tbuckley/cabot-search huggingface dataset:
Abstract #5376: Wip1 as a therapeutic target for high-grade gliomas
Authors: Marcos Seoane, Pablo Iglesias, Teresa Gonzalez, Maximo Fraga, Carlos Aliste, Fernando Dominguez, Jeronimo Forteza, Jose A. Costoya
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Recently it has been reported that p38MAPK pathway is activated upon cellular stress, blocking proliferation or promoting apoptosis. p38MAPK mediates multiple cellular processes but apparently its role in stress response is one of the key factors in oncogene-induced senescence (OIS), crucial for protection against cancer development. Oncogenic Ras is able to cooperate with Rb loss in oncogenic transformation in glioma through inhibition of p38MAPK pathway. Curiously, the oncogenic protein HRasV12 promotes in primary astrocytes proliferation both in vitro and in vivo. Despites that the oncogene expression activates a DNA damage response (DDR) and induces p38MAPK phosphorylation in astrocytes, this occurs in the absence of senescence or apoptosis. Moreover, when the expression of oncogenic Ras is combined with Rb deletion the levels of activated p38MAPK are depleted, due to the increased levels of protein phosphatase Wip1, promoting cellular transformation and tumor formation. The protein phosphatase Wip1 is encoded by PPM1D gene that is aberrantly amplified in a range of human tumors among which we can find high-grade gliomas. The activation of Wip1 results in negative regulation of p53 function and other tumor suppressor pathways by selective inactivation of p38MAPK by specific dephosphorylation of its conserved threonine residue. However, the issue of whether inhibition of Wip1 in glioma cells that overexpress this protein may affect tumor outcome has not yet been fully addressed. We show here that inhibition of Wip1, using two different chemical inhibitors (2E,5E)-2,5-Bis(2-thienylmethylene)-cyclopentanone (CCT007093) and Arsenic Trioxide, can indeed induce senescence and reduce the tumor progression. Interestingly enough, Wip1 chemical inhibition in transformed astrocytes leads to a significant decrease in the proliferative rate of these cells, which eventually enter in senescence as opposed to cells where Wip1 remains unaffected. Thus, Wip1 phosphatase plays a key role in the inhibition of tumor progression and specifically in malignant gliomas that continue to be among the most lethal of human cancer. These findings identify Wip1 as an important target for new therapeutic approaches. This study was supported by Spanish Ministry of Education and Science (SAF2005-00306) and Xunta de Galicia grants (PGIDIT05PXIB20801PR); Grupos emerxentes 2007/064) (J.A.C.), and by Fundacion de Investigacion Medica Mutua Madrilena (J.A.C., P.I.). J.A.C. is an Investigator of Ramon y Cajal Programme (Spanish Ministry of Education and Science).

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5376.
Review: Combination umeclidinium/vilanterol improved health status more than umeclidinium in COPD
Authors: Matthew B. Stanbrook
Journal: Annals of Internal Medicine (2015)

Source Citation Rodrigo GJ, Neffen H. A systematic review of the efficacy and safety of a fixed-dose combination of umeclidinium and vilanterol for the treatment of COPD. Chest. 2015;148:397-407. 25798635
Standard chemotherapy (CMF or AC) versus capecitabine in early-stage breast cancer (BC) patients aged 65 and older: Results of CALGB/CTSU 49907
Authors: H. B. Muss, D. L. Berry, C. Cirrincione, M. Theodoulou, A. Mauer, H. Cohen, A. H. Partridge, L. Norton, C. A. Hudis, E. P. Winer
Journal: Journal of Clinical Oncology (2008)

507 Background: Older women with BC are underrepresented in clinical trials. Scant data exist on the effects of adjuvant chemotherapy (CRx) in these patients (pts). CALGB/CTSU 49907 was designed to compare the efficacy of capecitabine (X) with standard treatment (S) in BC pts ≥ 65 yrs old. Methods: Pts were randomized to X or S (CMF or AC per physician choice). Eligibility: Stage T1–4, N0–3, M0; PS 0–2, ≤ 84 days from surgery; adequate organ function. Regimens (all doses per M2): CMF (C, 100 mg d1–14 oral; M 40 mg d1,8; FU 600 mg d1,8) q4wk×6 cycles; AC (A 60 mg; C 600 mg) q3wk×4; X (2,000 d1–14) q3wk×6. Endocrine therapy was recommended after completion of CRx for hormone receptor positive (HR+) pts. A Bayesian design addressed equivalence of X to S; total sample size planned 600–1,800 pts with serial monitoring. The primary endpoint was relapse-free survival (RFS) defined as locoregional or distant relapse or death. We calculate Bayesian measures, including the probability of inferiority of X (that the hazard ratio of X to S is greater than 1) and relate these to conventional p values. In unplanned subset analyses we repeat these calculations by HR status. Results: Pts were randomized between 9/2001 and 12/2006. Per protocol, accrual stopped with 633 pts (326 on S, 307 on X) based on predictive probability that with longer follow-up X was unlikely to be equivalent to S. Median follow-up is 2 yrs. Pt and tumor characteristics were similar in the 2 arms. Overall: 61% age 70+, 54% T > 2cm, 69% N+, 66% HR+. Adherence to X was excellent. Toxicity was moderate, with more myelosuppression on S, more hand-foot syndrome on X, and 2 drug-related deaths on X. Pts randomized to X were 2.4 (95% CI: 1.5–3.8) times more likely to experience an RFS event (adjusted p=0.0003) and 2.1 (95% CI: 1.2–3.7) times more likely to die (p=0.02). Probability of inferiority of X vs S was > 99% for both RFS and OS. Unplanned subset analysis showed a highly significant interaction between HR and CRx arm (p=0.0032 for RFS; p=0.0067 for OS). All advantage was for S in HR negative tumors; hazard ratios 5.1 (95% CI: 2.4–10.6) for RFS, 6.1 (95% CI: 2.1–18.0) for OS. Conclusions: X is inferior to S in older pts, particularly in those with HR-negative tumors. Analyses to be updated at ASCO 2008, including by HER-2 status. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Hoffman-La Roche Hoffman-La Roche
How to find the good and avoid the bad or ugly: a short guide to tools for rating quality of health information on the internet * Commentary: On the way to quality
Authors: P. Wilson
Journal: BMJ (2002)

# How to find the good and avoid the bad or ugly: a short guide to tools for rating quality of health information on the internet {#article-title-2}

Health related websites are frequently accessed on the internet. A poll in August 2001 concluded that almost 100 million American adults regularly go on line for information about health care.1 As over 100 000 sites offer health related information, “trying to get information from the internet is like drinking from a fire hose, you don't even know what the source of the water is.” 2 3

To help users discriminate between sites, a wide range of organisations have developed methods and tools for evaluating and rating the quality of websites. These tools aim to guide the site developers, filter content, and help consumers become discerning users of information.

A range of tools for rating quality exists, and their number has continued to grow since 1996 when the first initiatives produced codes of conduct for health information on the internet. 4 5 Some approaches focus on setting ethical standards and promoting the “good” whereas other more pragmatic approaches concentrate on sifting huge amounts of information into manageable chunks. Some approaches address general ethical principles about the nature of health related content whereas others focus on the mode of delivery and the integrity of the use of the web as a medium for the dissemination of information. I describe a classification of five types of approaches for rating the quality of English language websites (table). All start from the basic concept of an agreed set of criteria for good practice in the provision of health related information through websites.

#### Summary points

Health related websites are among the most widely used websites on the internet

A wide range of tools has been developed to assist site developers to produce good quality sites and for consumers to assess the quality of sites

These tools are classified into five broad categories: codes of conduct, quality labels, …
Abstract 674: Early integrated stress response induction of ATF4 is required for the anticancer effects of the dual Akt/ERK inhibitor and TRAIL pathway inducer ONC201/TIC10
Authors: Christina Leah Kline, Pieter van den Heuvel, Joshua E. Allen, David T. Dicker, Wafik S. El-Deiry
Journal: Cancer Research (2015)

Abstract ONC201/TIC10 is a first-in-class small molecule inducer of the tumor necrosis apoptosis-inducing ligand (TRAIL) pathway, inhibiting both Akt and ERK and consequently activating FOXO3a. Here we present a hitherto unrecognized and early mechanism that contributes to ONC201/TIC10's cytotoxic effects. ONC201/TIC10 activates the integrated stress response, thereby engaging the ATF4 pathway and consequently inducing expression of the pro-apoptotic proteins CHOP and DR5. Cells that are resistant to ONC201/TIC10 do not exhibit ATF4 pathway activation. Knocking down ATF4 and CHOP partially abrogates ONC201/TIC10's cytotoxicity and ONC201/TIC10-induced DR5 upregulation. We also report here that ONC201/TIC10 does not only cause apoptosis but also inhibits cell cycle progression, potentially explaining its broad-spectrum cytotoxicity against 22 out of the 23 tumor cell lines tested. ONC201/TIC10-induced cell cycle arrest was associated with downregulation of Cyclin D1 expression. ONC201/TIC10 induces CHOP and DR5 in cells regardless of whether cells are susceptible to ONC201/TIC10-induced apoptosis. Levels of the X-linked inhibitor of apoptosis (XIAP) influence whether a cell succumbs to proliferation inhibition or apoptosis in response to ONC201/TIC10. Our findings show that ONC201/TIC10 upregulates the TRAIL pathway not only by inhibiting Akt and ERK, and activating FOXO3a but also by engaging the ATF4/CHOP/DR5 pathway that leads to complementary and potent tumor cell killing. Our findings also suggest that CHOP expression may serve as a pharmacodynamic marker for ONC201/TIC10 activity. Citation Format: Christina Leah Kline, Pieter van den Heuvel, Joshua E. Allen, David T. Dicker, Wafik S. El-Deiry. Early integrated stress response induction of ATF4 is required for the anticancer effects of the dual Akt/ERK inhibitor and TRAIL pathway inducer ONC201/TIC10. [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 674. doi:10.1158/1538-7445.AM2015-674
Palliative first-line treatment with weekly high-dose 5-fluorouracil and sodium folinic acid (s-FA) (AIO-schedule) as 24h-infusion plus biweekly oxaliplatin (ox) in patients with definitively non-resectable metastatic colorectal cancer (CRC) following secondary (sec.) metastatic resection: An interdisciplinary phase II trial
Authors: H. Albrecht, F. Boxberger, K. Wolff, N. Ostermeier, U. Reulbach, G. Maennlein, T. Meyer, W. Hohenberger, E. G. Hahn, A. Wein
Journal: Journal of Clinical Oncology (2009)

e15073 Background: In an interdisciplinary phase II trial performed from 1995 to 1997 and based on a 5-FU monotherapy it was possible to achieve both a sec. metastatic resection after downsizing in 9 patients (17%) and a R0 resection offering curative option in 6 patients (11%) out of a total collective of 53 treated patients (Wein et al, Ann Oncol 2001). The objective of this phase II trial is to verify whether a combination therapy based on ox may improve the curative option in terms of a sec. metastatic resection in a patient cohort with identical inclusion - and exclusion criteria. Methods: Prospective evaluation of 50 patients.; palliative chemotherapy: ox (oxaliplatin, 85 mg/m 2 i.v. as a 2h-infusion (inf.); d 1, 15, 29 qd 57) followed by 5-FU (2000 mg/m 2 i.v. as a 24h- inf.; d 1, 8, 15, 22, 29, 36 qd 57) together with s-FA (Oncofolic, 500 mg/m 2 i.v. as a 24h-inf.; d 1, 8, 15, 22, 29, 36 qd 57) via a miniature pump system. Results: Last date of evaluation: Sep/30/2008; median age: 63 years; chemoth. appl.: total number: 935; higher grade toxicity (grade 3+4): diarrhea 20,0 %, nausea 4,0 %; vomitus 6,0 %; hand-foot-syndrome 2,0 %; fever/infection 2,0 %; response: CR: 2,0 %; PR: 52,0 %; SD: 32,0 %; PD: 12,0 %; not evaluable: 2,0 %; tumor control (CR, PR, SD): 86,0 %; sec. metastatic resection: R0: 28,0 %; R1: 2,0 %; R2 8,0 %; TTP (n = 50): 9,8 months. Conclusion: Combination chemotherapy with weekly 5-FU and s-FA (AIO) plus bi-weekly ox on an outpatient basis is an effective palliative treatment schedule offering a high rate of curative metastatic resection with solely low grade toxicity and no higher grade neurotoxic side effects. Final results in terms of median survival remain to be seen whereas they are certainly influenced by the second line therapy. No significant financial relationships to disclose.
The impact of HIV on the burden and severity of influenza illness in Malawian adults: The bash-flu study
Authors: Antonia Ho, Stephen J. Aston, Tamara Mitchell, Maaike Alaerts, Mavis Menyere, Jane Mallewa, Mulinda Nyirenda, Dean Everett, Robert S. Heyderman, Neil French
Journal: Journal of Infection (2015)
Lenalidomide for advanced hepatocellular cancer (HCC) in patients progressing on or intolerant to sorafenib.
Authors: H. Safran, K. Charpentier, A. Kaubisch, G. Dubel, G. Soares, K. E. Faricy-Anderson, T. J. Miner, Y. Eng, I. Ribizzi-Akhtar, A. M. Plette, N. J. Espat, D. Berz, A. Schumacher, D. Luppe, P. Bakalarski, P. Wingate, J. Victor, K. Rosati, D. Isdale
Journal: Journal of Clinical Oncology (2011)

4048 Background: Lenalidomide is an immunomodulatory and anti-angiogenic agent that appears to inhibit endothelial cell signaling induced by vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). FGF is an important growth factor in HCC. There is no standard of care for patients who progress on sorafenib. Therefore, we performed a phase II study to determine the activity of lenalidomide in second-line HCC therapy. Methods: Patients with advanced HCC who progressed on or were intolerant to sorafenib were eligible. Prior chemoembolization, RFA, or surgery was allowed. Eligibility criteria also included bilirubin <4 mg/dL, AST and ALT <5 times upper limit of normal, ECOG performance status 0-2, platelet count >60,000/mm3, absolute neutrophil count >1,000/mm3, and creatinine <2mg/dL. Patients were treated with lenalidomide 25mg orally days 1-21 of a 28 day cycle until progression or unacceptable toxicities. The planned sample size was 25 patients. Response to therapy was defined as a partial response by RECIST criteria or > 50% decline in AFP with stable radiographic disease. Results: Enrollment of the 25 planned patients has been completed. The median age was 62 years (36-88 years). Sixteen patients were Child-Pugh A, 7 were B, and 2 were C. Eleven had extrahepatic disease. Treatment was well tolerated with grade 4 neutropenia in 1 patient and grade 3 neutropenia in 2 patients. Seventeen had AFP >200ng/mL. Six of these 17 patients (35%) had > 50% decline in AFP including one with an AFP reduction from 56,900 to 5 ng/mL. Four of 25 (16%) had a radiographic partial response. Seven of 25 (28%) had either a radiographic response or a >50% reduction in AFP. Three patients have not progressed after 24, 21, and 10 months. Of these three patients, two had elevated AFP which fell dramatically, one had hepatitis C, 1 was Child-Pugh B, and 2 were Child-Pugh A. Conclusions: Lenalidomide is well tolerated in patients with advanced HCC and significant hepatic dysfunction. This study demonstrated promising and in some patients dramatic and durable activity. Investigations are needed to explore the mechanism of action of lenalidomide in HCC and to identify the subset of patients most likely to respond to lenalidomide.
Severe pulmonary infections due to biological therapy of rheumatic diseases
Authors: Gergely Lupkovics, Csongor Kiss, Akos Lantos, Erzsebet Fajt, Agnes Paraczki, Edina Tolnay
Journal: European Respiratory Journal (2011)

The use of biological therapy in patients suffering from rheumatoid arthritis and ankylosing spondylitis is getting more general. Basically with biologic therapy the action of a messenger of inflammation e.g. tumor necrosis factor (TNF) can be blocked - called anti-TNF therapy. The risk of this kind of impediment is becoming susceptible to infections or latent disease may turn into active and then may easier spread. The main danger is tuberculosis still other non-specific infections or malignant tumors may occur.  A retrospective study was made to analyze the data of patients treated with biological therapy and hospitalized in our institute because of severe pulmonary infections. The aim of this study was to detect the incidence and severity of these complications in a real life population.  Between 2008 and 2010 of 28705 patients with pulmonary disease were treated in our institute, 59 patients of them suffered rheumatic disease: 52 patients from rheumatoid arthritis and 7 of ankylosing spondylitis. 27 of 59 patients received some sort of non-biological therapy, 23 of 59 got no medication and we screened 3 patients before the biological therapy. Six of the 9 patients who received biological therapy had complications: 5 cases of tuberculosis, 1 case of pulmonary abscess, 1 case of invasive aspergillosis. We did not observed malignant tumor among them. In this particular period 1 patient treated by biological therapy died because of tuberculosis.  Our analysis assured the relevance of correct preliminary pulmonary examinations and follow-up during biologic therapy of rheumatic disease. Despite the possible occurrence of severe complications this therapy has got major efficiency in treating rheumatic diseases.
Comprehensive respiratory assessment in advanced COPD: a ‘campus to clinic’ translational framework
Authors: Michael C Steiner, Rachael A Evans, Neil J Greening, Robert C Free, Gerrit Woltmann, Nicole Toms, Michael D Morgan
Journal: Thorax (2015)

COPD is a clinical syndrome representing a spectrum of lung pathologies associated with systemic comorbidities and exacerbations, which contribute substantial morbidity and mortality. The ‘umbrella’ nature of the syndrome has resulted in the detailed investigation and description of multiple disease phenotypes relating to the heterogeneity of lung pathophysiology but also to other clinical features such as symptom burden, exacerbations, comorbidities, nutritional status and respiratory failure.1–5 Phenotype-specific therapies already exist, for example, lung volume reduction therapies, nutritional support and home non-invasive ventilation. Moreover, this may extend to other features such as increased cardiovascular risk and inflammometry-directed exacerbation management.6 ,7

These advances provide an opportunity to make a significant change in the care of patients with COPD both by personalising the management of patient symptoms and future health risk (as embodied in the updated Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging schema8) and by the proactive identification and treatment of systemic comorbidities that are known to impact on health outcomes. For these scientific developments to translate to patient care, a more detailed, systematic framework for clinical assessment is needed in routine clinical practice. Such an approach is also required to stratify care across the range of disease severity/complexity so that care can be individualised and services organised accordingly. In keeping with this, the UK National Health Service (NHS) National Outcomes Strategy for COPD recommends that the assessment of disease severity should be based on a ‘comprehensive assessment’ of clinical characteristics and that services should be integrated to ensure specialist care focuses on more ‘complex or unstable’ disease.9 Currently, however, in the UK and many other healthcare systems, proactive identification and management of complex medical, psychological and social care needs in COPD occurs infrequently and is poorly coordinated.10 By contrast, a structured approach to managing …
Topographic Mapping of the Synaptic Cleft into Adhesive Nanodomains
Authors: Karen Perez de Arce, Nikolas Schrod, Sarah W.R. Metzbower, Edward Allgeyer, Geoffrey K.-W. Kong, Ai-Hui Tang, Alexander J. Krupp, Valentin Stein, Xinran Liu, Jörg Bewersdorf, Thomas A. Blanpied, Vladan Lucić, Thomas Biederer
Journal: Neuron (2015)
Fucosylation enhances activity of cytotoxic T lymphocytes against breast cancer
Authors: Na Qiao, Elizabeth A Mittendorf, Mao Zhang, Pariya Sukhumalchandra, Jodie L Polan, Samantha Neal, Mikael Rauf, Victor Gall, Anne V Philips, Elizabeth J Shpall, Gheath Alatrash
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Fucosylation is a process by which fucose sugar groups are added to cell surface receptors. This process is mediated by fucosyl transferases that attach terminal fucose groups to acceptor molecules on the cell surface. Fucosylation of cord blood stem cells and human regulatory T
The Value of Cardiac Magnetic Resonance Imaging in Evaluation of Pediatric Patients for Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
Authors: Anneline S.J.M. te Riele, Frank I. Marcus, Cynthia A. James, Brittney A. Murray, Crystal Tichnell, Stefan L. Zimmerman, Ihab R. Kamel, Jane Crosson, Maarten J.M. Cramer, Birgitta K. Velthuis, Richard N.W. Hauer, Harikrishna Tandri, David A. Bluemke, Hugh Calkins
Journal: Journal of the American College of Cardiology (2015)