tbuckley/cabot-search huggingface dataset:
A Conserved RAS/Mitogen-Activated Protein Kinase Pathway Regulates DNA Damage–Induced Cell Death Postirradiation in Radelegans
Authors: Joanne B. Weidhaas, David M. Eisenmann, Justin M. Holub, Sunitha V. Nallur
Journal: Cancer Research (2006)

Abstract Although the epidermal growth factor receptor (EGFR) signaling pathway is overactive in more than half of human cancers and mediates resistance to cytotoxic therapy, the molecular mechanisms of EGFR pathway–mediated resistance have remained elusive in cancer research. This difficulty partly stems from the lack of tissue models enabling clear separation of the many forms of cell death that the downstream signaling pathways of EGFR affect. We have created a model in Caenorhabditis elegans of radiation-induced reproductive cell death (“Radelegans”) in isolation of all other forms of cell death. We have employed Radelegans to genetically define the role of the EGFR signaling pathway in protection from reproductive cell death, the primary form of tumor stem or clonogen cell death postirradiation. We have found that the RAS/mitogen-activated protein kinase (MAPK) downstream signal transduction pathway of EGFR is critical for protection from reproductive cell death in Radelegans. In addition, we have shown that RAS/MAPK pathway signaling is genetically linear with the DNA damage response pathway and acts downstream of the DNA damage checkpoint in the radioresponse, implicating this pathway in DNA repair post-cytotoxic therapy. These findings support the hypothesis that enhanced repair is a mechanism of RAS/MAPK pathway–mediated resistance to cytotoxic therapy through its interaction with the DNA damage response pathway postirradiation. We postulate that these findings also help explain why current treatment strategies, based on the presumption that tumors have ineffective repair compared with normal tissues, are ineffective in EGFR/RAS/MAPK pathway–mediated tumors. Radelegans is a platform to further define the genetic basis of the radiation response in tissues. (Cancer Res 2006; 66(21): 10434-8)
Phase I Study of Quizartinib Administered Daily to Patients With Relapsed or Refractory Acute Myeloid Leukemia Irrespective of FMS-Like Tyrosine Kinase 3–Internal Tandem Duplication Status
Authors: Jorge E. Cortes, Hagop Kantarjian, James M. Foran, Darejan Ghirdaladze, Mamia Zodelava, Gautam Borthakur, Guy Gammon, Denise Trone, Robert C. Armstrong, Joyce James, Mark Levis
Journal: Journal of Clinical Oncology (2013)

FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are associated with early relapse and poor survival. Quizartinib potently and selectively inhibits FLT3 kinase activity in preclinical AML models.Quizartinib was administered orally at escalating doses of 12 to 450 mg/day to 76 patients (median age, 60 years; range, 23 to 86 years; with a median of three prior therapies [range, 0 to 12 therapies]), enrolled irrespective of FLT3-ITD mutation status in a phase I, first-in-human study in relapsed or refractory AML.Responses occurred in 23 (30%) of 76 patients, including 10 (13%) complete remissions (CR) of any type (two CRs, three CRs with incomplete platelet recovery [CRp], five CRs with incomplete hematologic recovery [CRi]) and 13 (17%) with partial remissions (PRs). Of 17 FLT3-ITD-positive patients, nine responded (53%; one CR, one CRp, two CRis, five PRs); of 37 FLT3-ITD-negative patients, five responded (14%; two CRps, three PRs); of 22 with FLT3-ITD-indeterminate/not tested status, nine responded (41%; one CR, three CRis, five PRs). Median duration of response was 13.3 weeks; median survival was 14.0 weeks. The most common drug-related adverse events (> 10% incidence) were nausea (16%), prolonged QT interval (12%), vomiting (11%), and dysgeusia (11%); most were ≤ grade 2. The maximum-tolerated dose was 200 mg/day, and the dose-limiting toxicity was grade 3 QT prolongation. FLT3-ITD phosphorylation was completely inhibited in an in vitro plasma inhibitory assay.Quizartinib has clinical activity in patients with relapsed/refractory AML, particularly those with FLT3-ITD, and is associated with an acceptable toxicity profile.
Metastasis Suppressor NM23-H1 Promotes Repair of UV-Induced DNA Damage and Suppresses UV-Induced Melanomagenesis
Authors: Stuart G. Jarrett, Marian Novak, Sandrine Dabernat, Jean-Yves Daniel, Isabel Mellon, Qingbei Zhang, Nathan Harris, Michael J. Ciesielski, Robert A. Fenstermaker, Diane Kovacic, Andrzej Slominski, David M. Kaetzel
Journal: Cancer Research (2011)

Reduced expression of the metastasis suppressor NM23-H1 is associated with aggressive forms of multiple cancers. Here, we establish that NM23-H1 (termed H1 isoform in human, M1 in mouse) and two of its attendant enzymatic activities, the 3'-5' exonuclease and nucleoside diphosphate kinase, are novel participants in the cellular response to UV radiation (UVR)-induced DNA damage. NM23-H1 deficiency compromised the kinetics of repair for total DNA polymerase-blocking lesions and nucleotide excision repair of (6-4) photoproducts in vitro. Kinase activity of NM23-H1 was critical for rapid repair of both polychromatic UVB/UVA-induced (290-400 nm) and UVC-induced (254 nm) DNA damage, whereas its 3'-5' exonuclease activity was dominant in the suppression of UVR-induced mutagenesis. Consistent with its role in DNA repair, NM23-H1 rapidly translocated to sites of UVR-induced (6-4) photoproduct DNA damage in the nucleus. In addition, transgenic mice hemizygous-null for nm23-m1 and nm23-m2 exhibited UVR-induced melanoma and follicular infundibular cyst formation, and tumor-associated melanocytes displayed invasion into adjacent dermis, consistent with loss of invasion-suppressing activity of NM23 in vivo. Taken together, our data show a critical role for NM23 isoforms in limiting mutagenesis and suppressing UVR-induced melanomagenesis.
Authors’ reply to ‘Safety and tolerability of fluticasone furoate/vilanterol’
Authors: William W Busse, Leslie Andersen
Journal: Thorax (2013)

We thank Dr Lipworth for his response to our article on the safety and tolerability of fluticasone furoate/vilanterol (FF/VI) combination in asthma,1 in which he specifically discusses effects on urinary cortisol. We acknowledge the limitations of urinary cortisol assessment; however, as outlined in the online supplement, the urinary cortisol population in our study specifically excluded subjects with an incomplete urine collection and/or 24-h urinary creatinine levels below the lower limit of the threshold range. Thus, our data are not confounded …
H<scp>YDROXYLASE</scp>E<scp>NZYMES OF THE</scp>V<scp>ITAMIN</scp>D P<scp>ATHWAY</scp>: Expression, Function, and Regulation
Authors: John L. Omdahl, Howard A. Morris, Brian K. May
Journal: Annual Review of Nutrition (2002)

▪ Abstract Vitamin D is a secosteroid that is metabolically activated and degraded through the actions of three cytochrome P450 hydroxylase enzymes. Bioactivation occurs through the sequential actions of cytochromes P450C25 and P450C1, resulting in synthesis of the pleiotropic hormone 1,25-dihydroxyvitamin D (1,25VD), which regulates over 60 genes whose actions include those associated with calcium homeostasis and immune responses as well as cellular growth, differentiation, and apoptosis. Inactivation of 1,25VD occurs by C23/C24 oxidation pathways that are catalyzed by the multifunctional cytochrome P450C24 enzyme. Both P450C1 and P450C24 are highly regulated enzymes whose differential expression is controlled in response to numerous cellular modulatory agents such as parathyroid hormone (PTH), calcitonin, interferon gamma, calcium, phosphorus, and pituitary hormones as well as the secosteroid hormone 1,25VD. Most thoroughly studied at the molecular level are the actions of PTH to upregulate P450C1 gene expression and 1,25VD to induce the expression of P450C24. The regulatory action of PTH is mediated through the protein kinase A pathway and involves the phosphorylation of transcription factors that function at the proximal promoter of the P450C1 gene. The upregulation of P450C24 by 1,25VD has both a rapid nongenomic and a slower genomic component that are functionally linked. The rapid response involves protein kinase C and mitogen-activated protein kinase (MAPK) pathways that direct the phosphorylation of nuclear transcription factors. The slower genomic actions are linked to the binding of 1,25VD to the vitamin D receptor (VDR) and the interaction of the VDR-1,25VD complex with its heterodimer partner retinoid-X-receptor and associated coactivators. The regulatory complex is assembled on vitamin D response elements in the proximal promoter of the P450C24 gene and functions to increase the transcription rate.
Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis
Authors: Göran K. Hansson, Peter Libby, Uwe Schönbeck, Zhong-Qun Yan
Journal: Circulation Research (2002)

This review considers critically the evidence for the involvement of mediators of innate and acquired immunity in various stages of atherosclerosis. Rapidly mobilized arms of innate immunity, including phagocytic leukocytes, complement, and proinflammatory cytokines, contribute to atherogenesis. In addition, adaptive immunity, with its T cells, antibodies, and immunoregulatory cytokines, powerfully modulates disease activity and progression. Atherogenesis involves cross talk between and shared pathways involved in adaptive and innate immunity. Immune processes can influence the balance between cell proliferation and death, between synthetic and degradative processes, and between pro- and antithrombotic processes. Various established and emerging risk factors for atherosclerosis modulate aspects of immune responses, including lipoproteins and their modified products, vasoactive peptides, and infectious agents. As we fill in the molecular details, new potential targets for therapies will doubtless emerge.
Effects of yoga on anxiety and depression in women
Authors: Eskandar Rahimi, Sosan Bavaqar
Journal: British Journal of Sports Medicine (2010)

Purpose The purpose of this study was to examine the influence of yoga on anxiety and depression in Shirazian women. Anxiety and depression are illnesses that increasing in incidence worldwide. They have a profound effect on an individual's physical, emotional, mental and spiritual capacities. It seems that alternative medical systems such as yoga practice can be used for these disorders. Method Thirty-four Shirazian women age 34± volunteer participated in this study and were divided randomly in two control and experimental groups. Exercise protocol included 16 sessions Hata Yoga in the experimental group was carried out. The two training sessions a week and each session 90 M were performed. DASS questionnaire was used to assess anxiety and depression. Results Overall findings showed that anxiety and depression significant difference between pretest and post-test experimental group. Also, test anxiety and depression between the experimental and control groups at p &lt;0.05 was a significant difference. Conclusion The principle aim of this study was investigating the effect of Hata Yoga practices on anxiety and depression. Anxiety and depression are illnesses which are increasing in incidence worldwide, have a profound effect on an individual's physical, emotional, mental and spiritual capacities, and affect the community as a whole because of reduction persons, ability to perform. Not only does a person's ability to enjoy life decrease, but their ability to work, to fulfil their roles as spouse or parent, and to contribute to their community become impaired. As the result of this study and other similar studies yoga practice has benefits for the management of the symptoms of these illnesses, and can create balance in the physical, emotional, mental and spiritual capacities of individuals, so it can be used as alternative health practice to prevent depression and anxiety.
A Phase II Study of Gefitinib Monotherapy in Advanced Esophageal Adenocarcinoma: Evidence of Gene Expression, Cellular, and Clinical Response
Authors: David R. Ferry, Mark Anderson, Kate Beddard, Simon Tomlinson, Paul Atherfold, Jolanta Obszynska, Rebecca Harrison, Janusz Jankowski
Journal: Clinical Cancer Research (2007)

Abstract Purpose: At presentation, most cases of adenocarcinoma of the esophagus (ACE) are inoperable. Although chemotherapy can prolong survival, patients eventually die as a result of refractory disease. Epidermal growth factor receptor (EGFR) is almost universally expressed in ACE and is a negative prognostic factor. Experimental Design: This open-label, two-center, noncomparative, two-part phase II trial assessed the EGFR tyrosine kinase inhibitor gefitinib (500 mg/d) in patients with advanced, inoperable ACE. The primary end point was tumor response. The effect of EGFR inhibition was also evaluated by gene expression analysis of tumor biopsies taken before gefitinib treatment and 28 days after. Results: Twenty-seven patients were recruited and evaluable for tumor response and safety. Three patients had a partial response and seven had stable disease, giving a disease control rate (partial response + stable disease) of 37%. Drug-related adverse events were generally mild: diarrhea in 19 (grade 3 in three) and rash in 19 (grade 3 in five) patients, and there were no grade 4 drug-related adverse events. Microarray experiments on tumor biopsies showed that gefitinib also down-regulated oncogenes associated with tumor progression. Ki67 (a marker of tumor growth) expression decreased in five of seven biopsies taken before and after treatment. Conclusion: Gefitinib (500 mg/d) is an active and generally well-tolerated treatment for ACE. Studies on endoscopic biopsies are feasible and indicate that gefitinib inhibits both gene expression and cellular biology at 500 mg/d, and these may provide surrogate end points for predictive biomarkers. Further trials of gefitinib are warranted, particularly as patient response seems to be durable and current second-line chemotherapy options have no proven ability to prolong life.
Diabetic Retinopathy, Its Progression, and Incident Cardiovascular Events in the ACCORD Trial
Authors: Hertzel C. Gerstein, Walter T. Ambrosius, Ronald Danis, Faramarz Ismail-Beigi, William Cushman, Jorge Calles, MaryAnn Banerji, Ulrich Schubart, Emily Y. Chew
Journal: Diabetes Care (2012)

OBJECTIVE Both the presence of diabetic retinopathy and its severity are significantly associated with future cardiovascular (CV) events. Whether its progression is also linked to incident CV outcomes hasn’t been assessed. RESEARCH DESIGN AND METHODS The relationship between retinopathy, its 4-year progression, and CV outcomes (CV death or nonfatal myocardial infarction or stroke) was analyzed in participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial who also participated in the ACCORD Eye Study. Retinopathy was classified as either none, mild, moderate, or severe, and worsening was classified as a &amp;lt;2-step, 2–3-step, or &amp;gt;3-step change (that included incident laser therapy or vitrectomy). RESULTS Participants (n = 3,433) of mean age 61 years had baseline retinal photographs (seven stereoscopic fields). Compared with no retinopathy, the adjusted HRs (95% CI) for the CV outcome rose from 1.49 (1.12–1.97) for mild retinopathy to 2.35 (1.47–3.76) for severe retinopathy. A subset of 2,856 was evaluated for progression of diabetic retinopathy at 4 years. The hazard of the primary outcome increased by 38% (1.38 [1.10–1.74]) for every category of change in retinopathy severity. Additional adjustment for the baseline and follow-up levels of A1C, systolic blood pressure, and lipids either individually or together rendered the relationships between worsening and CV outcomes nonsignificant. CONCLUSIONS Both the severity of retinopathy and its progression are determinants of incident CV outcomes. The retina may provide an anatomical index of the effect of metabolic and hemodynamic factors on future CV outcomes.
Progress in Understanding What Is Being Statin(ed) in Prostate Cancer
Authors: Jorge D. Ramos, Evan Y. Yu
Journal: JAMA Oncology (2015)

tation status) on objective response rates with nivolumab, although this difference was not observed in the overall data analysis reported by Larkin et al. 1 Furthermore, while there are data to suggest synergy between BRAF-directed therapy and PD-1 blockade (an area of active investigation, although not approved for clinical use), current data do not support clear differences in clinical response rates to PD-1 blockade that can be related to the drug mechanism of action of prior BRAF inhibitor therapy.However, factors associated with prior BRAF inhibition, such as an increased baseline tumor size after prior therapy, may have an impact on response rates to PD-1 blockade, as previously described. 2verall, the results do suggest a similar response rate to PD-1 blockade in patients with and without BRAF mutant melanoma in this retrospective data analysis including a heterogeneous study population.The results are also consistent with those of prior studies of immune therapy with ipilimumab 3 in which BRAF mutation status does not have an impact on objective response rates and are also consistent with a prior report of PD-1 blockade with pembrolizumab in which response rates were similar in the BRAF-mutant and nonmutant patients enrolled in a large clinical trial. 4A prospective randomized clinical study in a uniform study population would be required to confirm that response rates are truly equal in patients with or without BRAF-mutant melanoma, and in patients with and without prior BRAF inhibitor therapy among the BRAF-mutant patients.The results are applicable to patients similar to those eligible for the clinical trials included in the analysis; that is, patients with a good performance status and normal organ function can be considered for treatment with PD-1 blockade with nivolumab regardless of BRAF mutation status.However, clinicians should exercise caution in applying these results to patients who would not meet the trial eligibility criteria of the study population-for example, patients with a poor performance status, because response rates to nivolumab may not be similar in patients with and without BRAF mutations in a nontrial population.BRAF-directed therapy may offer a higher chance of response and clinical benefit in some patients with BRAF-mutant melanoma and should be considered in all patients with BRAF-mutant melanoma.It is clear that patients both with and without BRAFactivating mutations gain benefit from PD-1 blockade, with durable responses observed in both subsets of patients, regardless of prior therapies.Ongoing studies will further define the role of sequencing of BRAF-targeted therapy and PD-1 or CTLA-4 blockade on clinical outcomes.Clinical trials that include PD-1 blockade as well as novel immune therapy combination studies or targeted therapy combination studies can be considered among the first line of therapy options for all patients with advanced melanoma.
Socioeconomic Inequalities in Lung Cancer Treatment: Systematic Review and Meta-Analysis
Authors: Lynne F. Forrest, Jean Adams, Helen Wareham, Greg Rubin, Martin White
Journal: PLoS Medicine (2013)

In a systematic review and meta-analysis, Lynne Forrest and colleagues find that patients with lung cancer who are more socioeconomically deprived are less likely to receive surgical treatment, chemotherapy, or any type of treatment combined, compared with patients who are more socioeconomically well off, regardless of cancer stage or type of health care system.
Outcome According to Tumor Ras Mutation Status in Crystal Study Patients with Metastatic Colorectal Cancer Randomized to Folfiri with or Without Cetuximab as First-Line Treatment
Authors: E. Van Cutsem, J. Lenz Heinz, C.H. Köhne, V. Heinemann, S. Tejpar, I. Melezinek, F. Beier, K. Duecker, H. van Krieken, F. Ciardiello
Journal: Annals of Oncology (2014)
Heme oxygenase-1 gene induction as an intrinsic regulation against delayed cerebral vasospasm in rats
Authors: Hidenori Suzuki, Kenji Kanamaru, Hiroshi Tsunoda, Hiroyasu Inada, Minoru Kuroki, Hong Sun, Shiro Waga, Toshio Tanaka
Journal: Journal of Clinical Investigation (1999)

Delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) causes cerebral ischemia and infarction. To date, the pathogenesis and gene expression associated with vasospasm remain poorly understood. The present study used fluorescent differential display to identify differentially expressed genes in a rat model of SAH. By using quantitative RT-PCR, we found that heme oxygenase-1 (HO-1) mRNA was prominently induced in the basilar artery and modestly in brain tissue in a rat vasospasm model. A significant correlation was observed between the degree of vasospasm and HO-1 mRNA levels in the basilar arteries exhibiting vasospasm. Intracisternal injection of antisense HO-1 oligodeoxynucleotide (ODN) significantly delayed the clearance of oxyhemoglobin and deoxyhemoglobin from the subarachnoid space and aggravated angiographic vasospasm. Antisense HO-1 ODN inhibited HO-1 induction in the basilar arteries but not in the whole brain tissue. This phenomenon was not observed in the nontreated, sense HO-1 ODN–treated, or scrambled ODN–treated arteries. We report the protective effects of HO-1 gene induction in cerebral vasospasm after SAH, a finding that should provide a novel therapeutic approach for cerebral vasospasm.
Trimodality therapy in stage III non-small cell lung cancer: prediction of recurrence by assessment of p185neu
Authors: M Thomas, C Rube, M Semik, M von Eiff, F Klinke, HN Macha, L Freitag, HH Scheld, N Willich, WE Berdel, K Junker
Journal: European Respiratory Journal (1999)

In a trimodality treatment approach for stage III non-small cell lung cancer the prognostic impact of pretherapeutic p185neu assessment was evaluated. Fifty-four patients were admitted to chemotherapy followed by twice-daily radiation with concomittant low-dose chemotherapy and subsequent surgery. Immunohistochemical assessment of p185neu expression was performed in paraffin-embedded mediastinal lymph node metastases, by mediastinoscopy biopsy prior to therapy. Paraffin-embedded biopsies of mediastinal lymph node metastases were available in 33 cases. Seven out of eight patients with positive p185neu staining developed distant metastases, in contrast to seven out of 25 negative cases. Expression of p185neu in mediastinal lymph node metastases was a significant predictor for progression-free survival (p=0.047) and resulted mainly from significant differences in metastases-free survival (p185neu-positive versus p185neu-negative: median, 11 versus 19 months; 2- and 3-yr rates, 13% and 0% versus 40% and 32%; p=0.04). On the basis of these preliminary results it was concluded that further evaluation of p185neu expression in trials on neoadjuvant and adjuvant therapy is warranted. When the prognostic impact of p185neu in such trials with larger patient numbers is confirmed, this may contribute to the identification of stratification variables for future treatment approaches of non-small cell lung cancer.
Group-Randomized Trial of a Proactive, Personalized Telephone Counseling Intervention for Adolescent Smoking Cessation
Authors: Arthur V. Peterson, Kathleen A. Kealey, Sue L. Mann, Patrick M. Marek, Evette J. Ludman, Jingmin Liu, Jonathan B. Bricker
Journal: JNCI Journal of the National Cancer Institute (2009)

BackgroundThe Hutchinson Study of High School Smoking randomized trial was designed to rigorously evaluate a proactive, personalized telephone counseling intervention for adolescent smoking cessation.