tbuckley/cabot-search huggingface dataset:
The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models
Authors: Jennifer Yen, Richard M White, David C Wedge, Peter Van Loo, Jeroen de Ridder, Amy Capper, Jennifer Richardson, David Jones, Keiran Raine, Ian R Watson, Chang-Jiun Wu, Jiqiu Cheng, Iñigo Martincorena, Serena Nik-Zainal, Laura Mudie, Yves Moreau, John Marshall, Manasa Ramakrishna, Patrick Tarpey, Adam Shlien, Ian Whitmore, Steve Gamble, Calli Latimer, Erin Langdon, Charles Kaufman, Mike Dovey, Alison Taylor, Andy Menzies, Stuart McLaren, Sarah O’Meara, Adam Butler, Jon Teague, James Lister, Lynda Chin, Peter Campbell, David J Adams, Leonard I Zon, E Elizabeth Patton, Derek L Stemple, P Andy Futreal
Journal: Genome biology (2013)

Abstract Background Melanoma is the most deadly form of skin cancer. Expression of oncogenic BRAF or NRAS , which are frequently mutated in human melanomas, promote the formation of nevi but are not sufficient for tumorigenesis. Even with germline mutated p53 , these engineered melanomas present with variable onset and pathology, implicating additional somatic mutations in a multi-hit tumorigenic process. Results To decipher the genetics of these melanomas, we sequence the protein coding exons of 53 primary melanomas generated from several BRAF V600E or NRAS Q61K driven transgenic zebrafish lines. We find that engineered zebrafish melanomas show an overall low mutation burden, which has a strong, inverse association with the number of initiating germline drivers. Although tumors reveal distinct mutation spectrums, they show mostly C &gt; T transitions without UV light exposure, and enrichment of mutations in melanogenesis, p53 and MAPK signaling. Importantly, a recurrent amplification occurring with pre-configured drivers BRAF V600E and p53 -/- suggests a novel path of BRAF cooperativity through the protein kinase A pathway. Conclusion This is the first analysis of a melanoma mutational landscape in the absence of UV light, where tumors manifest with remarkably low mutation burden and high heterogeneity. Genotype specific amplification of protein kinase A in cooperation with BRAF and p53 mutation suggests the involvement of melanogenesis in these tumors. This work is important for defining the spectrum of events in BRAF or NRAS driven melanoma in the absence of UV light, and for informed exploitation of models such as transgenic zebrafish to better understand mechanisms leading to human melanoma formation.
Immunoglobulin G4 Immunostaining of Gastric, Duodenal, or Colonic Biopsies Is Not Helpful for the Diagnosis of Autoimmune Pancreatitis
Authors: Vinciane Rebours, Yann Le Baleur, Dominique Cazals–Hatem, Carmen Stefanescu, Olivia Hentic, Frédérique Maire, Yoram Bouhnik, Pierre Bedossa, Pascal Hammel, Philippe Ruszniewski, Philippe Lévy, Anne Couvelard
Journal: Clinical Gastroenterology and Hepatology (2011)
Costs of asthma according to the degree of severity
Authors: J Serra-Batlles, V Plaza, E Morejon, A Comella, J Brugues
Journal: European Respiratory Journal (1998)

An increase in asthma-related morbidity and mortality has been reported recently, resulting in a substantial increase in the economic impact of this condition. Little information is available relating to the costs of asthma depending on the degree of severity of the disease. Total, direct and indirect costs generated by asthma patients who sought medical care for asthma control over a one-year period in a northern area of Spain were determined. Data were obtained from the patients themselves and severity of illness was classified into mild, moderate and severe according to the International Consensus Report on Diagnosis and Treatment of Asthma, 1992. The average total annual asthma-derived cost was estimated at US$2,879 per patient, with averages of US$1,336 in mildly asthmatic patients, US$2,407 in moderate asthma and US$6,393 in severe asthma. At all levels of severity, indirect costs were twice as high as direct costs, and at the same degree of severity, direct costs due to medication and hospitalization were higher among females than males. A minority of severe asthmatics incurred some 41% of the total costs. The cost of asthma was surprisingly high and varied substantially depending on the degree of severity of the disease. Further knowledge of the costs of asthma across various levels of severity will contribute to a better characterization of optimal intervention strategies for asthma care.
Second-line treatment of small-cell lung cancer with the camptothecin-derivative GI147211: A study of the EORTC Early Clinical Studies Group (ECSG)
Authors: C. Sessa, J. Wanders, M. Roelvink, P. Dombernowsky, D. Nielsen, R. Morant, P. Drings, P. Wissel, A.-R. Hanauske
Journal: Annals of Oncology (2000)
Phenotypic and functional analyses of dendritic cells in patients with lymphoproliferative disease of granular lymphocytes (LDGL)
Authors: Renato Zambello, Tamara Berno, Giovanna Cannas, Ilenia Baesso, Gianni Binotto, Emanuela Bonoldi, Pierantonio Bevilacqua, Marta Miorin, Monica Facco, Livio Trentin, Carlo Agostini, Gianpietro Semenzato
Journal: Blood (2005)
Sixty Years of CA: A Cancer Journal for Clinicians
Authors: T. Gansler, P. A. Ganz, M. Grant, F. L. Greene, P. Johnstone, M. Mahoney, L. A. Newman, W. K. Oh, C. R. Thomas, M. J. Thun, A. J. Vickers, R. C. Wender, O. W. Brawley
Journal: CA A Cancer Journal for Clinicians (2010)

We suspect that most of you have, by now, noticed the American Cancer Society (ACS)'s birthday-themed media campaign that began a little over a year ago.The point of that message is to memorably and concisely invite others to join us in working toward "a world with less cancer and more birthdays," and to summarize our strategy for accomplishing that goal-helping people "stay well" (prevention and early detection), "get well" (support and information for people facing cancer), "fight back" (advocacy), and "find cures" (research).This article, however, refers to a more literal birthday-the 60th anniversary of the first issue of CA: A Cancer Journal for Clinicians.Although some scientific and medical journals are far older, CA is among the most venerable of oncology and cancer control journals.Nearly all of the content in our journal is focused on current standards of care and on research likely to impact those standards in the near future.There is still so far to go toward the ACS's mission of "eliminating cancer as a major health problem" that time for retrospection is a luxury, especially for a journal with as few pages as CA.Nonetheless, we feel that after 60 years, it is reasonable to allocate a few pages to a brief look at where we have been.Members of this editorial board therefore set aside several hours for perusing content from the first decade of CA (still known at that time as CA: A Bulletin of Cancer Progress).It is impossible for us to summarize a decade of articles in a few pages, so we will briefly discuss only a few articles that represent each of 4 themes: prevention, early detection, treatment, and clinician-patient communication.For each theme, we have paired several articles from CA's first decade (1950-1959) and the most recent decade (2000-2009, 50 years later).
Synthetic Lethal Approaches Exploiting DNA Damage in Aggressive Myeloma
Authors: Francesca Cottini, Teru Hideshima, Rikio Suzuki, Yu-Tzu Tai, Giampaolo Bianchini, Paul G. Richardson, Kenneth C. Anderson, Giovanni Tonon
Journal: Cancer Discovery (2015)

Abstract Ongoing DNA damage is a common feature of epithelial cancers. Here, we show that tumor cells derived from multiple myeloma, a disease of clonal plasma cells, demonstrate DNA-replicative stress, leading to DNA damage. We identified a poor-prognosis subset of multiple myeloma with extensive chromosomal instability and replicative stress, which rely on ATR to compensate for DNA-replicative stress; conversely, silencing of ATR or treatment with a specific ATR inhibitor triggers multiple myeloma cell apoptosis. We show that oncogenes, such as MYC, induce DNA damage in multiple myeloma cells not only by increased replicative stress, but also via increased oxidative stress, and that reactive oxygen species–inducer piperlongumine triggers further DNA damage and apoptosis. Importantly, ATR inhibition combined with piperlongumine triggers synergistic multiple myeloma cytotoxicity. This synthetic lethal approach, enhancing oxidative stress while concomitantly blocking replicative stress response, provides a novel combination targeted therapy to address an unmet medical need in this subset of multiple myeloma. Significance: Multiple myeloma remains an incurable disease. We have identified a subset of multiple myeloma patients with poor prognosis, whose tumors present chromosomal instability, replicative and oxidative stress, and DNA damage. We define a synthetic lethal approach enhancing oxidative stress while targeting replicative stress response, inducing tumor cell apoptosis in this patient subset. Cancer Discov; 5(9); 972–87. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 893
Combination of arterial lactate levels and venous-arterial CO2 to arterial-venous O2 content difference ratio as markers of resuscitation in patients with septic shock
Authors: Gustavo A. Ospina-Tascón, Mauricio Umaña, William Bermúdez, Diego F. Bautista-Rincón, Glenn Hernandez, Alejandro Bruhn, Marcela Granados, Blanca Salazar, César Arango-Dávila, Daniel De Backer
Journal: Intensive Care Medicine (2015)

To evaluate the prognostic value of the Cv-aCO2/Da-vO2 ratio combined with lactate levels during the early phases of resuscitation in septic shock. Prospective observational study in a 60-bed mixed ICU. One hundred and thirty-five patients with septic shock were included. The resuscitation protocol targeted mean arterial pressure, pulse pressure variations or central venous pressure, mixed venous oxygen saturation, and lactate levels. Patients were classified into four groups according to lactate levels and Cv-aCO2/Da-vO2 ratio at 6 h of resuscitation (T6): group 1, lactate ≥2.0 mmol/L and Cv-aCO2/Da-vO2 >1.0; group 2, lactate ≥2.0 mmol/L and Cv-aCO2/Da-vO2 ≤1.0; group 3, lactate <2.0 mmol/L and Cv-aCO2/Da-vO2 >1.0; and group 4, lactate <2.0 mmol/L and Cv-aCO2/Da-vO2 ≤1.0. Combination of hyperlactatemia and high Cv-aCO2/Da-vO2 ratio was associated with the worst SOFA scores and lower survival rates at day 28 [log rank (Mantel–Cox) = 31.39, p < 0.0001]. Normalization of both variables was associated with the best outcomes. Patients with a high Cv-aCO2/Da-vO2 ratio and lactate <2.0 mmol/L had similar outcomes to hyperlactatemic patients with low Cv-aCO2/Da-vO2 ratio. The multivariate analysis revealed that Cv-aCO2/Da-vO2 ratio at both T0 (RR 3.85; 95 % CI 1.60–9.27) and T6 (RR 3.97; 95 % CI 1.54–10.24) was an independent predictor for mortality at day 28, as well as lactate levels at T6 (RR 1.58; 95 % CI 1.13–2.22). Complementing lactate assessment with Cv-aCO2/Da-vO2 ratio during early stages of resuscitation of septic shock can better identify patients at high risk of adverse outcomes. The Cv-aCO2/Da-vO2 ratio may become a potential resuscitation goal in patients with septic shock.
Acute viral hepatitis increases liver stiffness values measured by transient elastography
Authors: Umberto Arena, Francesco Vizzutti, Giampaolo Corti, Silvia Ambu, Cristina Stasi, Silvia Bresci, Stefania Moscarella, Vieri Boddi, Antonio Petrarca, Giacomo Laffi, Fabio Marra, Massimo Pinzani
Journal: Hepatology (2007)

Liver tissue alterations other than fibrosis may have an impact on liver stiffness measurement. In this study we evaluated 18 patients without a previous clinical history of liver disease, consecutively admitted for acute viral hepatitis. In each patient, aminotransferase determination and liver stiffness measurement were performed on the same study day, at 3 different points: (1) peak increase in aminotransferase; (2) aminotransferase 50% or less of the peak; (3) aminotransferase levels ≤2× the upper limit of normal. In all patients, the degree of liver stiffness at the time of the peak increase in aminotransferases exceeded the cutoff values proposed for the prediction of significant fibrosis or cirrhosis. A progressive significant reduction in liver stiffness values was observed ( P &lt; 0.0001) in the follow-up period in parallel with the reduction of aminotransferase levels ( P &lt; 0.0001). Moreover, a statistically significant, positive correlation between aminotransferases and liver stiffness measurement (LSM) at the onset of acute viral hepatitis was found ( r = 0.53, P = 0.02 and r = 0.51, P = 0.03 for alanine aminotransferase and aspartate aminotransferase, respectively). In conclusion, the extent of necroinflammatory activity needs to be carefully considered in future studies aimed at further validating transient elastography, particularly in patients with absent or low-stage liver fibrosis (in other words, F0-F2 METAVIR). LSM does not represent a reliable instrument to detect the presence of advanced fibrosis and cirrhosis in patients presenting with a clinical picture of acute hepatitis. (Hepatology 2007.)
Percutaneous cholangiography with the Okuda needle.
Authors: G De Hinde, P M Smith, J L Craven
Journal: Gut (1977)

Percutaneous cholangiography with the Okuda needle was performed in 42 consecutive patients with a clinical diagnosis of obstructive jaundice. Six had intrahepatic cholestasis. The technique demonstrated the biliary anatomy in 41 patients and the radiological diagnosis was confirmed by laparotomy, necropsy, or liver biopsy. There were no significant complications. Laparotomy, when indicated, was performed earlier in the course of the jaundice and it was avoided in seven patients. Precise knowledge of the site of the obstruction was of great help to the surgeon. We believe that this technique represents an important advance in the management of the jaundiced patient.
Cancer-Related Fatigue in Women With Breast Cancer: Outcomes of a 5-Year Prospective Cohort Study
Authors: David Goldstein, Barbara K. Bennett, Kate Webber, Fran Boyle, Paul L. de Souza, Nicholas R.C. Wilcken, Elizabeth M. Scott, Ruth Toppler, Penelope Murie, Linda O'Malley, Junie McCourt, Michael Friedlander, Ian B. Hickie, Andrew R. Lloyd
Journal: Journal of Clinical Oncology (2012)

Purpose Prolonged and disabling fatigue is prevalent after cancer treatment, but the early natural history of cancer-related fatigue (CRF) has not been systematically examined to document consistent presence of symptoms. Hence, relationships to cancer, surgery, and adjuvant therapy are unclear. Patients and Methods A prospective cohort study of women receiving adjuvant treatment for early-stage breast cancer was conducted. Women (n = 218) were enrolled after surgery and observed at end treatment and at 1, 3, 6, 9, and 12 months as well as 5 years. Structured interviews and self-report questionnaires were used to record physical and psychologic health as well as disability and health care utilization. Patients with CRF persisting for 6 months were assessed to exclude alternative medical and psychiatric causes of fatigue. Predictors of persistent fatigue, mood disturbance, and health care utilization were sought by logistic regression. Results The case rate for CRF was 24% (n = 51) postsurgery and 31% (n = 69) at end of treatment; it became persistent in 11% (n = 24) at 6 months and 6% (n = 12) at 12 months. At each time point, approximately one third of the patients had comorbid mood disturbance. Persistent CRF was predicted by tumor size but not demographic, psychologic, surgical, or hematologic parameters. CRF was associated with significant disability and health care utilization. Conclusion CRF is common but generally runs a self-limiting course. Much of the previously reported high rates of persistent CRF may be attributable to factors unrelated to the cancer or its treatment.
Urban air pollution, and asthma and COPD hospital emergency room visits
Authors: J I Halonen, T Lanki, T Yli-Tuomi, M Kulmala, P Tiittanen, J Pekkanen
Journal: Thorax (2008)

<h3>Background:</h3> There is little previous information of the effects of size fractioned particulate air pollution and source specific fine particles (PM<sub>2.5</sub>; &lt;2.5 μm) on asthma and chronic obstructive pulmonary disease (COPD) among children, adults and the elderly. <h3>Objectives:</h3> To determine the effects of daily variation in levels of different particle size fractions and gaseous pollutants on asthma and COPD by age group. <h3>Methods:</h3> Levels of particulate air pollution, NO<sub>2</sub> and CO were measured from 1998 to 2004 at central outdoor monitoring sites in Helsinki, Finland. Associations between daily pollution levels and hospital emergency room visits were evaluated for asthma (ICD10: J45+J46) in children &lt;15 years old, and for asthma and COPD (ICD10: J41+J44) in adults (15–64 years) and the elderly (⩾65 years). <h3>Results:</h3> Three to 5 day lagged increases in asthma visits were found among children in association with nucleation (&lt;0.03 μm), Aitken (0.03–0.1 μm) and accumulation (0.1–0.29 μm) mode particles, gaseous pollutants and traffic related PM<sub>2.5</sub> (7.8% (95% CI 3.5 to 12.3) for 1.1 μg/m<sup>3</sup> increase in traffic related PM<sub>2.5</sub> at lag 4). Pooled asthma–COPD visits among the elderly were associated with lag 0 of PM<sub>2.5</sub>, coarse particles, gaseous pollutants and long range transported and traffic related PM<sub>2.5</sub> (3.9% (95% CI 0.28 to 7.7) at lag 0). Only accumulation mode and coarse particles were associated with asthma and COPD among adults. <h3>Conclusions:</h3> Among children, traffic related PM<sub>2.5</sub> had delayed effects, whereas among the elderly, several types of particles had effects that were more immediate. These findings suggest that the mechanisms of the respiratory effects of air pollution, and responsible pollutants, differ by age group.
A randomized, placebo- and active-controlled, parallel-group, multicentre, investigator-blinded study of four treatment regimens of posaconazole in adults with toenail onychomycosis
Authors: B. Elewski, R. Pollak, S. Ashton, P. Rich, J. Schlessinger, A. Tavakkol
Journal: British Journal of Dermatology (2011)

Background Onychomycosis accounts for up to 50% of all onychopathies. Objectives To evaluate the efficacy of four posaconazole regimens compared with placebo in the treatment of toenail onychomycosis, to assess the safety and tolerability of posaconazole, and to estimate the relative efficacy of posaconazole against terbinafine. Methods A phase 2B, randomized, placebo‐ and active‐controlled, parallel‐group, multicentre, investigator‐blinded (double blind for placebo) study (ClinicalTrials.gov identifier: NCT00491764). Onychomycosis patients aged 18–75 years (n =218) were randomized equally to one of six treatment regimens: posaconazole (oral suspension) 100, 200 or 400 mg once daily (24 weeks); posaconazole 400 mg once daily (12 weeks); terbinafine (tablets) 250 mg once daily (12 weeks); or placebo (24 weeks). The primary efficacy variable was complete cure (negative mycology and 0% nail involvement) at week 48. Results All posaconazole treatment arms had a significantly (P ≤0·012) greater proportion of patients with complete cure at week 48 compared with placebo. The proportions of patients with complete cure were numerically higher for posaconazole 200 mg/24 weeks (54·1%) and 400 mg/24 weeks (45·5%), but lower for 400 mg/12 weeks (20%) compared with terbinafine (37%; differences were not statistically significant). Posaconazole was well tolerated. Seven patients receiving posaconazole withdrew because of asymptomatic liver enzyme increases, as mandated by protocol discontinuation criteria. Conclusions The efficacy and favourable safety profile of posaconazole suggest a potential new treatment for onychomycosis. The availability of low‐cost generic terbinafine may limit posaconazole use to second‐line treatment of infections refractory to, or patients intolerant of, terbinafine, or nondermatophyte mould infections.
Conditional inactivation of Akt three isoforms causes tau hyperphosphorylation in the brain
Authors: Long Wang, Shanshan Cheng, Zhenyu Yin, Congyu Xu, Shuangshuang Lu, Jinxing Hou, Tingting Yu, Xiaolei Zhu, Xiaoyan Zou, Ying Peng, Yun Xu, Zhongzhou Yang, Guiquan Chen
Journal: Molecular Neurodegeneration (2015)

Tau hyperphosphorylation plays a critical role in neurodegenerative diseases [EMBO Mol Med. 6:1142-60, 2014; Annu Rev Neurosci. 24:1121-59, 2001]. Recent evidence has shown that Akt is down-regulated in AD [J Pathol. 225:54-62, 2011]. However, it remained unknown which pathological process, e.g. tau pathology or neuron death, Akt may contribute to. In this study, Cre-loxP technique was employed to generate a viable Akt three isoforms conditional knockout (Akt cTKO) mouse in which total Akt levels were dramatically reduced in the adult brain.Significantly increased levels of tau phosphorylated (p-tau) at various sites were observed in Akt cTKO mice as compared to age-matched littermate controls. Increased levels for phosphorylated GSK3α and phosphorylated PKA substrates were detected in Akt cTKO brains. In contrast, no significant changes on p-tau levels were found in Akt1(-/-), Akt2(-/-) or Akt3(-/-) mice.Akt may regulate tau phosphorylation in the adult brain by affecting activities for PKA and GSK3α.
Vascular Normalization by Loss of Siah2 Results in Increased Chemotherapeutic Efficacy
Authors: Christina S.F. Wong, Jaclyn Sceneay, Colin M. House, Heloise M. Halse, Mira C.P. Liu, Joshy George, Titaina C.U. Potdevin Hunnam, Belinda S. Parker, Izhak Haviv, Ze'ev Ronai, Carleen Cullinane, David D. Bowtell, Andreas Möller
Journal: Cancer Research (2012)

Tumor hypoxia is associated with resistance to antiangiogenic therapy and poor prognosis. The Siah E3 ubiquitin ligases regulate the hypoxic response pathway by modulating the turnover of the master proangiogenic transcription factor hypoxia-inducible factor-1α (Hif-1α). In this study, we show that genetic deficiency in the Siah family member Siah2 results in vascular normalization and delayed tumor growth in an established transgenic model of aggressive breast cancer. Tumors arising in a Siah2(-/-) genetic background showed increased perfusion and pericyte-associated vasculature, similar to that occurring with antiangiogenic therapy. In support of the role of Siah2 in regulating levels of Hif-1α, expression of angiogenic factors was decreased in Siah2(-/-) tumors. Blood vessel normalization in Siah2(-/-) tumors resulted in an increased response to chemotherapy and prolonged survival. Together, our findings offer a preclinical proof of concept that targeting Siah2 is sufficient to attenuate Hif-1α-mediated angiogenesis and hypoxia signaling, thereby improving responses to chemotherapy.