tbuckley/cabot-search huggingface dataset:
A CDK4/6-Dependent Epigenetic Mechanism Protects Cancer Cells from PML-induced Senescence
Authors: Mariana Acevedo, Mathieu Vernier, Lian Mignacca, Frédéric Lessard, Geneviève Huot, Olga Moiseeva, Véronique Bourdeau, Gerardo Ferbeyre
Journal: Cancer Research (2016)

Promyelocytic leukemia (PML) plays a tumor suppressive role by inducing cellular senescence in response to oncogenic stress. However, tumor cell lines fail to engage in complete senescence upon PML activation. In this study, we investigated the mechanisms underlying resistance to PML-induced senescence. Here, we report that activation of the cyclin-dependent kinases CDK4 and CDK6 are essential and sufficient to impair senescence induced by PML expression. Disrupting CDK function by RNA interference or pharmacological inhibition restored senescence in tumor cells and diminished their tumorigenic potential in mouse xenograft models. Complete senescence correlated with an increase in autophagy, repression of E2F target genes, and an gene expression signature of blocked DNA methylation. Accordingly, treatment of tumor cells with inhibitors of DNA methylation reversed resistance to PML-induced senescence. Further, CDK inhibition with palbociclib promoted autophagy-dependent degradation of the DNA methyltransferase DNMT1. Lastly, we found that CDK4 interacted with and phosphorylated DNMT1 in vitro, suggesting that CDK activity is required for its stabilization. Taken together, our findings highlight a potentially valuable feature of CDK4/6 inhibitors as epigenetic modulators to facilitate activation of senescence programs in tumor cells. Cancer Res; 76(11); 3252-64. ©2016 AACR.
Lymphatic Mapping Using SPECT/CT in Vulvar Carcinoma
Authors: Lutz S Freudenberg, Ellen Görtz, Christiane Hagen, Edgar Harms, Walter W Koska, Robert J Marlowe, Shawqi Shadouh, Clemens Stock
Journal: Clinical Nuclear Medicine (2010)

In vulvar carcinoma, sentinel lymph node (SLN) biopsy with radiolabeled tracers is associated with up to 95% cancer detection rates. However, planar or single photon emission computed tomography (SPECT) images lack anatomic landmarks permitting SLN localization. We admitted a 48-year-old woman with pT1b vulvar carcinoma, for lymphatic mapping before sentinel biopsy. Dynamic scintigraphy and static planar scintigraphy were performed after peritumoral 99mTc-labeled nanocolloid injection (100 MBq/3.7 mCi). After SLN detection 30 minutes postinjection, SPECT/computed tomography (CT) 10 minutes later clearly localized this inguinal node, which in histologic work-up, harbored a micrometastasis. These findings suggest that hybrid imaging improves accuracy in staging and treating vulvar carcinoma.
Abstract 2967: Nucleolin phosphorylation by CK2 modulates its role in cell cycle checkpoint activation
Authors: Elif Caglar, Dibash Das, James Borowiec, Anjana Saxena
Journal: Cancer Research (2011)

Abstract Nucleolin is a multifunctional abundant nucleolar protein and its gene expression is transactivated by the proto-oncogene c-myc during exponential cellular growth. This non-ribosomal protein is a major nucleolar phosphoprotein which is involved in ribosomal RNA processing, RNA polymerase I-catalyzed transcription, and the regulation of apoptosis, demonstrating both positive and negative effects on cell proliferation. During an unperturbed cell-cycle, interphase (CK2) and mitotic (Cdc2) kinases regulate nucleolin phosphorylation, modulating its function and nucleolar localization. Following cellular stress, nucleolin has been shown to inhibit chromosomal replication and to relay nucleolar stress signals mediated by its re-localization within the nucleus. Nucleolin also interacts with prominent components of the ARF (Alternate Reading Frame)/p53 checkpoint pathway that controls growth upon oncogenic stress signals. We have previously demonstrated that nucleolin binds to the p53-antagonist Hdm2, inhibits Hdm2-mediated degradation of p53 and causes p53-mediated apoptosis in an ARF-independent manner. Here we further dissect role/s of nucleolin phosphorylation in regulating the ARF/p53 checkpoint. We have generated a novel system by engineering human osteocarcinoma (NARF6) cells to induce expression of nucleolin-wt (wild-type) or -S6A (a phospho-mutant with six consensus site serines mutated to alanine, impairing phosphorylation by CK2). This novel system can control expression of both nucleolin and ARF by different promoters, allowing us to dissect the downstream events that are solely nucleolin- or ARF- dependent, or regulated by both. We found that increased levels of nucleolin-S6A significantly decreased ARF protein levels as compared to nucleolin-wt. Nucleolin-S6A was significantly more nucleoplasmic and, interestingly, cells that express S6A lacked nucleolar ARF expression. Although a dramatic loss in both ARF and p21 protein levels is evident with nucleolin-S6A expression, there was a net increase in p53 levels. Significantly, nucleolin-S6A expression caused an increase in the fraction of G1 cells in an ARF-independent manner. Thus, reduction of nucleolin phosphorylation by CK2 acts as a molecular switch causing the sub-nuclear re-localization of both nucleolin and ARF. These events lead to p53 activation, and the control of growth in both normal and stressed cells. These results also provide validation of our unique cellular system that allows us to manipulate nucleolin wt and mutant levels, facilitating the study of its physiological functions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2967. doi:10.1158/1538-7445.AM2011-2967
Attention is more than prediction precision
Authors: Howard Bowman, Marco Filetti, Brad Wyble, Christian Olivers
Journal: Behavioral and Brain Sciences (2013)

Abstract A cornerstone of the target article is that, in a predictive coding framework, attention can be modelled by weighting prediction error with a measure of precision. We argue that this is not a complete explanation, especially in the light of ERP (event-related potentials) data showing large evoked responses for frequently presented target stimuli, which thus are predicted.
TCTAP C-166 Successful Percutaneous Fogarty Balloon Catheter Embolectomy in a Centenarian Patient with Subacute Limb Ischemia
Authors: Tomohito Hada, Yasuhiro Takahashi, Junya Matsuda, Ko Toshinori, Taisuke Sato, Wataru Shimizu
Journal: Journal of the American College of Cardiology (2015)
A Quest — Halting the Progression of Autosomal Dominant Polycystic Kidney Disease
Authors: David H. Ellison, Julie R. Ingelfinger
Journal: New England Journal of Medicine (2014)

Progression to end-stage kidney disease in autosomal dominant polycystic kidney disease (ADPKD) ultimately occurs in most patients, even with the best available therapy. Clinical trials that test strategies to prevent or at least forestall progression are emblematic of the current era, yet none, to date, have greatly affected outcome. Because elevated blood pressure in patients with this disease is associated with greater total kidney volume as well as activation of the renin–angiotensin–aldosterone system (RAAS) and the progression of kidney disease, trials of blood-pressure control and medications that might work are crucial. It has been suggested that treatment with multiple agents . . .
THU0237 Transcultural Adaptation and Validation of the Arabic Version of the Self-Assessment Questionnaire Impact of Rheumatoid Arthritis: Rheumatoid Arthritis Impact of Disease
Authors: A. Hari, S. Rostom, R. Lahlou, R. Bahiri, N. Hajjaj Hassouni
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> Translate, adapt and validate self-administered questionnaire: RAID (Rheumatoid Arthritis Impact Disease). <h3>Methods</h3> A cross sectional studyin patientswith rheumatoid arthritis according to the2010 ACR/EULAR criteria was conducted. A translation-adaptation ofRAIDin classical Arabic was performed according to the international guidelines for the translation questionnairesprocess (translation, back translation, expert committee,pre-tests).The validation of theArabic versionwas assessedby evaluatingits acceptability, reliability (internal consistency and reproducibility)and construct validity. External construct validity was assessed by analyzing the correlation between this instrument and the following parameters (visual analogic scale (VAS) for pain assessed by patient and physician, number of painful joints, number of swollen joints, ESR,CRP HAQ, Disease Activity Score 28 (DAS28), Routine Assessment of Patient Index Data3 (RAPID3) and Rheumatoid Arthritis Disease Activity Index 5 (RADAI5)). <h3>Results</h3> The mean age ofpatients was 51±11years with a female predominance (80%) and a mean of 7 years of evolution (3-14). The reliability was excellent for the RAID, the intraclass correlation coefficient of the total score RAID was 0.99 (confidence interval at 95%:0.98 to 0.99). The internal consistency measured by Cronbach9s alpha coefficient was 0.99 for the total score RAID. A good correlation was found betweentheRAID, the DAS28 (r=0.90), joint pain (r=0.91), swollen joints (r=0.6), the VAS pain(r=0.94), HAQ (r=0.85), the RAPID3 (r=0.92), the RADAI 5 (r=0.91), ESR (r=0.6). (For all p&lt;0.05). <h3>Conclusions</h3> The psychometric properties of theRAID were good.They can be used for the evaluation of the activity of rheumatoid arthritis as well as for Moroccan and Arabic patients. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5192
A Multi-Center Study To Determine the Optimum Duration of Neoadjuvant Letrozole on Tumour Regression To Permit Breast Conserving Surgery – An Interim Analysis.
Authors: R. Carpenter, J. Doughty, C. Cordiner, N. Moss, A. Gandhi, C. Wilson, C. Andrews, G. Gui
Journal: Cancer Research (2009)

Abstract Background: Neoadjuvant letrozole is an attractive alternative to chemotherapy for post menopausal women with large, ER positive breast cancer, who are destined for mastectomy but would prefer breast conservation. Prospective studies have not investigated treatment duration beyond 6 months and retrospective studies suggest useful responses can occur after this period.Materials and Methods: This trial is a prospective, UK centrally quality assured, multi-centre, longitudinal study to assess the optimal duration of neoadjuvant letrozole treatment to allow breast conserving surgery for a period of up to12 months. Post menopausal women with large (≥T2), ER and/or PgR positive primary tumours, not considered eligible for breast conservation, were commenced on neoadjuvant letrozole and response was assessed every 2 months with clinical and ultrasound examination until sufficient shrinkage for breast conservation, progression or 12 months had been reached. Ultrasound and Mammography were undertaken at baseline and end-point. We present the initial analysis for time to response and breast conservation.Results: By January 2009, 103 women were available for analysis. 23 (22.3%) had undergone a mastectomy, 60 (58.3%) had achieved breast conservation and 20 (19.4%) remained under evaluation within the trial. The mean age of the group was 74.1 years (52-92). 25 (24.3%) had invasive lobular cancer and 13 (12.6%) had grade 3 tumours. 22 (21.4%) were node positive.Figure 1. Kaplan-Meier plot for time (days) to response sufficient for breast conservation.25% had breast conservation by 5.8 months, 50% by 8.2 months and 75% by 12 months. Median time to breast conservation was 8.2 months (95% CI 6.4-9.3)Figure 2. Median change in tumour volume from baselineAfter an initial rapid response in the first 4 months, the rate of response was slower and constant for a further 6 months. Tumour volume reduction to permit breast conservation varied between 65 and 80% .Discussion: This interim analysis indicates that the conventional treatment period of 4 to 6 months of neoadjuvant letrozole should be revised. For most women longer duration will increase the likelihood of achieving sufficient volume reduction to allow breast conserving surgery. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1082.
Advances in Neurology
Authors: Sid Gilman
Journal: New England Journal of Medicine (1992)

MEDICAL neurology and the neurosciences have made astonishing progress in the past few decades. New imaging techniques permit visualization of not only the gross anatomy but also aspects of the biochemical and pharmacologic features of the living, working brain. Remarkable advances have clarified the pathogenesis of illnesses such as migraine and epilepsy, leading to specific and effective therapies for them. Cellular transplants have been placed in the brain to ameliorate at least partially the ravages of parkinsonism, and potential therapies for previously "untreatable" degenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis are being studied in laboratories. Never before . . .
AB0220 Disability and Health-Related Quality of Life of Filipino Patients with Rheumatoid Arthritis
Authors: A.-T. Magbitang, E. Salido
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Rheumatoid arthritis is associated with physical disability as the disease progresses. Disability, in turn, exerts a significant impact on general health satisfaction and mortality of the RA patient. High disease activity score (DAS 28), low educational attainment, low income, low BMI and longer disease duration are the proposed factors associated with disability. The Health Assessment Questionnaire Disability Index (HAQ-DI) is the gold standard in assessing functional status in RA. Identifying disability through this simple screening tool may help determine additional points of care for our patients. <h3>Objectives</h3> To determine the functional status and health-related quality of life of Filipino patients with rheumatoid arthritis. <h3>Methods</h3> We collected data on patient demographics, clinical characteristics, and disability using the Health Assessment Questionnaire Disability Index (HAQ-DI). <h3>Analysis</h3> T-test, Chi- square test or Fisher9s exact test were used to compare nominal data and determine association between population and disease characteristics and disability, as well as disability and health satisfaction. <h3>Results</h3> The study population consists of 101 patients with RA. The majority are females in their 6th decade of life who have current or previous employment. Eighty-three patients (82%) had low level of education. Most patients (58%) have rheumatoid arthritis that is more than 3 years in duration; average duration is 8.79 years. Fifty-seven patients (58%) have active RA disease activity (DAS-28 scores of &gt;3.2) at index consultation. Disability is present in 44% and the average HAQ DI score is 0.95 (SD 0.73). There is difficulty in performing activities in almost all domains, particularly in walking (73.27%), arising (65.35%), and gripping (66.34%). Disability is significantly associated with RA duration &gt;3 years (p=0.04), high disease activity (DAS 28 ≥3.2, p=0.02), and BMI &lt;18 kg/m<sup>2</sup> (p&lt;0.01). Forty-nine percent are not satisfied with their overall health. Dissatisfaction is significantly associated with disability (p&lt;0.001), DAS 28 ≥3.2 (p&lt;0.01) and BMI&lt;18 kg/m<sup>2</sup> (p=0.04). <h3>Conclusions</h3> More than 50% of RA patients at the Rheumatology clinic of the Philippine General Hospital have significant disability and greater health dissatisfaction. In particular, there is difficulty in walking, arising, and gripping. The HAQ Disability is a validated tool used in clinical trials that shows promise as an important clinical tool for global assessment of disability. This allows for timely and appropriate titration of treatment to improve care. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4770
Pulmonary Cement Embolism after Vertebroplasty
Authors: Jean-Pierre Tourtier, Sophie Cottez
Journal: New England Journal of Medicine (2012)

A 61-year-old man with spinal cord compression underwent therapeutic laminectomy of the fifth vertebra and laminectomy and vertebroplasty of the fourth vertebra. During the vertebroplasty, polymethylmethacrylate cement leaked into the paravertebral vascular system.
Abstract 1471: Glycoprotein 90K suppresses Wnt signaling via ISGylation-dependent ubiquitination of β-catenin that needs interaction with CD9/CD82
Authors: Jeong A Bae, Ji Hee Lee, Eun Gene Sun, Woo Kyun Bae, Sang Hee Cho, Ik Joo Chung, Kyung Keun Kim
Journal: Cancer Research (2010)

Abstract Backgrounds: Previously, we have observed that a tumor-associated 90K glycoprotein plays a potential tumor suppressor role in colorectal cancer (CRC) cells via antagonizing the canonical Wnt signaling pathway, which is functionally masked via interaction with extracellular galectin. Here, we investigated the signaling pathways of 90K action on CRC cells and its expression in human CRC tissues. Results: We identify a novel pathway comprising a secretory 90K and a CD9/CD82 tetraspanin web; in this pathway, 90K interacts with CD9/CD82, suppresses the Wnt/β-catenin signal via a novel proteasomal-ubiquitination mechanism of β-catenin that is dependent of ISG15 modification (ISGylation). In colon tissues from stage IV human CRC and invading cancer cells of corresponding metastatic liver tissues, in which β-catenin and galectin expression was higher, immunostained 90K and CD9/CD82 were lower than in adjacent hepatic tissues or colon tissues from stage I. Conclusions: 90K itself has antitumor activity in CRC cells via suppression of Wnt signaling with a novel mechanism of ISGylation-dependent ubiquitination of β-catenin when it interacts with CD9/CD82, but is downregulated in advanced CRC tissues. Our data suggest a strategy of strengthening this novel pathway with concomitant knockdown of galectins as a potential therapeutic approach to CRC progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1471.
Abstract P5-10-07: Luminal A breast cancer: identification of novel circulating miRNA biomarkers
Authors: AM McDermott, N Miller, G Ball, KJ Sweeney, MJ Kerin
Journal: Cancer Research (2012)

Abstract Introduction: Breast cancer is a prevalent disease in need of a reliable circulating biomarker with a role in combination with mammography to facilitate early diagnosis. Mi(cro)RNAs are a group of small molecules with ideal biomarker characteristics. The knowledge that miRNAs are aberrantly expressed in cancer, and can be detected in the circulation supports their potential role in minimally invasive cancer diagnostics. Intrinsic breast cancer subtypes provide well characterized phenotypes to study the biomarker potential of miRNAs. The aim of this study was to identify systemic miRNAs differentially expressed in Luminal A (ER+PR+HER2/neu−) breast cancer, and to study their utility as oncologic biomarkers in the clinical setting. Material and Method: Whole blood samples were collected prospectively from women diagnosed with Luminal A breast cancer (n = 57) and healthy controls (n = 57). Luminal A phenotype was confirmed by immunohistochemistry and fluorescence in situ hybridization (FISH). RNA was extracted, reverse transcribed and a Taqman Low-Density Array (TLDA, microarray) conducted on a test cohort (10 Luminal A; 10 Control). Differentially expressed miRNAs were identified using Artificial Neural Networks (ANN). Expression of specific miRNAs were validated using RQ-PCR on an independent whole blood cohort (n = 47 Luminal A; n=47 Control) and tissue (n = 30). Results were analyzed using Q-Base and Minitab V16.0. Results: The microarray performed on the test cohort identified 77 differentially expressed miRNAs. Artificial Neural Networking highlighted seven miRNAs for further analysis (Table 1). RQ-PCR quantification of expression of these seven candidate miRNAs in the validation group confirmed the biomarker potential of two miRNAs. MiR-181a and miR-652 were significantly under-expressed in the cancer group compared to the control group (p = 0.005 and p = 0.001 respectively). Circulating miR-181a expression correlated with invasive tumour size (r = −0.592, p = 0.008). Furthermore, a combination of these two miRNAs provided a sensitivity and specificity for detection of Luminal A breast cancer of 70% and 65%, respectively (Area Under the Curve, AUC=0.77). MiR-181a and miR-652 were also under-expressed in Luminal A tumor tissue compared to Tumor Associated Normal (TAN, p = 0.019 and p = 0.001, respectively). Conclusion: This study provides insight into the underlying molecular portrait of the Luminal A subtype by identifying 77 miRNAs with altered systemic expression levels. Two novel miRNA oncologic biomarkers are identified, which are altered in both the tumor and circulation. These miRNAs may have a role in combination with mammography to facilitate accurate subtype-specific breast tumor detection. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-10-07.
P293 Is Obstructive Sleep Apnoea A Risk Factor For Chronic Kidney Disease?
Authors: F. Rauf, J. Kerks, D. Comer, I. Dasgupta, M. Daniels, R. Mukherjee, S. Wharton
Journal: Thorax (2014)

<h3>Background</h3> Obstructive sleep apnoea (OSA) is associated with intermittent hypoxaemia which leads to activation of a number of pathways including oxidative stress, sympathetic nervous system, endothelial dysfunction and inflammation. These in turn lead to hypertension and atherosclerosis. There is some evidence that the same process may predispose to renal dysfunction. In this retrospective study, we compared a group people with hypertension and OSA on continuous positive airways pressure therapy (CPAP) with matched control group not known to have OSA. <h3>Method</h3> Patients with known OSA and controls matched for age, sex and BMI were selected retrospectively from a hypertension clinic database. The two groups were compared using the following parameters: mean 24-hour systolic blood pressure (SBP, mmHg), mean serum creatinine (micromol/l) and mean urine albumin/creatinine ratio (ACR. mg/mmol). <h3>Results</h3> Forty-nine patients were identified with confirmed OSA on CPAP. 6 were excluded due to insufficient data. Of the 43 remaining patients 35 were male, the mean age was 53.5 years and the mean BMI was 34.6 km/m<sup>2</sup>. The mean SBP was 143 in patients versus 135 in controls (p = 0.04). The mean serum creatinine was 94.0 in patients versus 93.4 in controls (p = 0.45). The mean ACR was 2.50 in patients versus 0.63 in controls (p = 0.031). <h3>Conclusion</h3> This retrospective case-control study shows a higher prevalence of hypertension and proteinuria in patients with treated OSA when compared with controls matched for age, sex and BMI. OSA in the patients may not have been adequately treated. There may have been undiagnosed OSA in the controls. Patients’ higher proteinuria may have been caused by their more severe hypertension. Causation is not proven. However this study raises the possibility that OSA might predispose to chronic kidney disease. A larger, prospective study might confirm this finding and provide information on causation.