tbuckley/cabot-search huggingface dataset:
In acute uncomplicated influenza, single-dose baloxavir decreased time to symptom relief compared with placebo
Authors: Bruno P. Granwehr
Journal: Annals of Internal Medicine (2018)

Source Citation Hayden FG, Sugaya N, Hirotsu N, et al; Baloxavir Marboxil Investigators Group. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med. 2018;379:913-23. 30184455
Aging‐Related Expression of Twinfilin‐1 Regulates Cholangiocyte Biological Response to Injury
Authors: Luca Maroni, Claudio Pinto, Debora Maria Giordano, Stefania Saccomanno, Jesus M. Banales, Daniele Spallacci, Maria Cristina Albertini, Fiorenza Orlando, Mauro Provinciali, Malgorzata Milkiewicz, Espen Melum, Ibone Labiano, Piotr Milkiewicz, Chiara Rychlicki, Luciano Trozzi, Marina Scarpelli, Antonio Benedetti, Gianluca Svegliati Baroni, Marco Marzioni
Journal: Hepatology (2018)

Disorders of the biliary tree develop and progress differently according to patient age. It is currently not known whether the aging process affects the response to injury of cholangiocytes. The aim of this study was to identify molecular pathways associated with cholangiocyte aging and to determine their effects in the biological response to injury of biliary cells. A panel of microRNAs (miRs) involved in aging processes was evaluated in cholangiocytes of young and old mice (2 months and 22 months of age, respectively) and subjected to a model of sclerosing cholangitis. Intracellular pathways that are common to elevated miRs were identified by in silico analysis. Cell proliferation and senescence were evaluated in Twinfilin‐1 ( Twf1 ) knocked‐down cells. In vivo , senescence‐accelerated prone mice ( Samp8 , a model for accelerated aging), Twf1‐/‐ , or their respective controls were subjected to DDC (3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine). Cholangiocytes from DDC‐treated mice showed up‐regulation of a panel of aging‐related miRs . Twf1 was identified by in silico analysis as a common target of the up‐regulated miRs . Twf1 expression was increased both in aged and diseased cholangiocytes, and in human cholangiopathies. Knock‐down of Twf1 in cholangiocytes reduced cell proliferation. Senescence and senescence‐associated secretory phenotype marker expression increased in Twf1 knocked‐down cholangiocytes following pro‐proliferative and pro‐senescent (10‐day lipopolysaccharide) stimulation. In vivo , Samp8 mice showed increased biliary proliferation, fibrosis, and Twf1 protein expression level, whereas Twf1‐/‐ had a tendency toward lower biliary proliferation and fibrosis following DDC administration compared with control animals. Conclusion: We identified Twf1 as an important mediator of both cholangiocyte adaptation to aging processes and response to injury. Our data suggest that disease and aging might share common intracellular pathways.
Advanced CT imaging features reflect distinct tissue immune profiles and exhibit high prognostic impact on NSCLC
Authors: G. Mazzaschi, P. Pagano, G. Milanese, D. Madeddu, A. Falco, G. Armani, G. Bocchialini, D. Marturano, L. Ampollini, B. Lorusso, C. Lagrasta, N. Sverzellati, M. Silva, M. Tiseo, F. Quaini, G. Roti
Journal: Annals of Oncology (2018)

Background: Intersecting genetic, biologic and clinico-pathological features with high-throughput imaging may pave the way to precision oncology. We advanced the hypothesis that the tumor immune microenvironment (TIME) may imprint on CT scan parameters in a qualitative and quantitative (radiomics) fashion, providing a non-invasive approach to identify new prognostic factors in NSCLC patients. Methods: In this study, we enrolled sixty (31 Adenocarcinoma, 29 Squamous Cell Carcinoma) surgically resected patients. We defined TIME by the quantitative assessment of PD-L1 expression and a detailed morphometric evaluation of Tumor Infiltrating Lymphocytes (TILs). Next, from each tumor associated images we extrapolated 841 CT radiomic features through an open-source (3d Slicer) software. Results: We observed high levels of tissue PD-L1 in radiologic lesions displaying a solid texture and any effect on the surrounding parenchyma (p < 0.05), while well defined CT margins were seen in TILs-rich cases (p < 0.05). The combined analysis of predetermined risk factors from TIME and CT texture had a striking impact on clinical outcome. Patients with low PD-1 expression on CD8+ TILs and CT evidence of tumor effect on parenchyma had significantly increased (p < 0.001) OS with respect to their counterpart (median 50 vs 30 months, HR = 16.82). We also documented prolonged survival (p < 0.05) in cases with well defined CT margins and high CD8-to-CD3 TILs (46 vs 35 months, HR = 2.66). Intriguingly, when an unsupervised hierarchical clustering model was applied to radiomics data, we identified two clusters (A and B) with oppositely regulated features: the first of 57 cases (A), further branching into two continuous different clusters, the second (B) comprised only three patients sharing a mutual genetic (EGFR and KRAS mutations), immunologic (PD-L1, CD3+ and CD8+ TILs, PD-1/CD8 ratio), radiologic (shape, effect, texture and structure) and clinical (relapse and death) profile. Conclusions: A highly significant prognostic score can be obtained in NSCLC by integrating TIME with CT features. Distinct tissue immune backgrounds may entail imaging textures potentially able to portray a radiologic signature of lung cancer. Legal entity responsible for the study: University of Parma. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Cost-Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Pediatric Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia
Authors: Reith R Sarkar, Nicholas J Gloude, Deborah Schiff, James D Murphy
Journal: JNCI Journal of the National Cancer Institute (2018)

Abstract Background Chimeric antigen receptor T-cell (CAR-T) therapy is a promising new class of cancer therapy but has a high up-front cost. We evaluated the cost-effectiveness of CAR-T therapy among pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Methods We built a microsimulation model for pediatric patients with relapsed/refractory B-ALL receiving either CAR-T therapy or standard of care. Outcomes included costs, quality of life (health utility), complications, and survival. We measured cost-effectiveness with the incremental cost-effectiveness ratio (ICER), with ICERs under $100 000 per quality-adjusted life-year (QALY) considered cost effective. One-way and probabilistic sensitivity analyses were used to test model uncertainty. Results Compared to standard of care, CAR-T therapy increased overall cost by $528 200 and improved effectiveness by 8.18 QALYs, resulting in an ICER of $64 600/QALY. The model was sensitive to assumptions about long-term CAR-T survival, the complete remission rate of CAR-T patients, and the health utility of long-term survivors. The base model assumed a 76.0% one-year survival with CAR-T, although if this decreased to 57.8%, then CAR-T was no longer cost effective. If the complete remission rate of CAR-T recipients decreased from 81% to 56.2%, or if the health utility of disease-free survivors decreased from 0.94 to 0.66, then CAR-T was no longer cost effective. Probabilistic sensitivity analysis found that CAR-T was cost effective in 94.8% of iterations at a willingness to pay of $100 000/QALY. Conclusion CAR-T therapy may represent a cost-effective option for pediatric relapsed/refractory B-ALL, although longer follow-up of CAR-T survivors is required to confirm validity of these findings.
Control of Human Hemoglobin Switching By LIN28B-Mediated Regulation of BCL11A Translation
Authors: Anindita Basak, Mathias Munschauer, Jacob C. Ulirsch, Kara E. Montbleau, Christina R. Hartigan, Monica Schenone, John Lian, Yaomei Wang, Yumin Huang, Xianfang Wu, Lee Gehrke, Charles M. Rice, Xiuli An, Helen A. Christou, Mohandas Narla, Steven A. Carr, Stuart H. Orkin, Jane-Jane Chen, Eric S. Lander, Vijay G. Sankaran
Journal: Blood (2018)
Abstract 17390: Pharmacologically Induced Hypothermia With the Cannabinoid Receptor Agonist Win55, 212-2 Eliminates Shivering in a Rat Model of Cardiac Arrest
Authors: Nikki Duggal, Yan Xiao, Qinyue Guo, Jin Yang, Weiping Huang, Zhangle Hu, Jennifer Bradley, Mary Ann Peberdy, Joseph P Ornato, Wanchun Tang
Journal: Circulation (2017)

Introduction: Mechanically induced hypothermia (MH) commonly causes shivering (S) that has many unwanted clinical effects. The cannabinoid receptor antagonist WIN55, 212-2 (WIN) induces hypothermia...
The Prognostic Calculator Easix Predicts Acute Gvhd, Non-Relapse Mortality and Overall Survival in Adult Patients Undergoing Reduced Intensity Conditioning Allogeneic HCT
Authors: Miriam Sanchez-Escamilla, Patrick Hilden, Molly Maloy, Samira A Fatmi, Doris Ponce, Craig S. Sauter, Sergio Giralt, Miguel-Angel Perales
Journal: Blood (2018)
A Pediatric Asthma Risk Score to better predict asthma development in young children
Authors: Jocelyn M. Biagini Myers, Eric Schauberger, Hua He, Lisa J. Martin, John Kroner, Gregory M. Hill, Patrick H. Ryan, Grace K. LeMasters, David I. Bernstein, James E. Lockey, S. Hasan Arshad, Ramesh Kurukulaaratchy, Gurjit K. Khurana Hershey
Journal: Journal of Allergy and Clinical Immunology (2018)
New Idiopathic Pulmonary Fibrosis Guidelines: Are Cryobiopsy and Surgery Competitive in Clinical Practice?
Authors: Claudia Ravaglia, Sara Tomassetti, Venerino Poletti
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

In previous studies, the presence of reticulation and traction bronchiectasis without GGO (previous possible IPF) usually yielded a UIP pathological diagnosis and a final diagnosis of IPF (5).Would it not be easier to remove GGO from probable UIP and keep this feature in the indeterminate UIP category?This will assist the clinician in opting not to do invasive procedures in UIP or probable UIP on highresolution computed tomography imaging.The various presentations of indeterminate UIP can then be better characterized in future studies.Finally, although beyond the scope of this discourse, the role of antifibrotics will need future clarification.From this article, subjects with inflammatory change (GGO) and fibrosis will potentially have the diagnosis of IPF.Antifibrotics may need to be combined with other modalities, such as antiinflammatory agents, in the new diagnosis of IPF.
Metastatic malignant transformation of teratoma to primitive neuroectodermal tumor (PNET): Results with PNET-based chemotherapy.
Authors: Amit Jain, Lawrence H. Einhorn, Mary J. Brames
Journal: Journal of Clinical Oncology (2012)

4598 Background: Metastatic germ cell cancers are highly chemosensitive and have 80% cure rate with cisplatin based chemotherapy. Post-chemotherapy teratoma can usually be surgically resected. However, teratoma, which is pleuripotent tissue, can undergo malignant transformation along mesodermal elements to PNET. Unlike teratoma, PNET can metastasize and render a patient unresectable and incurable. We report the results of treatment of patients with PNET with cyclophosphamide + doxorubicin + vincristine (CAV) alternating with ifosfamide + etoposide (IE). Methods: We reviewed 81 patients with histologically confirmed PNET transformed from testicular teratoma at Indiana University from 1998 to 2011. We identified 13 cases who were treated with chemotherapy comprising cyclophosphamide 1000-1200 mg/m 2 , doxorubicin 50-75 mg/m 2 , and vincristine 2 mg alternating with ifosfamide 1.8 grams/m 2 plus etoposide 100 mg/m 2 for 5 days. Treatment was given every 3 weeks with a maximum of 6 cycles or until progression or undue toxicity. Hematopoeitic growth factors were usually incorporated. The remaining 68 patients underwent surgical resection. Results: Ten patients had unresectable disease and 3 were treated in an adjuvant setting. Median age was 31 years (range 20-53). Ten of 13 patients had received prior platinum based chemotherapy. Eight of 10 evaluable patients achieved objective response. Five of those were rendered with no evidence of disease(NED) with further surgery. Although 4 of the 5 patients subsequently relapsed, 1 patient remains alive with NED at 69 months. The 3 patients who received adjuvant treatment after retroperitoneal lymph node dissection (RPLND) are alive with NED at 1, 4 and 8 years. Conclusions: CAV and IE alternating chemotherapy has high objective response rate for PNET transformed from teratoma and results in occasional long term disease free survival when combined with subsequent resection. We recommend adjuvant CAV alternating with IE chemotherapy for patients with PNET after RPLND due to the high probability of recurrent disease and their high chemosensitivity to this regimen.
An adapted anti-CTLA4 therapeutic aimed at mitigating the toxicities of checkpoint inhibition
Authors: Jarushka Naidoo, Arbor Dykema, Franco D’Alessio
Journal: Journal of Clinical Investigation (2018)

Antibodies that target immune checkpoint molecules, such as CTLA4, provide robust antitumor effects in a subset of patients. Unfortunately, not all patients respond to immune checkpoint inhibition, and some develop life-threatening immune-related adverse events (irAEs). The mechanisms that underlie irAEs from immune checkpoint inhibition are not fully understood, and treatment strategies are currently limited to targeting inflammatory mediators. In this issue of the JCI, Pai et al. report on their development of a modified CTLA4 antibody that shields the inner CTLA4-binding domain until the antibody is within the protease-rich tumor microenvironment. In a lymphopenic murine model reconstituted with naive CD4+ T cells, adapted anti-CTLA4 reduced the occurrence of irAEs and enhanced antitumor effects. This thought-provoking study lays the groundwork for further exploration of this adapted antibody in immunocompetent hosts and introduction of this adaptation to other immune checkpoint molecules. It also suggests that this approach may reduce the incidence of irAEs.
Polyphyly in 16S rRNA-Based LVTree <i>Versus</i> Monophyly in Whole-Genome-Based CVTree
Authors: Guanghong Zuo, Ji Qi, Bailin Hao
Journal: Genomics Proteomics & Bioinformatics (2018)

Abstract We report an important but long-overlooked manifestation of low-resolution power of 16S rRNA sequence analysis at the species level, namely, in 16S rRNA-based phylogenetic trees polyphyletic placements of closely-related species are abundant compared to those in genome-based phylogeny. This phenomenon makes the demarcation of genera within many families ambiguous in the 16S rRNA-based taxonomy. In this study, we reconstructed phylogenetic relationship for more than ten thousand prokaryote genomes using the CVTree method, which is based on whole-genome information. And many such genera, which are polyphyletic in 16S rRNA-based trees, are well resolved as monophyletic clusters by CVTree. We believe that with genome sequencing of prokaryotes becoming a commonplace, genome-based phylogeny is doomed to play a definitive role in the construction of a natural and objective taxonomy.
Effect of PI3K inhibitor LY294002 combined with RAD001, a mTOR specificity inhibitor, on proliferation and apoptosis of triple-negative breast cancer cell lines MDA-MB-231 through PI3K/AKT/mTOR pathway in vitro.
Authors: SUN Gang, MA Bin, Huai LEI, MA BIN Lin
Journal: Journal of Clinical Oncology (2015)

e12088 Background: Research of targeted therapies about PI3K/Akt/mTOR pathway have became a hotspot recently,and related researches have been extended from a single-target suppression to multiple-targets combined inhibition. In this study,by using LY294002 and RAD001,the specific inhibitors of PI3K and mTOR,to observe whether the anti-tumor effects on the proliferation,cycle distribution and apoptosis of combined inhibitors were a synergistic effect,and were differences between different molecular characteristics of human breast cancer cells alone and in combination in vitro. Methods: Routinely cultured MCF-7, SK-BR-3 and MDA-MB-231 cells in vitro. Logarithmic phase cells among each cells were selected and divided into the blank control group , LY294002 group, RAD001 group and the combination group. MTT assay and flow cytometry were used to detect the cell proliferation,cell cycle distribution and cell apoptosis of different groups. Results: LY294002 and RAD001 could significantly inhibit the proliferations of MCF-7,SK-BR-3 and MDA-MB-231 cells with a dose-dependent manner respectively,and compared with other cells,MDA-MB-231 cells were more sensitive to both drugs. The anti-tumor effects were significantly increased in combination groups of different cells,and showed an additive effects. When two inhibitors were combined,the apoptosis rates of the different cells were significantly increased compared with single drug, especially in MDA-MB-231 cell. Conclusions: Targeted therapy on P13K/Akt/mTOR pathway could significantly inhibit the proliferation of human breast cancer cell lines by inducing apoptosis and arresting cell cycle distribution. By using a combination of different inhibitors which were targeted on different related genes of this pathway such as PI3K and mTOR,the anti-tumor effects were more significant increasd compared with monotherapy,especially in MDA-MB-231 cell line which were negative with ER, PR and HER-2. It was important to provide new research ideas for individualized treatment and translational medicine of breast cancer.
Comparative Assessment of Clinical Benefit Using the ESMO-Magnitude of Clinical Benefit Scale Version 1.1 and the ASCO Value Framework Net Health Benefit Score
Authors: Nathan I. Cherny, Elisabeth G.E. de Vries, Urania Dafni, Elizabeth Garrett-Mayer, Shannon E. McKernin, Martine Piccart, Nicola J. Latino, Jean-Yves Douillard, Lowell E. Schnipper, Mark R. Somerfield, Jan Bogaerts, Dimitris Karlis, Panagiota Zygoura, Katerina Vervita, George Pentheroudakis, Josep Tabernero, Christoph Zielinski, Dana S. Wollins, Richard L. Schilsky
Journal: Journal of Clinical Oncology (2019)

PURPOSE To better understand the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) and the ASCO Value Framework Net Health Benefit score version 2 (ASCO-NHB v2), ESMO and ASCO collaborated to evaluate the concordance between the frameworks when used to assess clinical benefit attributable to new therapies. METHODS The 102 randomized controlled trials in the noncurative setting already evaluated in the field testing of ESMO-MCBS v1.1 were scored using ASCO-NHB v2 by its developers. Measures of agreement between the frameworks were calculated and receiver operating characteristic curves used to define thresholds for the ASCO-NHB v2 corresponding to ESMO-MCBS v1.1 categories. Studies with discordant scoring were identified and evaluated to understand the reasons for discordance. RESULTS The correlation of the 102 pairs of scores for studies in the noncurative setting is estimated to be 0.68 (Spearman’s rank correlation coefficient; overall survival, 0.71; progression-free survival, 0.67). Receiver operating characteristic curves identified thresholds for ASCO-NHB v2 for facilitating comparisons with ESMO-MCBS v1.1 categories. After applying pragmatic threshold scores of 40 or less (ASCO-NHB v2) and 2 or less (ESMO-MCBS v1.1) for low benefit and 45 or greater (ASCO-NHB v2) and 4 to 5 (ESMO-MCBS v1.1) for substantial benefit, 37 discordant studies were identified. Major factors that contributed to discordance were different approaches to evaluation of relative and absolute gain for overall survival and progression-free survival, crediting tail of the curve gains, and assessing toxicity. CONCLUSION The agreement between the frameworks was higher than observed in other studies that sought to compare them. The factors that contributed to discordant scores suggest potential approaches to improve convergence between the scales.
DNA Methylation Controls Metastasis-Suppressive 14q32-Encoded miRNAs
Authors: Go Oshima, Elizabeth C. Poli, Michael J. Bolt, Alexandre Chlenski, Martin Forde, Jessica M.S. Jutzy, Neha Biyani, Mitchell C. Posner, Sean P. Pitroda, Ralph R. Weichselbaum, Nikolai N. Khodarev
Journal: Cancer Research (2018)

Expression of 14q32-encoded miRNAs is a favorable prognostic factor in patients with metastatic cancer. In this study, we used genomic inhibition of DNA methylation through disruption of DNA methyltransferases DNMT1 and DNMT3B and pharmacologic inhibition with 5-Aza-2'-deoxycytidine (5-Aza-dC, decitabine) to demonstrate that DNA methylation predominantly regulates expression of metastasis-suppressive miRNAs in the 14q32 cluster. DNA demethylation facilitated CCCTC-binding factor (CTCF) recruitment to the maternally expressed gene 3 differentially methylated region (MEG3-DMR), which acts as a cis-regulatory element for 14q32 miRNA expression. 5-Aza-dC activated demethylation of the MEG3-DMR and expression of 14q32 miRNAs, which suppressed adhesion, invasion, and migration (AIM) properties of metastatic tumor cells. Cancer cells with MEG3-DMR hypomethylation exhibited constitutive expression of 14q32 miRNAs and resistance to 5-Aza-dC-induced suppression of AIM. Expression of methylation-dependent 14q32 miRNAs suppressed metastatic colonization in preclinical models of lung and liver metastasis and correlated with improved clinical outcomes in patients with metastatic cancer. These findings implicate epigenetic modification via DNA methylation in the regulation of metastatic propensity through miRNA networks and identify a previously unrecognized action of decitabine on the activation of metastasis-suppressive miRNAs. SIGNIFICANCE: This study investigates epigenetic regulation of metastasis-suppressive miRNAs and the effect on metastasis.
Abstract 13292: Comprehensive Cardiac Rehabilitation versus Treatment as Usual For Implantable Cardioverter Defibrillator Recipients Improves Exercise Capacity, General Health and Mental Health - Mixed Methods Approach Embedding Data from a Randomised Clinical Trial with Qualitative Data
Authors: Selina K Berg, Preben U Pedersen, Ann-Dorthe Zwisler, Per Winkel, Christian Gluud, Birthe Pedersen, Jesper Hastrup Svendsen
Journal: Circulation (2012)

Selina K Berg, 2012 Finalist and Presenting Author
Locking wards has no place in psychiatric rehabilitation, says royal college
Authors: Jacqui Thornton
Journal: BMJ (2018)

The Royal College of Psychiatrists has said that it is increasingly concerned about the use of locked rehabilitation wards for people with serious mental health problems, which were stopping them getting better as quickly as possible.

Last week an independent review of the Mental Health Act found that in 2017-18 some 49 551 people in England and Wales were detained under the legislation and that the average cost of each detention has been estimated at £18 315 (€20 400; $23 200), totalling more than £900m a year.1 It recommended major investment in community services to prevent patients reaching a crisis and to support them outside hospital, and bringing dilapidated specialist inpatient mental health hospitals up …
Choosing Core Outcomes for Use in Clinical Trials in Ophthalmology: Perspectives from Three Ophthalmology Outcomes Working Groups
Authors: Ian J. Saldanha, Jimmy T. Le, Sharon D. Solomon, Michael X. Repka, Esen K. Akpek, Tianjing Li, Natalie Afshari, Andre Ambrus, Penny Asbell, Christophe Baudoin, Vatinee Bunya, Emily Chew, Roy Chuck, Diana Do, Malvina Eydelman, Darren Gregory, Andzrej Grzybowski, Julia Haller, Pedram Hamrah, Jonathan Holmes, Rahul Khurana, Douglas Jabs, Henry Jampel, Leslie Jones, Anat Loewenstein, Flora Lum, Maureen Maguire, Steven Maskin, Norman Medow, Elisabeth Messmer, Victor Perez, Hank Perry, Rebecca Petris, Jose Pulido, Ursula Schmid-Erfurth, Christopher Starr, Kazuo Tsubota, Susan Vitale, Adam Wenick
Journal: Ophthalmology (2018)