tbuckley/cabot-search huggingface dataset:
The spatial distribution and etiology of genomic instability in organotypic bronchial epithelial cell cultures
Authors: Walter N. Hittelman, Guiying Wang, Ja Seok Peter Koo, Tao Lu
Journal: Cancer Research (2005)

3527   Chromosome in situ hybridization and molecular genetic analyses of bronchial biopsies of smokers demonstrate genetic instability and clonal/subclonal bronchial cell outgrowths that continue despite tobacco cessation. To better understand the molecular underpinnings of genomic instability in the lungs of former smokers, an organotypic culture model was established whereby bronchial epithelial cells at different stages of lung tumorigenesis were plated onto transwell-clear culture filter inserts, allowed to reach confluence, and an air-liquid interface created. The cell types utilized included normal human bronchial epithelial cells (NHBE), NHBE cells immortalized (Jerry Shay) with hTERT and cdk4 (HccBE), NHBE cells immortalized (Klein-Szanto) with Ad12/SV40 (Beas2B), and immortalized (1799), transformed (1198), and tumorigenic (1170I) carcinogen-treated Beas2B cells. These cultures evolved into multi-layer cultures resembling normal (NHBE and HccBE) or dysregulated stratified bronchial epithelium (Beas2B, 1799, 1198, 1170I). Confocal microscopy of cultures after BrdU pulse labeling or phospho-histone H3 (P-H3) immunostaining demonstrated that NHBE cells preferentially undergo DNA synthesis and mitosis at the basal layer, HccBE cells proliferate at the basal and peribasal layers, whereas more advanced bronchial epithelial cells proliferate throughout the multi-layer cultures. Examination of anaphase cells in these populations by propidium iodide staining and confocal microscopy demonstrated that NHBE cells showed less than 2% anaphases with either lagging chromosomes or chromosome bridges compared to more than 10% in other cell types. Visualization of mitotic figures with P-H3 immunostaining demonstrated that P-H3 staining was strong at metaphase and uniformly disappeared during anaphase in cells at the basal layer, whereas P-H3 staining was not uniform in cells dividing away from the basal layer with lagging chromosomes and chromosome bridges differentially P-H3-positive in late anaphase. To determine when the chromosome regions involved in aberrations had been replicated, cultures were pulse-labeled with BrdU, harvested at various times following the pulse label, and analyzed for BrdU staining patterns of the lagging chromosomes and chromosome bridges. More than 90% of the aberrant chromosome regions were labeled in cells harvested 3-4 hours after BrdU labeling (i.e., replicated in late S phase) whereas less than 60% were labeled at 9-10 hours after BrdU labeling (i.e., replicated in early-mid S phase). These results suggest that proliferation away from the basal layer in these organotypic cultures is associated with increased genomic instability, possibly associated with dysregulated cell cycle control and abnormal mitotic progression. Supported in part by DAMD 17-02-1-0706 and W81XWH-04-1-01-42, and NIH/NCI P01 CA-91844 and EDRN CA-86390.
Genome-Wide CRISPR Screen for Essential Cell Growth Mediators in Mutant KRAS Colorectal Cancers
Authors: Edwin H. Yau, Indrasena Reddy Kummetha, Gianluigi Lichinchi, Rachel Tang, Yunlin Zhang, Tariq M. Rana
Journal: Cancer Research (2017)

Targeting mutant KRAS signaling pathways continues to attract attention as a therapeutic strategy for KRAS-driven tumors. In this study, we exploited the power of the CRISPR-Cas9 system to identify genes affecting the tumor xenograft growth of human mutant KRAS (KRASMUT) colorectal cancers. Using pooled lentiviral single-guide RNA libraries, we conducted a genome-wide loss-of-function genetic screen in an isogenic pair of human colorectal cancer cell lines harboring mutant or wild-type KRAS. The screen identified novel and established synthetic enhancers or synthetic lethals for KRASMUT colorectal cancer, including targetable metabolic genes. Notably, genetic disruption or pharmacologic inhibition of the metabolic enzymes NAD kinase or ketohexokinase was growth inhibitory in vivo In addition, the chromatin remodeling protein INO80C was identified as a novel tumor suppressor in KRASMUT colorectal and pancreatic tumor xenografts. Our findings define a novel targetable set of therapeutic targets for KRASMUT tumors. Cancer Res; 77(22); 6330-9. ©2017 AACR.
4D flow cardiovascular magnetic resonance parameters represent novel imaging biomarkers in heart failure and correlate with conventional prognostic remodelling parameters and myocardial energetics
Authors: V Stoll, A Hess, J Eriksson, C Rodgers, W Clarke, P Dyverfeldt, T Ebbers, S Myerson, C J Carlhall, S Neubauer
Journal: European Journal of Heart Failure (2016)
Sunitinib in patients with metastatic renal cell carcinoma: Clinical outcome according to IMDC risk group.
Authors: Brian I. Rini, Thomas E. Hutson, Robert A. Figlin, Mariajose Lechuga, Olga Valota, Lucile Serfass, Michelle Casey, Robert J. Motzer
Journal: Journal of Clinical Oncology (2017)

4584 Background: In a phase III study (NCT00083889), treatment-naïve patients (pts) with metastatic renal cell carcinoma (mRCC) of all prognostic risk groups were treated with sunitinib or interferon-α (IFN-α). Since sunitinib has become the reference standard of care and serves as the comparator in multiple randomized trials sometimes restricted to prespecified risk groups, a retrospective analysis of outcome according to prognostic group from the phase III study was performed. Methods: Investigator-assessed efficacy data were analyzed for pts based on risk group (International mRCC Database Consortium [IMDC] criteria). The objective was to determine objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) benchmarks by risk group. Results: Of sunitinib-treated pts, 134 were favorable, 205 were intermediate, and 34 were poor risk. The median sunitinib treatment duration/median number of cycles was 16.7 mo/12 cycles, 11.0 mo/8 cycles and 2.6 mo/2.0 cycles for favorable-, intermediate-, and poor-risk pts, respectively. ORR, PFS, and OS benchmarks for sunitinib-treated pts are shown in the Table. In sunitinib-treated intermediate-risk pts with 1 vs 2 risk factors, respectively: ORR was 43.3% vs 40.8%, mPFS (95% confidence interval [95% CI]) was 11.2 (9.7–13.6) vs 8.5 (5.6–10.7) mo, and mOS (95% CI) was 28.2 (23.0–not estimable) vs 16.3 (13.2–19.4) mo. Conclusions: This retrospective analysis provides ORR, PFS, and OS benchmarks for current and future clinical trial interpretation in mRCC pts with different prognostic risk treated with sunitinib. [Table: see text]
Physical Activity and Mortality in Patients With Stable Coronary Heart Disease
Authors: Ralph A.H. Stewart, Claes Held, Nermin Hadziosmanovic, Paul W. Armstrong, Christopher P. Cannon, Christopher B. Granger, Emil Hagström, Judith S. Hochman, Wolfgang Koenig, Eva Lonn, José C. Nicolau, Philippe Gabriel Steg, Ola Vedin, Lars Wallentin, Harvey D. White
Journal: Journal of the American College of Cardiology (2017)
Distinct role of nuclear receptor corepressor 1 regulated de novo fatty acids synthesis in liver regeneration and hepatocarcinogenesis in mice
Authors: Qing Ou‐Yang, Xi‐Meng Lin, Yan‐Jing Zhu, Bo Zheng, Liang Li, Ying‐Cheng Yang, Guo‐Jun Hou, Xin Chen, Gui‐Juan Luo, Feng Huo, Qi‐Bin Leng, Frank J. Gonzalez, Xiao‐Qing Jiang, Hong‐Yang Wang, Lei Chen
Journal: Hepatology (2017)

It is urgent that the means to improve liver regeneration (LR) be found, while mitigating the concurrent risk of hepatocarcinogenesis (HCG). Nuclear receptor corepressor 1 (NCoR1) is a co-repressor of nuclear receptors, which regulates the expression level of metabolic genes; however, little is known about its potential contribution for LR and HCG. Here, we found that liver-specific NCoR1 knockout in mice (NCoR1Δhep ) dramatically enhances LR after partial hepatectomy and, surprisingly, blocks the process of diethylnitrosamine (DEN)-induced HCG. Both RNA-sequencing and metabolic assay results revealed improved expression of Fasn and Acc2 in NCoR1Δhep mice, suggesting the critical role of de novo fatty acid synthesis (FAS) in LR. Continual enhanced de novo FAS in NCoR1Δhep mice resulted in overwhelmed adenosine triphosphate ATP and nicotinamide adenine dinucleotide phosphate (NADPH) consumption and increased mitochondrial reactive oxygen species production, which subsequently attenuated HCG through inducing apoptosis of hepatocytes at an early stage after DEN administration.NCoR1 functions as a negative modulator for hepatic de novo FAS and mitochondria energy adaptation, playing distinct roles in regeneration or carcinogenesis. (Hepatology 2018;67:1071-1087).
Cancer patients in the hospital damaged by the Japan earthquake and tsunami.
Authors: Naoto Morikawa, Satoru Yanagisawa, Hajime Iwasashi, Toshiharu Tabata, Tatsuya ABE, Ryuji Nakamura, Koichi Tabayashi
Journal: Journal of Clinical Oncology (2012)

e19508 Background: On March 11, the Great East Japan Earthquake hit the Sendai City. Water supplies and electric facilities were damaged seriously in many establishments, and our hospital was no exception. Because our hospital wards itself were also in the danger of collapsing, whole the oncologic patients were to be discharged. We investigated what became of the patients with cancer after the earthquake. Methods: We extracted the medical records of the patients with cancer, who were hospitalized when an earthquake occurred. Then, we retrospectively analyzed the destinations after the discharge and prognosis of each patient. Results: Among the 400 patients admitted, there stayed 75 patients with cancer, on March 11. Of these, the 75 patients were discharged to their home later, and the 48 patients were transferred to the other hospitals. The remaining four patients died in the hospital, all of which were due to their primary cancer. The earthquake did not cause any death. Although, most of the patients with cancer were relatively in good physical condition, their discharge to the home did not go on smoothly. Some patients could not make any contacts with their families, and others lost their houses because of the earthquake or resultant tsunami, all of which prevented them to return home. Public networks such as Disaster Medical Assistance Team (DMAT) did not have use for coordinating where the patients should be transferred, because they gave the first priority to the acutely-ill patients, such as trauma patients. Transfer to another hospitals largely depended on the personal networking between each physicians. Conclusions: On the face of the national disasters, the current emergency care system must prioritize the acutely-ill patients, sometimes at the sacrifice of chronically-ill patients such as oncologic patients. It seems necessary to create the medical cooperation system for the patients with cancer.
High pretreatment level of soluble interleukin-2 receptor is a robust prognostic factor in patients with follicular lymphoma treated with R-CHOP-like therapy
Authors: Y Kusano, M Yokoyama, Y Terui, N Inoue, A Takahashi, H Yamauchi, N Tsuyama, N Nishimura, Y Mishima, K Takeuchi, K Hatake
Journal: Blood Cancer Journal (2017)

High pretreatment level of soluble interleukin-2 receptor is a robust prognostic factor in patients with follicular lymphoma treated with R-CHOP-like therapy CI, 74.4-90.2), Figure 1a, P o 0.0001) and TTNT (49.4% (95% CI, 37.4-60.3)versus 81.1% (95% CI, 69.2-88.8), Figure 1b, P o 0.0001) were significantly lower in the high sIL-2R group.Six-year OS was not different statistically (96.2% (95% CI, 90.2-98.6)and 89.9% (95% CI, 80.7-94.9), Figure 1c, P = 0.06).When both sIL-2R (high or low) and RM (yes or no) were considered as covariates, 6-year PFS and TTNT of the non-RM/high sIL-2R group were significant lower than those of other three groups (Figure 1d ande).The addition of high sIL-2R as a covariate led to a reduction in PFS and TTNT not only in the non-RM group (P o 0.001) but also in the RM group (P o 0.001).Six-year PFS and TTNT of the RM/high sIL-2R group were almost the same as those of the non-RM/low sIL-2R group.No influence was observed in OS (Figure 1f).Univariate analyses were conducted using the following variables to determine independent prognostic markers for FL in this cohort (Table 1): variables of FLIPI, high FLIPI, variables of FLIPI2, high FLIPI2, male gender, no RM and high sIL2R at diagnosis.Multivariate analysis 1 using the variables selected by univariate analysis except high FLIPI and high FLIPI2 revealed that high sIL-2R was an independent prognostic marker in this cohort.Both multivariate analysis 2, which included high FLIPI, high sIL-2R, and no RM and multivariate analysis 3, which included high FLIPI2,
Incidence of hidradenitis suppurativa among tobacco smokers: a population-based retrospective analysis in the U.S.A.
Authors: A. Garg, V. Papagermanos, M. Midura, A. Strunk
Journal: British Journal of Dermatology (2017)

The relationship between tobacco use and hidradenitis suppurativa (HS) is controversial.To determine the incidence of HS among tobacco smokers.Retrospective cohort analysis identifying incident HS cases among adult tobacco smokers and nonsmokers sampled from a demographically heterogeneous population-based sample of over 50 million unique patients across all census regions in the U.S.A.We identified 3 924 310 tobacco smokers, which included 7860 patients newly diagnosed with HS. Tobacco smokers diagnosed with HS were most commonly aged 18-39 years (3795 of 7860; 48·3%), women (5640 of 7860; 71·8%), white (5200 of 7860; 66·2%) and those with body mass index (BMI) ≥ 30 (5690 of 7860; 72·4%). Overall incidence of HS was 0·20% (7860 of 3 924 310) among tobacco smokers and 0·11% (8430 of 8 027 790) among nonsmokers (P < 0·001). Incidence was greatest among tobacco smokers who were aged 30-39 years (0·35%), women (0·28%), African Americans (0·46%) and those with BMI ≥ 30 (0·33%). The overall adjusted odds of developing HS was 1·90 (95% confidence interval 1·84-1·96) among tobacco smokers, compared with nonsmokers (P < 0·001). HS incidence among tobacco smokers remained increased within each demographic subgroup.Incidence of HS appears to be doubled among tobacco smokers. These findings may support evidence-based counselling efforts for the cessation of smoking in populations at risk for HS.
Primary ciliary dyskinesia ciliated airway cells show increased susceptibility to <i>Haemophilus influenzae</i> biofilm formation
Authors: Woolf T. Walker, Claire L. Jackson, Raymond N. Allan, Samuel A. Collins, Michael J. Kelso, Ardeshir Rineh, Nageshwar R. Yepuri, Ben Nicholas, Laurie Lau, David Johnston, Peter Lackie, Saul N. Faust, Jane S.A. Lucas, Luanne Hall-Stoodley
Journal: European Respiratory Journal (2017)

Non-typeable <i>Haemophilus influenzae</i> (NTHi) is the most common pathogen in primary ciliary dyskinesia (PCD) patients. We hypothesised that abnormal ciliary motility and low airway nitric oxide (NO) levels on airway epithelial cells from PCD patients might be permissive for NTHi colonisation and biofilm development. We used a primary epithelial cell co-culture model to investigate NTHi infection. Primary airway epithelial cells from PCD and non-PCD patients were differentiated to ciliation using an air–liquid interface culture and then co-cultured with NTHi. NTHi adherence was greater on PCD epithelial cells compared to non-PCD cells (p&lt;0.05) and the distribution of NTHi on PCD epithelium showed more aggregated NTHi in biofilms (p&lt;0.001). Apart from defective ciliary motility, PCD cells did not significantly differ from non-PCD epithelial cells in the degree of ciliation and epithelial integrity or in cytokine, LL-37 and NO production. Treatment of PCD epithelia using exogenous NO and antibiotic significantly reduced NTHi viability in biofilms compared with antibiotic treatment alone. Impaired ciliary function was the primary defect in PCD airway epithelium underlying susceptibility to NTHi biofilm development compared with non-PCD epithelium. Although NO responses were similar, use of targeted NO with antibiotics enhanced killing of NTHi in biofilms, suggesting a novel therapeutic approach.
Three-dimensional genome architecture and emerging technologies: looping in disease
Authors: Arpit Mishra, R. David Hawkins
Journal: Genome Medicine (2017)

Genome compaction is a universal feature of cells and has emerged as a global regulator of gene expression. Compaction is maintained by a multitude of architectural proteins, long non-coding RNAs (lncRNAs), and regulatory DNA. Each component comprises interlinked regulatory circuits that organize the genome in three-dimensional (3D) space to manage gene expression. In this review, we update the current state of 3D genome catalogues and focus on how recent technological advances in 3D genomics are leading to an enhanced understanding of disease mechanisms. We highlight the use of genome-wide chromatin conformation capture (Hi-C) coupled with oligonucleotide capture technology (capture Hi-C) to map interactions between gene promoters and distal regulatory elements such as enhancers that are enriched for disease variants from genome-wide association studies (GWASs). We discuss how aberrations in architectural units are associated with various pathological outcomes, and explore how recent advances in genome and epigenome editing show great promise for a systematic understanding of complex genetic disorders. Our growing understanding of 3D genome architecture-coupled with the ability to engineer changes in it-may create novel therapeutic opportunities.
Negative hyper-selection of metastatic colorectal cancer patients for anti-EGFR monoclonal antibodies: the PRESSING case–control study
Authors: C. Cremolini, F. Morano, R. Moretto, R. Berenato, E. Tamborini, F. Perrone, D. Rossini, A. Gloghini, A. Busico, G. Zucchelli, C. Baratelli, E. Tamburini, M. Tampellini, E. Sensi, G. Fucà, C. Volpi, M. Milione, M. Di Maio, G. Fontanini, F. De Braud, A. Falcone, F. Pietrantonio
Journal: Annals of Oncology (2017)
Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-to-severe atopic dermatitis: a phase II, multicentre, randomized, vehicle-controlled clinical study
Authors: H. Nakagawa, O. Nemoto, A. Igarashi, T. Nagata
Journal: British Journal of Dermatology (2017)

JTE‐052 is a novel Janus kinase inhibitor presently under clinical development for the topical treatment of atopic dermatitis (AD). To evaluate the efficacy and safety of JTE‐052 ointment in Japanese adult patients with AD. Patients with moderate‐to‐severe AD were randomized (2: 2: 2: 2: 1: 1) to receive JTE‐052 ointment at 0·25%, 0·5%, 1% or 3%, the vehicle ointment or tacrolimus 0·1% ointment (reference) twice daily for 4 weeks. The primary efficacy end point was the percentage change in modified Eczema Area Severity Index (mEASI) score from baseline at the end of treatment (EOT). Secondary efficacy end points included change from baseline in the pruritus numerical rating scale (NRS) score. In total, 327 patients were enrolled. At EOT, the least‐squares mean percentage changes from baseline in mEASI score for JTE‐052 at 0·25%, 0·5%, 1% and 3% and the vehicle ointment were −41·7%, −57·1%, −54·9%, −72·9% and −12·2%, respectively. All JTE‐052 groups showed significant reductions of mEASI score vs. the vehicle group (P < 0·001 for all). In the tacrolimus group, the mean percentage change in mEASI score was −62·0%. The JTE‐052 groups also showed significant improvement in other parameters; notably, the pruritus NRS score was reduced as early as day 1 night‐time. JTE‐052 ointment at doses up to 3% was safe and well tolerated. Topical JTE‐052 markedly and rapidly improved clinical signs and symptoms in Japanese adult patients with moderate‐to‐severe AD, with a favourable safety profile. The study results indicate that topical JTE‐052 is a promising therapeutic option for AD. The trial registration number is JapicCTI‐152887.
Lesinurad combination therapy with allopurinol in gout: do CLEAR studies make the treatment of gout clearer?
Authors: Ritu Valiyil, Bruce Schechter
Journal: Annals of the Rheumatic Diseases (2017)

In his recent editorial commenting on the Combining Lesinurad with Allopurinol in Inadequate Responders studies,1 Dr Singh provides a thorough overview of the phase 3 trials demonstrating the efficacy and safety of lesinurad given in combination with allopurinol for the treatment of gout in patients who do not reach serum uric acid goal on …
CT-based radiomic analysis of hepatocellular carcinoma patients to predict key genomic information.
Authors: Derek L West, Aikaterini Kotrotsou, Andrew Scott Niekamp, Tagwa Idris, Dunia Giniebra Camejo, Nicolas James Mazal, Nicolas James Cardenas, Jackson L. Goldberg, Rivka R. Colen
Journal: Journal of Clinical Oncology (2017)

e15623 Background: The utilization of computed tomography (CT) has virtually replaced the need for tissue diagnosis in hepatocellular carcinoma (HCC). Imaging features (e.g. size, shape and vascularity) have been associated with patient survival. However, the full potential of CT in HCC diagnosis may not be reached, as high-throughput computing allows for extraction of quantitative features that are not part of radiologists’ lexicon. The purpose of this study was to investigate the ability of radiomic analysis to successfully identify specific doxorubicin chemoresistant genes on CT images of treatment-naïve hepatocellular carcinoma (HCC). Methods: We identified 27 treatment-naïve patients with a single HCC tumor from The Cancer Genome Atlas (TCGA) whom had gene expression profiles. Baseline CT images were obtained from The Cancer Imaging Archive (TCIA). 3D Slicer software was used for manual tumor segmentation and final segmented images were reviewed by a board-certified radiologist. Following tumor segmentation, texture analysis was performed on MATLAB environment. A total of 310 rotation invariant texture features, which measure tumor heterogeneity, were obtained (first-order histogram and grey level co-occurrence matrix). The mRMR method was used to select the most relevant radiomic features. ROC analysis and LOOCV were used to assess the performance of five specific genes known to confer doxorubicin chemoresistance (TP53, TOP2A, CTNNB1, CDKN2A and AKT1). Results: Radiomic analysis identified TP53 (AUC = 86.61%, Specificity = 92.31%, Sensitivity = 92.9%), TOP2A (AUC = 78.0%, Specificity = 69%, Sensitivity = 85.7%), CTNNB1 (AUC = 86.8%, Specificity = 92.3%, Sensitivity = 85.7%), CDKN2A (AUC = 76.9%, Specificity = 76.9%, Sensitivity = 78.6%) and AKT1 (AUC = 72.5%, Specificity = 69.2%, Sensitivity = 85.7%) in treatment-naïve HCC CT studies. Conclusions: The identification of specific genes that confer chemoresistance to doxorubicin can be reliably ascertained via the use of radiomic analysis. This study may help tailor future treatment paradigms via the ability to categorize HCC tumors on genetic level and identify tumors which may not have a favorable response to doxorubicin based therapies.