tbuckley/cabot-search huggingface dataset:
Abstract 1972: LIN28 gene targets are key mediators of breast cancer disease processes
Authors: Harriet K. Kinyamu, Jun Yang, Brian Bennett, Sara Grimm, Pierre Bushel, Trevor Archer
Journal: Cancer Research (2015)

Abstract LIN28 is an evolutionally conserved RNA-binding protein with critical functions in developmental timing, pluripotency and reprogramming. At the molecular level, most studies indicate that LIN28 modulates gene networks and biological processes by negatively regulating miRNA biogenesis and post-transcriptionally regulating mRNA translation. In addition, increasing evidence suggests that LIN28 is an oncogene, promoting cell growth in various cancers, including breast cancer; however the molecular mechanisms underlying these effects are not known. To provide mechanistic insights into how LIN28 modulates the gene networks that control breast cancer disease processes, we integrate next generation technologies, biochemical approaches and computational analysis to identify LIN28 mRNA targets. Our results demonstrated that endogenous LIN28 binds 843 mRNAs, ∼3.5% of the total human reference genome in breast cancer cells. Gene ontology analyses reveal that the genes targeted by LIN28 are enriched in those that control cell metabolism. Furthermore, using proteomics analysis, we identify heteronuclear ribonucleoprotein A1 (hnRNP A1), a protein with multiple roles in mRNA metabolism, as a LIN28 interacting partner. Importantly, hnRNP A1 is overexpressed and linked to increased cell proliferation and transformation in a wide variety of cancers, including breast cancer. Moreover, and consistent with the observation that majority of mRNAs bound by LIN28 are involved in metabolism, hnRNP A1 is known to regulate the expression of key enzymes that control metabolism in cancer cells. In-depth analysis of the transcriptomes of LIN28 and hNRNPA1 siRNA-treated cells reveal that these two proteins cooperate to regulate alternative splicing and the steady state mRNA expression of genes implicated in various aspects of breast cancer biology. Most notably, depleting LIN28 results in differential isoform expression of the ENAH gene, which is linked to breast cancer metastasis. In summary, by integrating genomic, biochemical and computational approaches, we identify a broad network of LIN28 targets that modulate cancer cell metabolism, cancer cell invasiveness and the immune response, processes that are hallmarks of breast cancer. Citation Format: Harriet K. Kinyamu, Jun Yang, Brian Bennett, Sara Grimm, Pierre Bushel, Trevor Archer. LIN28 gene targets are key mediators of breast cancer disease processes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1972. doi:10.1158/1538-7445.AM2015-1972
The incremental shuttle walking test in elderly people with chronic airflow limitation
Authors: C A E Dyer
Journal: Thorax (2002)

Background: There is a concern that comorbidity or frailty in older people could limit the usefulness of currently available exercise tests for chronic lung disease. This study evaluated the feasibility and reproducibility of the incremental shuttle walking test (SWT) in people aged 70 years or over, compared exercise tolerance with other disability markers, and assessed whether the SWT is responsive to change after bronchodilators. Methods: Fifty elderly patients with chronic airflow limitation (CAL) and 32 controls without airflow limitation attempted the SWT before and after combined nebulised salbutamol/ipratropium bromide. Subjects also completed the Nottingham Extended Activities of Daily Living index (NEADL) and the London Handicap score (LHS). Results: Forty four subjects with CAL (88%) and 29 controls (84%) completed the SWT, including many with co-morbidities. Two week repeatability was good and the SWT was strongly associated with EADL (<i>r</i>=0.51, p&lt;0.001) and LHS (<i>r</i>=0.43, p&lt;0.004), but only weakly with forced expiratory volume in 1 second (FEV<sub>1</sub>) (<i>r</i>=0.31, p=0.05). Subjects with CAL walked a mean distance of 177.7 m compared with 243.3 m in controls (p&lt;0.001); following bronchodilator therapy the distance walked increased in the CAL group by 13.2% (p=0.009). Conclusion: The SWT is a feasible and reproducible measure of exercise tolerance in elderly people with and without airflow obstruction and correlates with other markers of disability. It is sensitive to change following bronchodilation in subjects with CAL, although the change correlates less well with improvements in FEV<sub>1</sub>. Overall, these results suggest that the SWT might be an appropriate measure to assess interventions in elderly people.
Advanced Glycation End Products Activate a Chymase-Dependent Angiotensin II–Generating Pathway in Diabetic Complications
Authors: Vijay Koka, Wansheng Wang, Xiao Ru Huang, Shokei Kim-Mitsuyama, Luan D. Truong, Hui Y. Lan
Journal: Circulation (2006)

Angiotensin II is a key mediator of diabetes-related vascular disease. It is now recognized that in addition to angiotensin-converting enzyme, chymase is an important alternative angiotensin II-generating enzyme in hypertension and diabetes. However, the mechanism of induction of chymase in diabetes remains unknown.
Radiation-Related Risk of Basal Cell Carcinoma: A Report From the Childhood Cancer Survivor Study
Authors: Tanya C. Watt, Peter D. Inskip, Kayla Stratton, Susan A. Smith, Stephen F. Kry, Alice J. Sigurdson, Marilyn Stovall, Wendy Leisenring, Leslie L. Robison, Ann C. Mertens
Journal: JNCI Journal of the National Cancer Institute (2012)

BackgroundBasal cell carcinoma (BCC) is the most common malignancy in the United States. Ionizing radiation is an established risk factor in certain populations, including cancer survivors. We quantified the association between ionizing radiation dose and the risk of BCC in childhood cancer survivors.
The role of subregions of the rat major histocompatibility complex in the rejection and passive enhancement of renal allografts.
Authors: G G Gallico, G W Butcher, J C Howard
Journal: The Journal of Experimental Medicine (1979)

The laboratory recombinant haplotype H-1acl of the Norway rat has been used in studies of the rejection and passive enhancement of kidney allografts. While the full H-1a haplotype provoked acute rejection, neither of the isolated subregions, H-1Aa and H-1Ba, did so. It was also found that alloantisera raised against either the H-1Aa or the H-1Ba antigens would enhance the grafts. It is suggested that both MHC subregions contain a histocompatibility locus (i) for kidney (as they do for skin) and that in the genetic combinations studied only incompatibility for both provokes a response sufficient for rejection. In other combinations, however, single region incompatibilities may be sufficient.
Inhibition of inducible nitric oxide synthase in the human intestinal epithelial cell line, DLD-1, by the inducers of heme oxygenase 1, bismuth salts, heme, and nitric oxide donors
Authors: M Cavicchi
Journal: Gut (2000)

<h3>BACKGROUND</h3> The inducible isoform of nitric oxide synthase (iNOS) may be involved in the mucosal injury associated with inflammatory bowel disease (IBD). In contrast with iNOS, the inducible heme oxygenase 1 (HO-1) is considered to act as a protective antioxidant system. <h3>AIMS</h3> To evaluate the effects of the known HO-1 inducers, cadmium and bismuth salts, heme, and nitric oxide (NO) donors, on iNOS activity, and expression in the human intestinal epithelial cell line DLD-1. <h3>METHODS</h3> iNOS activity was assessed by the Griess reaction and the radiochemicall-arginine conversion assay. iNOS mRNA and iNOS protein expression were determined by northern and western blotting, respectively. <h3>RESULTS</h3> Cytokine exposure led to induction of iNOS activity, iNOS mRNA, and iNOS protein expression. Preincubation of DLD-1 cells with heme (1–50 μM) inhibited cytokine induced iNOS activity in a concentration dependent manner. This inhibitory effect was abolished by the HO-1 specific inhibitor tin protoporphyrin. Preincubation with NO donors sodium nitroprusside (SNP 1–1000 μM) or S-nitroso-acetyl-penicillamine (SNAP 1–1000 μM), or with the heavy metals cadmium chloride (10–40 μM), bismuth citrate, or ranitidine bismuth citrate (10–3000 μM) inhibited iNOS activity in a concentration dependent manner. Moreover, SNP and heme abolished cytokine induced iNOS protein as well as iNOS mRNA expression, whereas cadmium chloride did not modify iNOS protein expression. <h3>CONCLUSIONS</h3> Heme, the heavy metals cadmium and bismuth, as well as NO donors, are potent inhibitors of cytokine induced iNOS activity. Heme and NO donors act at the transcriptional level inhibiting iNOS mRNA expression. Such findings suggest the potential for interplay between the iNOS and HO-1 systems, which may modulate the progress of IBD.
Extended Lung Cancer Incidence Follow-up in the Mayo Lung Project and Overdiagnosis
Authors: Pamela M. Marcus, Erik J. Bergstralh, Mark H. Zweig, Ann Harris, Kenneth P. Offord, Robert S. Fontana
Journal: JNCI Journal of the National Cancer Institute (2006)

A troubling aspect of cancer screening is the potential for overdiagnosis, i.e., detection of disease that, in the absence of screening, would never have been diagnosed. Overdiagnosis is of particular concern in lung cancer screening because newer screening modalities can identify small nodules of unknown clinical significance. Previously published analyses of data from the Mayo Lung Project, a large randomized controlled trial conducted among 9211 male cigarette smokers in the 1970s and early 1980s indicated that overdiagnosis might exist in lung cancer screening. At the end of follow-up (July 1, 1983), no difference in lung cancer mortality was observed, but an excess of 46 cases in the intervention arm suggested overdiagnosis. Because that excess could instead have resulted from short follow-up time, we investigated this possibility by conducting long-term lung cancer incidence follow-up.We investigated the lung cancer status through 1999 of the 7118 participants in the Mayo Lung Project who were alive and without diagnosed lung cancer in 1983 by use of medical records, surveys mailed to participants or next-of-kin, and state death certificates.Information was available for 6101 participants, including 811 with inconclusive lung cancer status. From November 1971 through December 31, 1999, 585 participants in the intervention arm and 500 in the usual-care arm were diagnosed with lung cancer.The persistence of excess cases in the intervention arm after 16 additional years of follow-up provides continued support for overdiagnosis in lung cancer screening.
Is the EBUS TBNA cytology adequate for EGFR analysis
Authors: Mohammed Harris, Shahul Leyakathali khan, Sarah Diver, Saba Bokhari, Jane Edwards, Joanna Pickles, Mohammed Munavvar
Journal: European Respiratory Journal (2012)

Background: Endobronchial ultrasound (EBUS) guided transbronchial needle aspiration (TBNA) allows safe and reliable sampling of mediastinal and hilar lymph nodes with excellent specificity and good sensitivity. It is a well established technique in the diagnosis and staging of lung cancer including pathologic sub-typing and recent studies have shown that the samples may also be adequate for molecular testing.  Aim: To evaluate the adequacy of EBUS TBNA samples used for epidermal growth factor receptor (EGFR) mutation screening.  Methods: Retrospective study of 46 consecutive EBUS-TBNA samples obtained from lymph nodes > 5mm short-axis and central lung parenchymal lesions. Fisher9s exact test was used to compare the 2 groups.  Results: Of the 46 EBUS TBNA samples sent for EGFR testing, 38 were obtained from lymph nodes (19 subcarinal, 9 right paratracheal, 4 left paratracheal, 10 right hilar and 4 left hilar) and 8 from central lung parenchymal masses.  In the lymph node group, 35 (92%) samples were negative for EGFR mutation, 3(8%) failed testing and none were positive for EGFR; 30 had adenocarcinoma, 1 adenosquamous, 2 squamous and 5 NSCLC-NOS(not otherwise specified). In the central lung mass group (n=8), one positive with exon19 deletion, 6 negative and one failed testing or was inadequate; 3 had adenocarcinoma, 3 NSCLC-NOS, 1 squamous and 1 adenosquamous.  The overall EBUS-TBNA adequacy from both lymph nodes and central lung masses was 91% and there was no difference between the groups.  Conclusion: Molecular testing of EBUS TBNA samples obtained from mediastinal and hilar lymph nodes is feasible and our study shows a higher proportion of 92% adequacy. The common reason for failed testing was paucicellular specimen and degraded DNA.
Prime role of IL-17A in neutrophilia and airway smooth muscle contraction in a house dust mite–induced allergic asthma model
Authors: Julie Chesné, Faouzi Braza, Gilliane Chadeuf, Guillaume Mahay, Marie-Aude Cheminant, Jennifer Loy, Sophie Brouard, Vincent Sauzeau, Gervaise Loirand, Antoine Magnan
Journal: Journal of Allergy and Clinical Immunology (2015)
DNA Damage in Cancer Therapeutics: A Boon or a Curse?
Authors: Anchit Khanna
Journal: Cancer Research (2015)

Millions of DNA-damaging lesions occur every day in each cell of our bodies due to various stresses. The failure to detect and accurately repair these lesions can give rise to cells with high levels of endogenous DNA damage, deleterious mutations, or genomic aberrations. Such genomic instability can lead to the activation of specific signaling pathways, including the DNA damage response (DDR) pathway. Constitutive activation of DDR proteins has been observed in human tumor specimens from different cancer stages, including precancerous and metastatic cancers, although not in normal tissues. The tumor-suppressive role of DDR activity during the premalignant stage has been studied, and strong evidence is emerging for an oncogenic role for DDR proteins such as DNA-PK and CHK1 during the later stages of tumor development. However, the majority of current cancer therapies induce DNA damage, potentially exacerbating protumorigenic genomic instability and enabling the development of resistance. Therefore, elucidating the molecular basis of DNA damage-mediated genomic instability and its role in tumorigenesis is critical. Finally, I discuss the potential existence of distinct DNA damage thresholds at various stages of tumorigenesis and what the ramifications of such thresholds would be, including the ambiguous role of the DDR pathway in human cancers, therapy-induced malignancies, and enhanced therapies.
An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma
Authors: T.E. Witzig, J.M. Vose, P.L. Zinzani, C.B. Reeder, R. Buckstein, J.A. Polikoff, R. Bouabdallah, C. Haioun, H. Tilly, P. Guo, D. Pietronigro, A.L. Ervin-Haynes, M.S. Czuczman
Journal: Annals of Oncology (2011)
Reciprocal Activation of Prostate Cancer Cells and Cancer-Associated Fibroblasts Stimulates Epithelial-Mesenchymal Transition and Cancer Stemness
Authors: Elisa Giannoni, Francesca Bianchini, Lorenzo Masieri, Sergio Serni, Eugenio Torre, Lido Calorini, Paola Chiarugi
Journal: Cancer Research (2010)

Abstract Although cancer-associated fibroblasts (CAF) are key determinants in the malignant progression of cancer, their functional contribution to this process is still unclear. Analysis of the mutual interplay between prostate carcinoma cells and CAFs revealed a mandatory role of carcinoma-derived interleukin-6 in fibroblast activation. In turn, activated fibroblasts through secretion of metalloproteinases elicit in cancer cells a clear epithelial-mesenchymal transition (EMT), as well as enhancement of tumor growth and development of spontaneous metastases. CAF-induced EMT leads prostate carcinoma cells to enhance expression of stem cell markers, as well as the ability to form prostaspheres and to self-renew. Hence, the paracrine interplay between CAFs and cancer cells leads to an EMT-driven gain of cancer stem cell properties associated with aggressiveness and metastatic spread. Cancer Res; 70(17); 6945–56. ©2010 AACR.
Multifocal Lung Cancers--Clonality vs Field Cancerization and Does It Matter?
Authors: A. F. Gazdar, J. D. Minna
Journal: JNCI Journal of the National Cancer Institute (2009)

JNCI | Editorials 541 More than 50 years ago, Slaughter et al. ( 1 ) noted that smokers developed multiple preneoplastic lesions and synchronous (ie, those detected simultaneously) or metachronous (ie, those detected within a relatively short period) tumors in the squamous epithelium of the oral cavity, a phenomenon they termed “field cancerization.” They attributed these findings to tobacco carcinogens damaging the entire field at risk — the oral mucosa. Several years later, Strong et al. ( 2 ) extended this concept (and the clinical implications) to the entire upper aerodigestive tract. Multifocal primary tumors having similar histological appearance have been described in many organs but are especially common in lung cancer. In this issue of the Journal, Wang et al. ( 3 ) investigate the mechanisms by which these tumors arise. The results of these studies pose both important biological and clinical management questions. Smokers cured of one aerodigestive cancer, including lung cancer, are at greatly increased risk of developing a second primary malignancy ( 4 ). This event may occur several years later, may involve tumors of differing histological types, or the tumors may arise in different anatomical regions of the fi eld (such as larynx and lung). The origin of these tumors has been attributed to a “fi eld” effect. More controversial are multifocal tumors of similar histology that arise synchronously or metachronously in the same organ. Multifocal tumors may be localized to multiple (satellite) nodules within a small region of the lung, involve a single lobe or multiple
High-frequency vagus nerve stimulation improves portal hypertension in cirrhotic rats
Authors: Ilse Bockx, Katrien Verdrengh, Ingrid Vander Elst, Jos van Pelt, Frederik Nevens, Wim Laleman, David Cassiman
Journal: Gut (2011)

<h3>Objective</h3> The liver is innervated by the vagus nerve. Its efferent neurotransmitters acetylcholine (ACh) and vasoactive intestinal peptide (VIP) are both well-known vasodilators. A study was undertaken to determine whether electrical vagus nerve stimulation (STIM) influences portal vein pressure. <h3>Methods</h3> The left vagus nerve upstream of the hepatic branch was stimulated at 5 Hz (ACh release) and 10 Hz (VIP release) in normal and cirrhotic rats. <h3>Results</h3> STIM at both frequencies decreased portal pressure in normal rats while, in cirrhotic rats, only 10 Hz STIM resulted in long-lasting reduction of portal pressure. Hepatic branch vagotomy prevented the STIM-induced decrease in pressure, proving that the effect is a direct hepatic effect. Deafferentation of the left vagus nerve by pretreatment with capsaicin did not change the effect of STIM, showing that the vagus efferents and not the afferents are responsible for the decrease in portal pressure. Injecting microspheres before and after STIM showed that STIM did not lead to redistribution of systemic blood flow but decreased portal pressure by lowering intrahepatic resistance. Using in situ liver perfusion to evaluate the intrahepatic effect of ACh and VIP, both neurotransmitters significantly decreased the perfusion pressure in normal rats. VIP also decreased portal pressure in cirrhotic rats, confirming the results of STIM. This VIP-induced decrease in pressure could be prevented by a VIP receptor 2 antagonist. L-NAME did not inhibit the VIP effect in cirrhotic rats, indicating that VIP does not act via nitric oxide. <h3>Conclusion</h3> High-frequency electrical vagus stimulation improves portal hypertension in cirrhotic rats, most likely through release of VIP, binding to VIP receptor 2. As the technology is already in use for other applications, vagus nerve stimulation might be an important new strategy in the treatment of portal hypertension.
Evidence for bistable bacteria-neutrophil interaction and its clinical implications
Authors: Roy Malka, Baruch Wolach, Ronit Gavrieli, Eliezer Shochat, Vered Rom-Kedar
Journal: Journal of Clinical Investigation (2012)

Neutropenia, which may develop as a consequence of chemotherapy, increases the risk of bacterial infection. Similarly, increased risk of bacterial infection appears in disorders of phagocytic functions, such as the genetic disorder chronic granulomatous disease. To elucidate the organizing principles behind these distinct immunodeficiency conditions, we investigated the interaction between in vitro bacteria and human neutrophils by experiments and mathematical modeling. The model and the experiments showed that the in vitro bacterial dynamics exhibit bistability for a certain range of neutrophil concentration and function. Thus, there is a critical bacterial concentration above which infection develops, and below which neutrophils defeat the bacteria. Whereas with normal neutrophil concentration and function, an infection may develop when the initial bacterial concentration is very high, under neutropenic conditions or when there is neutrophil dysfunction, the critical bacterial concentration can be lower, within the clinically relevant range. We conclude that critical bacterial concentration has clinically relevant implications. The individual maximum bearable bacterial concentration depended on neutrophil concentration, phagocytic activity, and patient barrier integrity; thus, the resulting maximal bearable bacterial concentration may vary by orders of magnitude between patients. Understanding the interplay between neutrophils and bacteria may enhance the development of new therapeutic approaches to bacterial infections.