tbuckley/cabot-search huggingface dataset:
What did we learn from multiple omics studies in asthma?
Authors: Olga Ivanova, Levi B. Richards, Susanne J. Vijverberg, Anne H. Neerincx, Anirban Sinha, Peter J. Sterk, Anke H. Maitland‐van der Zee
Journal: Allergy (2019)

Abstract More than a decade has passed since the finalization of the Human Genome Project. Omics technologies made a huge leap from trendy and very expensive to routinely executed and relatively cheap assays. Simultaneously, we understood that omics is not a panacea for every problem in the area of human health and personalized medicine. Whilst in some areas of research omics showed immediate results, in other fields, including asthma, it only allowed us to identify the incredibly complicated molecular processes. Along with their possibilities, omics technologies also bring many issues connected to sample collection, analyses and interpretation. It is often impossible to separate the intrinsic imperfection of omics from asthma heterogeneity. Still, many insights and directions from applied omics were acquired—presumable phenotypic clusters of patients, plausible biomarkers and potential pathways involved. Omics technologies develop rapidly, bringing improvements also to asthma research. These improvements, together with our growing understanding of asthma subphenotypes and underlying cellular processes, will likely play a role in asthma management strategies.
Caution Does Not Preclude Predictive and Testable Models of Cytoplasmic Incompatibility: A Reply to Shropshire et al.
Authors: John F. Beckmann, Manon Bonneau, Hongli Chen, Mark Hochstrasser, Denis Poinsot, Hervé Merçot, Mylène Weill, Mathieu Sicard, Sylvain Charlat
Journal: Trends in Genetics (2019)
Localized injection of miRNA-21-enriched extracellular vesicles effectively restores cardiac function after myocardial infarction
Authors: Yu Song, Cheng Zhang, Jinxiang Zhang, Zhanying Jiao, Nianguo Dong, Guobin Wang, Zheng Wang, Lin Wang
Journal: Theranostics (2019)

Myocardial infarction (MI), a main cause of heart failure, leads to irreversible cardiomyocytes loss and cardiac function impairment.Current clinical treatments for MI are largely ineffective as they mostly aim to alleviate symptoms rather than repairing the injured myocardium.Thus, development of more effective therapies is compelling.This study aims to investigate whether the extracellular vesicles (EVs) carrying specific anti-apoptotic miRNA can be efficiently internalized into myocardium to achieve desired therapeutic outcomes.Methods: EVs were isolated from HEK293T cells overexpressing miRNA-21 (miR21-EVs) and identified.The RNase resistant rate of miR21-EVs was calculated by real-time PCR and compared with liposomes and polyethylenimine (PEI).Confocal laser scanning microscopy was used for visualizing the cellular internalization of miR21-EVs in primary cultured mouse neonatal cardiomyocytes (CMs), H9c2 rat cardiomyoblasts, and human umbilical vein endothelial cells (HUVECs).The effect of miR21-EVs on the expression of PDCD4, a pro-apoptotic protein that plays an important role in regulating myocardial apoptosis, was also evaluated in these three cell types by real-time PCR and Western blot analysis.In vivo, miR21-EVs was directly injected into the infarct zone following ligation of the left anterior descending of coronary artery in mice.The miR21-EVs distribution and blood vessel (capillary and arteriole) density were evaluated by immunofluorescence staining.Fluorescence in situ hybridization of miRNA-21 was also carried out to confirm the miR21-EVs distribution in vitro and in vivo.The protein level of PDCD4 in myocardium was assessed by immunohistochemical staining.The anti-apoptotic effect of miR21-EVs in cardiomyocytes and endothelial cells were measured using TUNEL staining.Four weeks after injection, the cardiac histological and functional recovery was evaluated by histochemistry staining and echocardiography, respectively.Results: In contrast to liposomes and PEI, EVs significantly inhibited miRNA-21 degradation.MiR21-EVs efficiently delivered miRNA-21 into cardiomyocytes and endothelial cells within 4 hours.Exogenous miRNA-21 in turn significantly reduced PDCD4 expression and attenuated cell apoptosis in vitro.Consistently and importantly, in a preclinical MI animal model, miRNA-21-loaded EVs effectively sent miRNA-21 into cardiomyocytes and endothelial cells, drastically inhibited cell apoptosis and led to significant cardiac function improvement. Conclusion:Our results suggest the cell-derived, genetically engineered EVs may be used therapeutically for the delivery of miRNAs for the rescue of MI and may benefit patients in the future.
PS-144-Autotaxin mediates lipid dysregulation in acute-on-chronic liver failure, promoting persistence of systemic inflammation via lysophosphatidic acid-mediated monocyte activation
Authors: Mark J W McPhail, Francesca Trovato, Evangelos Triantafyllou, Rabiya Zia, Kate Wolfer, Xiaohong Huang, Liane Rabinowich, Vishal C Patel, Elaine Holmes, Nigel Heaton, Michael Heneghan, William Bernal, Georg Auzinger, Muireann Coen, Julia Wendon, Harry Antoniades
Journal: Journal of Hepatology (2019)
Benefit of immunotherapy (IT) in advanced non-small cell lung cancer (NSCLC) in elderly patients (EP)
Authors: E. Corral de la Fuente, A. Barquín García, C. Saavedra Serrano, M.E. Olmedo García, R. Martin Huertas, J.J. Serrano Domingo, V. Albarrán Artahona, A. Gómez Rueda
Journal: Annals of Oncology (2019)

Background: Despite EP (aged ≥70 years) represent the majority of patients with advanced NSCLC, the efficacy and toxicity rates of IT remain poorly described, as they are under-represented in clinical trials. Furthermore, the age-related decline in the immune system might affect efficacy of IT. Methods: We retrospectively reviewed advanced NSCLC patients treated with IT (antiPD-1, anti-PD-L1) monotherapy as first, second and subsequent-line settings, between 2014 and 2018 in our hospital. Patient and tumor features, irAEs, concomitant and subsequent treatments were collected. Stata 14.1 was used for the analysis. Results: 98 patients were included. Mean age was 62 years (41-85). 73.5% were men. 73.5% had >30 smoked pack-years (py), 64.3% were adenocarcinoma (ADC), of which 41% were KRAS mutated; and 25.5% were squamous (SCC). PDL1 was known in a 50% of patients (11% <1%, 13% 1-49%, 25% >50%). IT was administered mainly as a second line (61%) and third or later (24.5%). Most employed drug was nivolumab (52%) (Table). Response Rate (RR) was 32.7% (partial response 28%, complete response 5%). Disease control rate (DCR) was 55%. Overall Survival (OS) was significantly lower in EP compared to patients aged <70 years (5.5 vs 13 months (m) HR 3.86; IC 2.073- 7.214; P < 0.0001). Progression-free survival (PFS) was significantly worse for EP than for younger patients (1.8 vs 3.6m, HR 2.1; IC 1.181 - 3.744; p = 0.012). Regarding toxicity, 30.6% irAEs were reported. There were no statistically significant differences in terms of irAEs between EP and younger patients (p = 0.535). The development of irAEs was associated with better PFS in younger patients (13.3 vs 5.5m, HR 0.45; IC 0.244 - 0.840; p = 0.012) without significant impact on OS.Table169P_PRFeatureN (%)Sex Male Female72 (73.5) 26 (26.5)Age <70 ≥7071 (72.5) 27 (27.5)Tobacco ≥30 py < 30 py Never Unknown72 (73.5) 17 (17.4) 2 (2) 7 (7)Histology SCC ADC Unspecified25 (25.5) 63 (64.29) 10 (10)PDL1 <1% 1-49% ≥50% Unknown11 (11.2) 13 (13.3) 25 (25.5) 49 (50) Open table in a new tab Conclusions: Our results suggest that EP could have worse survival outcomes than younger patients, without differences in terms of toxicity, but prospective trials are needed to confirm this hypothesis. Legal entity responsible for the study: Elena Corral de la Fuente. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Suboptimal response rates to hypomethylating agent therapy in chronic myelomonocytic leukemia; a single institutional study of 121 patients
Authors: Tucker Coston, Prateek Pophali, Rangit Vallapureddy, Terra L. Lasho, Christy M. Finke, Rhett P. Ketterling, Ryan Carr, Moritz Binder, Abhishek A. Mangaonkar, Naseema Gangat, Aref Al‐Kali, Mark Litzow, Darci Zblewski, Animesh Pardanani, Ayalew Tefferi, Mrinal M. Patnaik
Journal: American Journal of Hematology (2019)

Abstract Hypomethylating agents (HMA) are currently the only FDA approved therapy for patients with chronic myelomonocytic leukemia (CMML). In the current retrospective study, we assessed response rates as adjudicated by the IWG (International Working Group) MDS (myelodysplastic syndrome) and MDS/MPN myeloproliferative neoplasm overlap syndrome response criteria, in 121 CMML patients treated with Azacitidine (AZA, n = 56) and Decitabine (DAC, n = 65). The overall response rates were 41% by the IWG MDS (AZA‐ 45%, DAC‐39%), and 56% by the IWG MDS/MPN (AZA‐56%, DAC‐58%) response criteria, with CR (complete remission) rates of &lt;20% for both agents, by both criteria. There were no significant differences in response rates between proliferative and dysplastic CMML. Moreover, 29% of CMML patients in a CR with HMA progressed to AML (blast transformation), underscoring the limited impact of these agents on disease biology. Progression after HMA response was associated with a median overall‐survival (OS) of 8 months, while median OS in patients with primary HMA failure was 4 months. Lower serum LDH levels (&lt;250 Units/L) were associated with HMA responses by both criteria; while ASXL1 and TET2 mutational status had no impact. HMA treated patients had a longer median OS (31 vs 18 months; P = .01), in comparison to those treated with conventional care regimens (excluding observation only patients), without any differences between AZA vs DAC ( P = .37). In conclusion, this study highlights the inadequacies of HMA therapy in CMML, retrospectively validates the IWG MDS/MPN response criteria and underscores the need for newer, rationally derived therapies.
FRI-017-High prevalence of possible PSC recurrence post transplant evaluated by protocol biopsies
Authors: Lise Katrine Engesæter, Henrik Reims, Krzysztof Grzyb, Andreas Abildgaard, Tom H. Karlsen, Kristian Bjøro, Kirsten Muri Boberg, Johannes Roksund Hov, Espen Melum
Journal: Journal of Hepatology (2019)
SAT-424-Spleen transient elastography and suprahepatic vein dumping index can be useful to identify patients without acute and chronic response to beta-blockers
Authors: Elba Llop, Christie Perelló, Teresa Fontanilla, Juan De la Revilla, Marta Hernández Conde, Marta López-Gómez, Javier Minaya, Carlos Ferre, Javier Abad Guerra, José Luis Martínez Porras, Natalia Fernández Puga, Maria Trapero, José Luis Calleja Panero
Journal: Journal of Hepatology (2019)
FRI-163-Reduced liver-related complications after 13 years of follow-up of interferon-alpha treatment for HBeAg-positive chronic hepatitis B: The ELITE-B study
Authors: Hannah S.J. Choi, Margo J.H. van Campenhout, Cedric de Jong, Hanneke van Vuuren, Milan Sonneveld, Robert De Knegt, Bettina Hansen, Harry Janssen
Journal: Journal of Hepatology (2019)
Class 1, 2, and 3<i>BRAF</i>-Mutated Metastatic Colorectal Cancer: A Detailed Clinical, Pathologic, and Molecular Characterization
Authors: Marta Schirripa, Paola Biason, Sara Lonardi, Nicoletta Pella, Maria Simona Pino, Federica Urbano, Carlotta Antoniotti, Chiara Cremolini, Salvatore Corallo, Filippo Pietrantonio, Fabio Gelsomino, Stefano Cascinu, Armando Orlandi, Giada Munari, Umberto Malapelle, Serena Saggio, Gabriella Fontanini, Massimo Rugge, Claudia Mescoli, Stefano Lazzi, Luca Reggiani Bonetti, Giovanni Lanza, Angelo Paolo Dei Tos, Giovanna De Maglio, Maurizio Martini, Francesca Bergamo, Vittorina Zagonel, Fotios Loupakis, Matteo Fassan
Journal: Clinical Cancer Research (2019)

Abstract Purpose: BRAF mutations are grouped in activating RAS-independent signaling as monomers (class 1–V600E) or as dimers (class 2–codons 597/601), and RAS-dependent with impaired kinase activity (class 3–codons 594/596). Although clinical, pathologic, and molecular features of V600EBRAF-mutated metastatic colorectal cancer (mCRC) are well known, limited data are available from the two other classes. Experimental Design: Data from 117 patients with BRAF (92 class 1, 12 class 2, and 13 class 3)-mutated mCRC were collected. A total of 540 BRAF wt mCRCs were included as control. IHC profiling was performed to determine the consensus molecular subtypes (CMS), cytokeratin 7/20 profiles, tumor-infiltrating lymphocyte infiltration, and BM1/BM2 categorization. Overall survival (OS) and progression-free survival were evaluated by Kaplan–Meier and log-rank test. Results: Class 3 BRAF-mutated mCRC was more frequently left sided (P = 0.0028), pN0 (P = 0.0159), and without peritoneal metastases (P = 0.0176) compared with class 1, whereas class 2 cases were similar to class 1. Hazard ratio for OS, as compared with BRAF wt, was 2.38 [95% confidence interval (CI), 1.61–3.54] for class 1, 1.90 (95% CI, 0.85–4.26) for class 2, and 0.93 (95% CI, 0.51–1.69) for class 3 (P &amp;lt; 0.0001). Class 2 and 3 tumors were all assigned to CMS2-3. A higher median CD3/CD8-positive lymphocyte infiltration was observed in BRAF-mutated class 2 (P = 0.033) compared with class 3 cases. Conclusions: For the first time, different clinical and pathologic features and outcome data were reported according to the three BRAF mutation classes in mCRC. Specific targeted treatment strategies should be identified in the near future for such patients.
Breast cancer in their twenties: Clinical outcome of very young breast cancer patients in a cancer hospital in Pakistan.
Authors: Samreen umer Khan, Hasan Ali, Zoona Feroza, Taskheer Abbas, Huma Majeed Khan, Mohammad Zulqarnain Chaudhary, Amina Iqbal Khan
Journal: Journal of Clinical Oncology (2015)

e12056 Background: Young age breast cancer remains a clinical challenge. The following study aims to review the outcome and treatment options rendered to patients below 30 years of age presenting with breast cancer in a Pakistan Cancer Hospital. Methods: Retrospective review of consecutive patients under 30 years of age presenting to Shaukat Khanum Memorial Cancer Hospital from 2002 to 2009. Results: A total of 195 patients were reviewed. All patients were between 20-29 years with mean age of 26.34 years. Invasive ductal carcinoma was found in 187 (96.4%) of patients with 83% of them presenting with Grade 3 tumors. None of the patients reviewed had an In Situ component. There were 108 (55.4%) ER/PR negative cases. Primary surgery was BCS in 89 (45.6%) patients with 96.6% receiving radiotherapy. Ninety-four (48%) patients had a mastectomy and 87.8% of these patients received post mastectomy radiotherapy. A large proportion (45%) of the BCT patients had surgery outside our hospital and were offered re-excision to negative margins. The remaining majority (47.2%) in the BCT group comprised of patients with T2 tumors. In comparison, patients who had mastectomy 33% had Tx tumors and 36.3% had T3-T4 tumors (p = 0.00). Complete nodal response was detected in 65% of the patients having BCT and 40% having mastectomy (p = 0.006). Overall 40% of the patients reported recurrence of any type with 28% of these recurring within 2 years of initial presentation. Recurrence was seen in 27 (30%) BCT and 42 (47%) mastectomy patients (p = 0.015). Average follow up was 61 months (Range 3-151 months). After controlling for grade of tumor, tumor size, nodal status, ER/PR and treatment (chemotherapy/radiation) Cox regression model showed no significant difference in survival in patients treated with BCT or mastectomy. Conclusions: Breast cancer in young women is an aggressive and challenging disease with high mastectomy and recurrence rates. Targeted studies are required to optimize care of these young patients.
Stress related disorders and risk of cardiovascular disease: population based, sibling controlled cohort study
Authors: Huan Song, Fang Fang, Filip K Arnberg, David Mataix-Cols, Lorena Fernández de la Cruz, Catarina Almqvist, Katja Fall, Paul Lichtenstein, Gudmundur Thorgeirsson, Unnur A Valdimarsdóttir
Journal: BMJ (2019)

Abstract Objective To assess the association between stress related disorders and subsequent risk of cardiovascular disease. Design Population based, sibling controlled cohort study. Setting Population of Sweden. Participants 136 637 patients in the Swedish National Patient Register with stress related disorders, including post-traumatic stress disorder (PTSD), acute stress reaction, adjustment disorder, and other stress reactions, from 1987 to 2013; 171 314 unaffected full siblings of these patients; and 1 366 370 matched unexposed people from the general population. Main outcome measures Primary diagnosis of incident cardiovascular disease—any or specific subtypes (ischaemic heart disease, cerebrovascular disease, emboli/thrombosis, hypertensive diseases, heart failure, arrhythmia/conduction disorder, and fatal cardiovascular disease)—and 16 individual diagnoses of cardiovascular disease. Hazard ratios for cardiovascular disease were derived from Cox models, after controlling for multiple confounders. Results During up to 27 years of follow-up, the crude incidence rate of any cardiovascular disease was 10.5, 8.4, and 6.9 per 1000 person years among exposed patients, their unaffected full siblings, and the matched unexposed individuals, respectively. In sibling based comparisons, the hazard ratio for any cardiovascular disease was 1.64 (95% confidence interval 1.45 to 1.84), with the highest subtype specific hazard ratio observed for heart failure (6.95, 1.88 to 25.68), during the first year after the diagnosis of any stress related disorder. Beyond one year, the hazard ratios became lower (overall 1.29, 1.24 to 1.34), ranging from 1.12 (1.04 to 1.21) for arrhythmia to 2.02 (1.45 to 2.82) for artery thrombosis/embolus. Stress related disorders were more strongly associated with early onset cardiovascular diseases (hazard ratio 1.40 (1.32 to 1.49) for attained age &lt;50) than later onset ones (1.24 (1.18 to 1.30) for attained age ≥50; P for difference=0.002). Except for fatal cardiovascular diseases, these associations were not modified by the presence of psychiatric comorbidity. Analyses within the population matched cohort yielded similar results (hazard ratio 1.71 (1.59 to 1.83) for any cardiovascular disease during the first year of follow-up and 1.36 (1.33 to 1.39) thereafter). Conclusion Stress related disorders are robustly associated with multiple types of cardiovascular disease, independently of familial background, history of somatic/psychiatric diseases, and psychiatric comorbidity.
Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial
Authors: Stuart R Dalziel, Meredith L Borland, Jeremy Furyk, Megan Bonisch, Jocelyn Neutze, Susan Donath, Kate L Francis, Cynthia Sharpe, A Simon Harvey, Andrew Davidson, Simon Craig, Natalie Phillips, Shane George, Arjun Rao, Nicholas Cheng, Michael Zhang, Amit Kochar, Christine Brabyn, Ed Oakley, Franz E Babl
Journal: The Lancet (2019)
FRI-110-A nutraceutical supplement rich in docosahexaenoic acid improves portal hypertension in a pre-clinical model of chronic liver disease
Authors: Zoe Boyer-Diaz, Nicolo Manicardi, Peio Aristu, Laia Abad, Begoña Cordobilla, Anabel Fernández Iglesias, Martí Ortega Ribera, Joan Carles Domingo, Paloma Morata, Jaime Bosch, Jordi Gracia-Sancho
Journal: Journal of Hepatology (2019)
Unique arrangement of bone matrix orthogonal to osteoblast alignment controlled by Tspan11-mediated focal adhesion assembly
Authors: Yohei Nakanishi, Aira Matsugaki, Kosuke Kawahara, Takafumi Ninomiya, Hiroshi Sawada, Takayoshi Nakano
Journal: Biomaterials (2019)

During tissue construction, cells coordinate extracellular matrix (ECM) assembly depending on the cellular arrangement. The traditional understanding of the relationship between the ECM and cells is limited to the orientation-matched interaction between them. Indeed, it is commonly accepted that the bone matrix (collagen/apatite) is formed along osteoblast orientation. Nonetheless, our recent findings are contrary to the above theory; osteoblasts on nanogrooves organize formation of the bone matrix perpendicular to cell orientation. However, the precise molecular mechanisms underlying the orthogonal organization of bone matrix are still unknown. Here, we show that mature fibrillar focal adhesions (FAs) facilitate the perpendicular arrangement between cells and bone matrix. The osteoblasts aligned along nanogrooves expressed highly mature fibrillar FAs mediated by integrin clustering. Microarray analysis revealed that Tspan11, a member of the transmembrane tetraspanin protein family, was upregulated in cells on the nanogrooved surface compared with that in cells on isotropic, flat, or rough surfaces. Tspan11 silencing significantly disrupted osteoblast alignment and further construction of aligned bone matrix orthogonal to cell orientation. Our results demonstrate that the unique bone matrix formation orthogonal to cell alignment is facilitated by FA maturation. To the best of our knowledge, this report is the first to show that FA assembly mediated by Tspan11 determines the direction of bone matrix organization.
THU-097-Serum infrared spectral profile is predictive of the degree of hepatic fibrosis in chronic hepatitis C patients
Authors: Gérard Thiéfin, Dominique Bertrand, Valérie Untereiner, Roselyne Garnotel, Marc Offroy, Jean-Pierre Bronowicki, Ganesh Sockalingum
Journal: Journal of Hepatology (2019)
Monoamine Oxidase B Binding of 18F-THK5351 to Visualize Glioblastoma and Associated Gliosis
Authors: Tetsuro Tago, Jun Toyohara, Renpei Sengoku, Shigeo Murayama, Kenji Ishii
Journal: Clinical Nuclear Medicine (2019)

An 86-year-old woman with cognitive impairment and left hemiparesis underwent F-THK5351 PET 4 months before her death. In addition to "normal" off-target binding in the basal ganglia, abnormal accumulation was observed along the pyramidal tract and around the right basal ganglia as ring-shaped uptake that overlapped a gadolinium-enhanced lesion. Postmortem pathological examination revealed that she had glioblastoma multiforme with associated gliosis, in which monoamine oxidase B (MAO-B) activity is increased. In vitro autoradiography of the corresponding lesion demonstrated specific binding of F-THK5351, which was blocked by an MAO-B-selective ligand. Thus, F-THK5351 PET may reflect glioblastomas and associated gliosis by binding to MAO-B.