tbuckley/cabot-search huggingface dataset:
Airway pathology in severe asthma is related to airflow obstruction but not symptom control
Authors: D. S. Ferreira, R. M. Carvalho‐Pinto, M. G. Gregório, R. Annoni, A. M. Teles, M. Buttignol, B. B. Araújo‐Paulino, E. H. Katayama, B. L. Oliveira, H. S. Del Frari, A. Cukier, M. Dolhnikoff, R. Stelmach, K. F. Rabe, T. Mauad
Journal: Allergy (2017)

Abstract Background Patients with asthma present structural and inflammatory alterations that are believed to play a role in disease severity. However, airway remodeling and inflammation have not been extensively investigated in relation to both symptom control and airflow obstruction in severe asthmatics. We aimed to investigate several inflammatory and structural pathological features in bronchial biopsies of severe asthmatics that could be related to symptom control and airflow obstruction after standardized treatment. Methods Fifty severe asthmatics received prednisone 40 mg/d for 2 weeks and maintenance therapy with budesonide/formoterol 400/12 μg twice daily + budesonide/formoterol 200/6 μg as needed for 12 weeks. Endobronchial biopsies were performed at the end of 12 weeks. We performed extensive immunopathological analyses of airway tissue inflammation and remodeling features in patients stratified by asthma symptom control and by airflow obstruction. Results Airway tissue inflammation and remodeling were not associated with symptom control. Asthmatics with persistent airflow obstruction had greater airway smooth muscle (Asm) area with decreased periostin and transforming growth factor beta‐positive cells within Asm bundles, in addition to lower numbers of chymase‐positive mast cells in the submucosa compared to patients with nonpersistent obstruction. Conclusions Symptom control in severe asthmatics was not associated with airway tissue inflammation and remodeling, although persistent airflow obstruction in these patients was associated with bronchial inflammation and airway structural changes.
OATP1B1 and DAA treatment for hepatitis C in patients with hepatocellular carcinoma
Authors: Haithem Chtioui
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. TO THE EDITOR: I read with great interest the article by Soria et al.1 on viral relapses in hepatitis C virus (HCV)‐infected patients with hepatocellular carcinoma (HCC) who are treated with direct‐acting antivirals (DAAs). By the current state of knowledge, the complex issue of HCC recurrence after DAA therapy remains unclear, and several authors have emphasized the need for further investigation.2 In this context, raising the question of the influence of HCC itself on the outcome of hepatitis C treatment with DAAs is of considerable interest. A recent study suggests that the presence of active HCC at the time of HCV treatment initiation is associated with reduced chances of achieving a sustained virologic response.4 A clear explanation is still lacking, but the possibility of unequal drug distribution to the HCC area has been hypothesized. In the case series presented by Soria et al., all five patients with active HCC diagnosed within 5‐42 weeks after DAA initiation experienced viral relapse. However, it is not clear whether all patients had active HCC while being treated with DAAs. Among other hypotheses, the authors propose reduced uptake of DAA into HCC cells due to down‐regulation of the OATP1B1 (SLCO1B1) influx membrane transporter as a possible reason for DAA failure. This hypothesis is attractive, but the authors should have stressed that it may apply only to two out of the five reported patients with HCC. According to the data of the manufacturers, sofosbuvir, ledipasvir, daclatasvir, and ribavirin are not substrates of the OATP1B1 transporter.5 Thus, their intracellular disposition should not be altered by reduced OATP1B1 expression. Moreover, daclatasvir is an inhibitor of OATP1B1 and may impair the transport of substrate drugs through OATP1B1. In fact, only paritaprevir and simeprevir are substrates of OATP1B1. Presenting the hypothesis in the light of the affinity of the DAAs for the OATP1B1 transporter may have generated a more balanced discussion. To add another level of complexity, little is known about the replication of HCV in HCC cells in vivo. Further work will be required to address this important issue.
Abstract 20108: A Newly Identified Interaction Between Desmoplakin and COP9 Signalsome Subunit 6 Reveals a New Mechanism Underlying Sudden Death
Authors: Yan Liang, Robert Lyon, Jason Pellman, Valeria Mezzano, Yusu Gu, Nancy Dalton, Mong-Hong Lee, Tomoo Iwakuma, Vishal Nigam, Kirk Peterson, Farah Sheikh
Journal: Circulation (2016)

Arrrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic based cardiomyopathy, characterized by ventricular dysfunction, fibrofatty replacement of the ventricle and ventricular arrhythm...
Long-Term Air Pollution Exposure and Amyotrophic Lateral Sclerosis in Netherlands: A Population-based Case–control Study
Authors: Meinie Seelen, Rosario A. Toro Campos, Jan H. Veldink, Anne E. Visser, Gerard Hoek, Bert Brunekreef, Anneke J. van der Kooi, Marianne de Visser, Joost Raaphorst, Leonard H. van den Berg, Roel C.H. Vermeulen
Journal: Environmental Health Perspectives (2017)

Background: Recently, there has been increasing evidence that exposure to air pollution is linked to neurodegenerative diseases, but little is known about the association with amyotrophic lateral sclerosis (ALS). Objectives: We investigated the association between long-term exposure to air pollution and risk of developing ALS. Methods: A population-based case–control study was conducted in Netherlands from 1 January 2006 to 1 January 2013. Data from 917 ALS patients and 2,662 controls were analyzed. Annual mean air pollution concentrations were assessed by land use regression (LUR) models developed as part of the European Study of Cohorts for Air Pollution Effects (ESCAPE). Exposure estimates included nitrogen oxides (NO2, NOx), particulate matter (PM) with diameters of <2.5μm (PM2.5), <10μm (PM10), between 10μm and 2.5μm (PMcoarse), and PM2.5 absorbance. We performed conditional logistic regression analysis using two different multivariate models (model 1 adjusted for age, gender, education, smoking status, alcohol use, body mass index, and socioeconomic status; model 2 additionally adjusted for urbanization degree). Results: Risk of ALS was significantly increased for individuals in the upper exposure quartile of PM2.5 absorbance [OR=1.67; 95% confidence interval (CI): 1.27, 2.18], NO2 (OR=1.74; 95% CI: 1.32, 2.30), and NOx concentrations (OR=1.38; 95% CI: 1.07, 1.77). These results, except for NOx, remained significant after adjusting additionally for urbanization degree. Conclusions: Based on a large population-based case–control study, we report evidence for the association between long-term exposure to traffic-related air pollution and increased susceptibility to ALS. Our findings further support the necessity for regulatory public health interventions to combat air pollution levels and provide additional insight into the potential pathophysiology of ALS. https://doi.org/10.1289/EHP1115
Phase I/II trial of combination nab-paclitaxel and pemetrexed in advanced solid tumor patients (pts) with emphasis on non-small cell lung cancer (NSCLC).
Authors: Jonathan Riess, Cheryl Ho, Angela M. Davies, Derick Lau, Primo Lara, Helen K. Chew, Laurel Beckett, Randeep S. Sangha, Philip C. Mack, David R. Gandara
Journal: Journal of Clinical Oncology (2013)

e19147 Background: Despite advances in targeted therapies, there is an ongoing need to develop new and effective cytotoxic drug combinations in NSCLC. Preclinical evaluation has demonstrated additive cytotoxicity of pemetrexed and taxanes. We evaluated the safety and efficacy of combining nab-paclitaxel (nP) and pemetrexed (P) in solid tumors with a focus on NSCLC for the phase II expansion. Methods: A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Three dose levels were tested: P 500 mg/m 2 day 1 plus nP on day 1 at doses of 180, 220, and 260 mg/m 2 every 21 days. Dose limiting toxicity (DLT) in cycle 1 was defined as: grade 4 platelets or grade 3 platelets with bleeding, neutropenia with fever or documented infection, or other grade ≥ 3 non-heme toxicity. Phase II eligibility included advanced NSCLC, ≤ 2 line prior therapy, PS 0-1, adequate organ function. Primary endpoint for further study was response rate (RR) ≥ 25%. Results: Planned dose escalation during the Phase I portion was completed without reaching the MTD. The RP2D was P 500 mg/m 2 and nP 260 mg/m 2 . The phase II portion accrued 37 pts before early closure due to increasing use of first-line pemetrexed/platinum doublet therapy in non-squamous NSCLC. Phase II patient characteristics: median 63 (45-77); M:F 23:14; median cycles 3. In 31 assessable patients: 5 PR, 12 SD and 14 PD. Efficacy: RR =14%; disease control rate (DCR) = 46%; median survival time (MST) = 8.7 months. Pts in the DCR group had a MST of 15.4 vs 4 months in the PD group (p=0.02). Conclusions: P 500 mg/m 2 day 1 with nP 260 mg/m 2 was feasible and well tolerated. The phase II component demonstrated activity in second-line therapy of advanced NSCLC. Practice patterns have evolved; so further trials of this regimen are not planned. Clinical trial information: NCT00470548.
Recent Advances in the Generation of Antibody–Nanomaterial Conjugates
Authors: Amal J. Sivaram, Andri Wardiana, Christopher B. Howard, Stephen M. Mahler, Kristofer J. Thurecht
Journal: Advanced Healthcare Materials (2017)

Abstract Targeted nanomedicines have significantly changed the way new therapeutics are designed to treat disease. Central to successful therapeutics is the ability to control the dynamics of protein–nanomaterial interactions to enhance the therapeutic effect of the nanomedicine. The aim of this review is to illustrate the diversity and versatility of the conjugation approaches involved in the synthesis of antibody–nanoparticle conjugates, and highlight significant new advances in the field of bioconjugation. Such nanomedicines have found utility as both advanced therapeutic agents, as well as more complex imaging contrast agents that can provide both anatomical and functional information of diseased tissue. While such conjugates show significant promise as next generation targeted nanomedicines, it is recognized that there are in fact no clinically approved targeted therapeutics on the market. This fact is reflected upon within this review, and attempts are made to draw some reasoning from the complexities associated with the bioconjugation chemistry approaches that are typically utilized. Present trends, as well as future directions of next generation targeted nanomedicines are also discussed.
Corollary Discharge, Self-agency, and the Neurodevelopment of the Psychotic Mind
Authors: Michele Poletti, Eva Gebhardt, Andrea Raballo
Journal: JAMA Psychiatry (2017)

This article discusses the need for integrating dysfunctional corollary discharge in premorbid stages of psychosis with converging insights from developmental psychopathology and phenomenology to better understand causal psychopathological cascades in the genesis of psychotic symptoms.
ASXL3 Is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer
Authors: Vivek Shukla, Mahadev Rao, Hongen Zhang, Jeanette Beers, Darawalee Wangsa, Danny Wangsa, Floryne O. Buishand, Yonghong Wang, Zhiya Yu, Holly S. Stevenson, Emily S. Reardon, Kaitlin C. McLoughlin, Andrew S. Kaufman, Eden C. Payabyab, Julie A. Hong, Mary Zhang, Sean Davis, Daniel Edelman, Guokai Chen, Markku M. Miettinen, Nicholas P. Restifo, Thomas Ried, Paul A. Meltzer, David S. Schrump
Journal: Cancer Research (2017)

Abstract In this study, we generated induced pluripotent stem cells (iPSC) from normal human small airway epithelial cells (SAEC) to investigate epigenetic mechanisms of stemness and pluripotency in lung cancers. We documented key hallmarks of reprogramming in lung iPSCs (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAECs. Of particular novelty, we identified the PRC2-associated protein, ASXL3, which was markedly upregulated in Lu-iPSCs and small cell lung cancer (SCLC) lines and clinical specimens. ASXL3 overexpression correlated with increased genomic copy number in SCLC lines. ASXL3 silencing inhibited proliferation, clonogenicity, and teratoma formation by Lu-iPSCs, and diminished clonogenicity and malignant growth of SCLC cells in vivo. Collectively, our studies validate the utility of the Lu-iPSC model for elucidating epigenetic mechanisms contributing to pulmonary carcinogenesis and highlight ASXL3 as a novel candidate target for SCLC therapy. Cancer Res; 77(22); 6267–81. ©2017 AACR.
Putting a Small Number of Health Care Plan Choices in Perspective
Authors: Peter V. Lee
Journal: JAMA Internal Medicine (2017)

There has been much flux in the health insurance exchange market this year, with more clearly to come. In this issue of JAMA Internal Medicine, Zhu et al1 estimated that 2017 premiums in insurance markets with a single issuer increased 30% compared with 15% in markets having 4 or more issuers.
Pattern analysis of microtubule inhibitor combination effects on cells
Authors: Carol Heckman, Sonal Uppal, Yingxin Li, Elizabeth Wendt, Nancy Boudreau, Marilyn Cayer
Journal: Cancer Research (2007)

3237   The purpose of this work was to determine whether or how reversal of the morphological properties of cultured cells relates to the therapeutic effect of inhibitor combinations. The phenotype of single cells can be deconstructed using computerized morphometry classification. In experiments, such phenotypes can be solved by comparison with a database of normal and oncogenically transformed cells. Previously, a combination of microtubule-depolymerizing and -polymerizing agents, colchicine and paclitaxel, was found to lead to reversal of phenotype. The suggestion that such combinations might be effective clinically was rapidly followed by clinical trials employing docetaxel and microtubule-depolymerizing agent, vinorelbine (D + V). Classification of cells based on principal components, called latent factors, was used to learn whether all combinations had similar effects as of paclitaxel and colchicine on cell features. Reports of delivery schedule and drug ratio in D + V clinical trials were subjected to statistical analysis. Microtubule arrangement and cell cycle were studied by indirect immunocytochemistry and flow cytometry, respectively. Paclitaxel in combination with any microtubule-depolymerizing agent (podophyllotoxin, nocodazole, or vinblastine) reverted the cells to a normal phenotype. Cell features represented by a total of six latent factors were significantly affected by at least one of the combinations. The factor accounting for the single largest difference between normal and transformed cells (#4 filopodia) was only affected by combinations containing colchicine or podophyllotoxin. Its values were changed in the direction expected of a more normal phenotype. Another factor for cell edge features, #7, was altered in most of the combination treatments but in the direction expected of a more transformed cell. In reviewing the clinical studies, we found that the highest efficacy of D + V is observed when the two inhibitors are administered together, not interspersed with a single agent. The treated cells showed several differences in microtubule arrangement, including straighter microtubules, and suppression of the microtubule-organizing center. A perpendicular arrangement of microtubules to the cell edge may be a morphological indicator of reversal. The results suggested a novel mechanism of the inhibitor combination as chemotherapy.
CUX1 stimulates APE1 enzymatic activity and increases the resistance of glioblastoma cells to the mono-alkylating agent temozolomide
Authors: Simran Kaur, Zubaidah M Ramdzan, Marie-Christine Guiot, Li Li, Lam Leduy, Dindial Ramotar, Siham Sabri, Bassam Abdulkarim, Alain Nepveu
Journal: Neuro-Oncology (2017)

Cut Like homeobox 1 (CUX1), which encodes an auxiliary factor in base excision repair, resides on 7q22.1, the most frequently and highly amplified chromosomal region in glioblastomas. The resistance of glioblastoma cells to the mono-alkylating agent temozolomide is determined to some extent by the activity of apurinic/apyrimidinic endonuclease 1 (APE1).To monitor the effect of CUX1 and its CUT domains on APE1 activity, DNA repair assays were performed with purified proteins and cell extracts. CUX1 protein expression was analyzed by immunohistochemistry using a tumor microarray of 150 glioblastoma samples. The effect of CUX1 knockdown and overexpression on the resistance of glioblastoma cell lines to temozolomide was investigated.We show that CUT domains stimulate APE1 activity. In agreement with these findings, CUX1 knockdown causes an increase in the number of abasic sites in genomic DNA and a decrease in APE1 activity as measured in cell extracts. Conversely, ectopic CUX1 expression increases APE1 activity and lowers the number of abasic sites. Having established that CUX1 is expressed at high levels in most glioblastomas, we next show that the resistance of glioblastoma cells to temozolomide and to a combined treatment of temozolomide and ionizing radiation is reduced following CUX1 knockdown, but increased by overexpression of CUX1 or a short protein containing only 2 CUT domains, which is active in DNA repair but devoid of transcriptional activity.These findings indicate that CUX1 expression level impacts on the response of glioblastoma cells to treatment and identifies the CUT domains as potential therapeutic targets.
Breathlessness despite optimal pathophysiological treatment: on the relevance of being chronic
Authors: Peter M.A. Calverley
Journal: European Respiratory Journal (2017)

Morélot-Panzini and colleagues response to the paper by Johnson et al. [1] is an important contribution to the debate about the chronic breathlessness syndrome, which I called for in my editorial [2] and to which others have already contributed [3, 4]. English is a greedy language using words that mean the same in their original tongue to denote slight differences in meaning in English. In this case, dyspnoea is the technical term for breathlessness. In 40 years of clinical practice I never met a patient who complained of dyspnoea but saw many who were greatly affected by what they called breathlessness. This distinction between the symptom and its impact are at the heart of the discussions around the chronic breathlessness syndrome. I strongly support the need to provide more holistic care that looks at the consequences of breathlessness as well as their causes. However, important secondary effects on mood, behaviour and lifestyle occur in many chronic conditions not fully controlled by medical-management strategies. Should we refer to chronic arthritis syndrome or chronic cluster headache syndrome or any of the numerous other examples which readily suggest themselves? Whether or not we use the word syndrome these patients need better care than they currently receive. Chronic breathlessness is an under-recognised problem irrespective of the terminology used to describe it <http://ow.ly/kKQs30es6A8>
Gladys Mary Tinker
Authors: Anne Freeman, Philip Routledge, Hamsaraj Shetty, Dwarak Sastry
Journal: BMJ (2017)

Gladys Mary Tinker was born in Montrose, Scotland, the daughter of the late Leonard and Sylvia Purvis. Not only was she joint top academic scholar at school, but in her last year of secondary school was awarded the title of sports champion of the school. In her youth, she and her sister were keen rifle shots and competed all over Scotland.

She graduated from the University of Edinburgh in 1969, and after house jobs there she started her junior training in Cardiff and in 1976 was senior registrar in Carmarthen and then to the late Professor John Pathy in Cardiff.

Gladys was appointed consultant in geriatric medicine in Cardiff in 1980 and chose …
Comparative oncogenomic analysis of hepatocellular carcinoma in human and rodent models for revealing putative cancer genes
Authors: Kuen-Tyng Lin, Yuh-Shan Jou, Su Wen-Hui
Journal: Cancer Research (2007)

3709   Recently, several studies using cross-species comparative genomic analysis has proved to be a powerful strategy to identify putative cancer genes. The alignment of chromosome aberration and the consistence of gene expression between mouse and human tumors could effective narrowed down the minimum overlapping region and help to identify putative cancer genes. Previously, we have constructed an open access database OncoDB.HCC (http://oncodb.hcc.ibms.sinica.edu.tw) which integrated various genomic data in HCC to provide lines of evidence for revealing important aberrant cancer target genes and loci. Via comparative mapping of HCC loci in between human aberrant chromosomal  regions and quantitative trait loci (QTLs) of mouse and rat HCC models we revealed 12 syntenic HCC  regions and the putative human cancer genes located in those regions. In this study, the microarray data of mouse and rat HCC models were downloaded from public database. The comparative oncognomic analysis was performed by comparing the expression profiles between orthologous genes and then combined with the syntenic HCC region data. First, the human and rodent orthologous genes with concordant expression patterns in both species were listed. From the analysis of mouse and human expression profiles, 133 genes with concordant up (64 genes) and down (69 genes) regulated expression patterns were identified. From the rat and human expression profile analysis, 17 genes with concordant up (7 genes) and down (10 genes) regulated expression patterns were identified. The concordantly expressed genes in between human and rodent HCCs were analyzed by gene ontology and pathway analysis. We further integrated those concordant expressed genes onto 12 syntenic HCC regions and mouse/rat QTL for identification of putative cancer genes. In total, 5 putative oncogenes were found to be concordantly up regulated in both human and rat microarrays and located in human HCC chromosome copy number increase regions as well as mouse QTL syntenic regions. On the other hand, 2 putative oncogenes from rat microarray studies using similar criteria. Interestingly, no putative tumor suppressor genes were identified in this comparative oncogenomic analysis. Our results also suggested those genes could be the potential cancer genes for the corresponding rodent HCC models and played an important role in tumorigenesis of human and rodent. Further experimental validation should be performed using those rodent models. In conclusion, the cross-species comparative oncogenomic analysis could effectively filter putative cancer genes from heterogeneous and complicated oncogenomic data. Furthermore, this strategy would be valuable in dissecting the HCC tumorigenesis pathway between human and rodent as well as identifying representative rodent HCC models which would have plenty application in the HCC diagnosis and therapy.
FDA Approval of Tisagenlecleucel
Authors: Peter B. Bach, Sergio A. Giralt, Leonard B. Saltz
Journal: JAMA (2017)

This Viewpoint uses FDA approval of tisagenlecleucel, the first chimeric antigen receptor T-cell (CAR-T) agent approved for human use, to discuss escalating drug prices for oncology therapies and the complex considerations of outcomes and value that should justify the pricing.