivo immunogenicity was analyzed in mouse tumor prophylactic vaccination model. <h3>Results</h3> We determined the optimal concentrations of the photosensitizers and found that at a light dose of 20 J/cm<sup>2</sup> (λex 615–635 nm) both PS and PD efficiently induced cell death in glioma GL261 and fibrosarcoma MCA205 cells. We demonstrate that PS localized predominantly in the lysosomes and that the cell death induced by PS-PDT was inhibited by zVAD-fmk (apoptosis inhibitor) and by ferrostatin-1 and DFO (ferroptosis inhibitors), but not by the necroptosis inhibitor necrostatin-1 s. By contrast, PD accumulated in the endoplasmic reticulum and Golgi apparatus, and the cell death induced by PD-PDT was inhibited only by z-VAD-fmk. Dying cancer cells induced by PS-PDT or PD-PDT emit calreticulin, HMGB1 and ATP and they were efficiently engulfed by BMDCs, which then matured, became activated and produced IL-6. Using dying cancer cells induced by PS-PDT or PD-PDT, we demonstrate the efficient vaccination potential of ICD in vivo. <h3>Conclusions</h3> Altogether, these results identify PS and PD as novel ICD inducers that could be effectively combined with PDT in cancer therapy.
Single-cell RNA-seq analysis identifies meniscus progenitors and reveals the progression of meniscus degeneration
Authors: Hao Sun, Xingzhao Wen, Hongyi Li, Peihui Wu, Minghui Gu, Xiaoyi Zhao, Ziji Zhang, Shu Hu, Guping Mao, Ruofan Ma, Weiming Liao, Zhiqi Zhang
Journal: Annals of the Rheumatic Diseases (2019)

The heterogeneity of meniscus cells and the mechanism of meniscus degeneration is not well understood. Here, single-cell RNA sequencing (scRNA-seq) was used to identify various meniscus cell subsets and investigate the mechanism of meniscus degeneration.scRNA-seq was used to identify cell subsets and their gene signatures in healthy human and degenerated meniscus cells to determine their differentiation relationships and characterise the diversity within specific cell types. Colony-forming, multi-differentiation assays and a mice meniscus injury model were used to identify meniscus progenitor cells. We investigated the role of degenerated meniscus progenitor (DegP) cell clusters during meniscus degeneration using computational analysis and experimental verification.We identified seven clusters in healthy human meniscus, including five empirically defined populations and two novel populations. Pseudotime analysis showed endothelial cells and fibrochondrocyte progenitors (FCP) existed at the pseudospace trajectory start. Melanoma cell adhesion molecule ((MCAM)/CD146) was highly expressed in two clusters. CD146+ meniscus cells differentiated into osteoblasts and adipocytes and formed colonies. We identified changes in the proportions of degenerated meniscus cell clusters and found a cluster specific to degenerative meniscus with progenitor cell characteristics. The reconstruction of four progenitor cell clusters indicated that FCP differentiation into DegP was an aberrant process. Interleukin 1β stimulation in healthy human meniscus cells increased CD318+ cells, while TGFβ1 attenuated the increase in CD318+ cells in degenerated meniscus cells.The identification of meniscus progenitor cells provided new insights into cell-based meniscus tissue engineering, demonstrating a novel mechanism of meniscus degeneration, which contributes to the development of a novel therapeutic strategy.
WHO draft guidelines on dietary saturated and trans fatty acids: time for a new approach?
Journal: BMJ (2019)

While revising this Analysis article (BMJ 2019;366:l4137, doi:10.1136/bmj.l4137) the authors mistakenly included a section on the reanalysis of the Minnesota Coronary Experiment. The authors had originally agreed among themselves not to include the section in the final manuscript for two reasons. First, the key message of the article is to move from recommendations of single nutrients into food based recommendations because saturated fat is a heterogeneous group of fatty acids with divergent health effects, and the effect is furthermore dependent on the food matrix they exist in. For that reason, the authors felt the section was redundant. Second, for a discussion of the health effects of polyunsaturated fat, the authors did not feel that the section provided a balanced and complete analysis of the issue. Soon after publication the authors contacted The BMJ to notify the journal of the mistake and request correction of the article by removing the following paragraphs, which does not substantially change the message or argument of the Analysis: “Reanalysis of the Minnesota Coronary Experiment (a double blind randomised controlled trial that tested whether replacing saturated fat with polyunsaturated fat reduced coronary heart disease and death) also supports the claim that serum cholesterol is not a valid surrogate biomarker for cardiovascular disease risk when making dietary changes.10 Despite the finding that the polyunsaturated fat diet produced a 13% greater reduction in serum cholesterol than the saturated fat diet, there was no reduction in cardiovascular disease endpoints.10 “The reanalysis found a 22% higher mortality for each 0.78 mmol/L reduction in serum cholesterol caused by the polyunsaturated diet.10 A meta-analysis found that cholesterol lowering using polyunsaturated fat diets did not show any evidence of benefit on mortality from coronary heart disease (1.13, 0.83 to 1.54) or all cause mortality (1.07, 0.90 to 1.27).10” These paragraphs have been removed from the article online.
Assessment of Tanning Beds in 3 Popular Gym Chains
Authors: Sherry L. Pagoto, David E. Conroy, Kelsey Arroyo, Jared Goetz, Ashley B. West, Samantha Mulcahy, Molly E. Waring
Journal: JAMA Network Open (2019)

This cross-sectional study examines the proportion of gyms from 3 large national chains in the United States that offer tanning services, the number of tanning beds offered by these gyms, and regional differences in the number of gyms that provide tanning services.
Prophylactic Transjugular Intrahepatic Portosystemic Shunt Placement for Cirrhosis Management in Pregnancy
Authors: Shruti Chandramouli, William M. Lee, Julie Lo, Seth Toomay, Shannan Tujios
Journal: Hepatology (2019)

Chandramouli, Shruti; Lee, William M.; Lo, Julie; Toomay, Seth; Tujios, Shannan Author Information