tbuckley/cabot-search huggingface dataset:
Surgical nodulectomies can heal in patients with lymphoedema secondary to podoconiosis in resource-poor settings
Authors: Wendemagegn E. Yeshanehe, A. Tamiru, L.C. Fuller
Journal: British Journal of Dermatology (2017)

In Ethiopia severe lymphoedema of the legs resulting from podoconiosis affects approximately 1 million people1. Woody-hard fibrous nodules which complicate this renders the condition resistant to conventional treatment. We present a series of nodulectomies performed in a rural, resource limited setting.

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Use of Genomic Technologies to Identify Novel Genetic Abnormalities and Therapeutic Targets In Acute Lymphoblastic Leukemia.
Authors: Cheryl L. Willman, Huining Kang, Richard C. Harvey, I-Ming Chen, Charles Mullighan, James R. Downing, Mary V. Relling, Jinghui Zhang, Daniela Gerhard, Malcolm Smith, Kevin K. Dobbin, Gregory Reaman, Stephen Hunger
Journal: Blood (2008)
Abstract PR04: Integration of CRISPR-Cas9, RNAi and pharmacologic screens identify actionable targets in a rare cancer
Authors: Andrew L. Hong, Yuen-Yi Tseng, Glenn Cowley, Oliver Jonas, Jaime Cheah, Mihir Doshi, Bryan Kynnap, Coyin Oy, Paula Keskula, Gregory Kryukov, Michael Cima, Robert Langer, Stuart Schreiber, David Root, Jesse Boehm, William Hahn
Journal: Clinical Cancer Research (2016)

Abstract Loss-of-function screening using RNAi technologies over the past decade and more recently with CRISPR-Cas9 technologies have been applied to well-established cancer models. We asked if minimally passaged cancer models would tolerate such screening modalities, particularly perturbations focused on actionable drug targets. We have established a patient derived model, CLF-PED-015-T, as a proof of concept to test this question. After validating that the cell line retains the major genomic, transcriptomic and tumorigenic properties of the tissue it was derived from, we then performed systematic genetic screens using both CRISPR-Cas9 and RNAi to identify potentially actionable vulnerabilities. We then overlapped this with pharmacologic screens. We identified dependencies to CDK4 and XPO1 that spanned all three screens. These dependencies have subsequently validated in an in vivo model. These results suggest use of such technologies at early stages of patient derived model development is feasible. This abstract is also being presented as Poster B14. Citation Format: Andrew L. Hong, Yuen-Yi Tseng, Glenn Cowley, Oliver Jonas, Jaime Cheah, Mihir Doshi, Bryan Kynnap, Coyin Oy, Paula Keskula, Gregory Kryukov, Michael Cima, Robert Langer, Stuart Schreiber, David Root, Jesse Boehm, William Hahn. Integration of CRISPR-Cas9, RNAi and pharmacologic screens identify actionable targets in a rare cancer. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr PR04.
OP04. PREDICTING SITES OF TREATMENT FAILURE AND TUMOUR RECURRENCE IN THE INVASIVE MARGIN OF GLIOBLASTOMAS (PRAM-GBM) - TRIAL
Authors: Mr Stephen Price, Dr Tomasz Matys, Dr Alexis Joannides, Dr Raj Jena, Prof Neil Burnet
Journal: Neuro-Oncology (2017)

AIM: The invasive nature of glioblastomas ensures that residual disease is inevitable following surgery. As this cannot be identified with conventional imaging, radiotherapy volumes must include normal brain to treat this occult invasion. We need an imaging biomarker to identify this residual tumour and predict the site of tumour progression. Such a biomarker would redefine surgical targets and allow personalisation of radiotherapy treatment volumes. Diffusion tensor imaging (DTI) is one potential biomarker as it can identify a larger abnormality than conventional MRI and biopsies of these abnormalities confirm invasive tumour. This study aims to qualify an imaging biomarker that can accurately predict sites of glioblastoma progression, allowing personalisation of radiotherapy and surgical targets. METHOD: We have developed a multicentre, pragmatic, longitudinal observational cohort study of 120 patients from 6 centres. Patients with a glioblastoma suitable for radical resection and chemoradiotherapy, aged 16–75 years with good performance status and no contraindication to contrast-enhanced MRI will be recruited. Patients will be imaged pre-operatively and pre-radiotherapy with DTI and perfusion MR. Primary endpoint is the diagnostic accuracy of DTI to predict site of progressive tumour. Secondary endpoints will explore time-to-progression, location of DTI/perfusion abnormalities in relation to radiotherapy treatment volumes, potential for extended surgical resection and comparison of central vs. local analysis of data. RESULT: Our previous work suggests DTI can identify a larger abnormality than conventional MRI and biopsies of these abnormalities confirm invasive tumour. Follow up studies show it predicts the site of tumour progression with 89% sensitivity. Interestingly the extent of resection appears to be a key contributor to the pattern of recurrence. In a small study 6 patients (40%) had residual contrast enhancement on immediate post-operative MRI. This group appeared to progress sooner than the complete resection group (PFS 283 days vs. 507 days; P<0.01) and in all cases progression occurred at the site of contrast enhancement. In 8/9 of the patients without residual enhancing tumour the invasive pattern of the DTI identified the site of tumour progression. In 4 cases progression was identified >2cm from the edge of the resection cavity. Technical development of DTI as a biomarker has shown that it can be acquired on any MR system at both 1.5 and 3 Tesla, and scanner variability is less of a concern as it is being used in a non-quantitative manner. Data suggests good inter- and intra-rater repeatability. Imaging processing will be aided by developing an automated, cloud-based analysis platform. CONCLUSION: This study will redefine both radiotherapy and surgical targets and this data will lead to safety and efficacy trials of using these targets to plan both radiotherapy and surgery.
Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington’s disease
Authors: Motomasa Tanaka, Koko Ishizuka, Yoko Nekooki-Machida, Ryo Endo, Noriko Takashima, Hideyuki Sasaki, Yusuke Komi, Amy Gathercole, Elaine Huston, Kazuhiro Ishii, Kelvin Kai-Wan Hui, Masaru Kurosawa, Sun-Hong Kim, Nobuyuki Nukina, Eiki Takimoto, Miles D. Houslay, Akira Sawa
Journal: Journal of Clinical Investigation (2017)

Huntington's disease (HD) is a polyglutamine (polyQ) disease caused by aberrant expansion of the polyQ tract in Huntingtin (HTT). While motor impairment mediated by polyQ-expanded HTT has been intensively studied, molecular mechanisms for nonmotor symptoms in HD, such as psychiatric manifestations, remain elusive. Here we have demonstrated that HTT forms a ternary protein complex with the scaffolding protein DISC1 and cAMP-degrading phosphodiesterase 4 (PDE4) to regulate PDE4 activity. We observed pathological cross-seeding between DISC1 and mutant HTT aggregates in the brains of HD patients as well as in a murine model that recapitulates the polyQ pathology of HD (R6/2 mice). In R6/2 mice, consequent reductions in soluble DISC1 led to dysregulation of DISC1-PDE4 complexes, aberrantly increasing the activity of PDE4. Importantly, exogenous expression of a modified DISC1, which binds to PDE4 but not mutant HTT, normalized PDE4 activity and ameliorated anhedonia in the R6/2 mice. We propose that cross-seeding of mutant HTT and DISC1 and the resultant changes in PDE4 activity may underlie the pathology of a specific subset of mental manifestations of HD, which may provide an insight into molecular signaling in mental illness in general.
Cancer control (CC) and African (AF) renaissance: The role of expatriate professionals and scientists
Authors: Christopher K. Williams
Journal: Cancer Research (2006)

676  The last 2-3 decades have been momentous in the annals of health care (HC) of the people of AF evidenced by HIV/AIDS pandemic, political instability, escalating economic hardship, poor leadership and governance of AF countries, resulting in virtual collapse of the educational system, and erosion of academic heritage of institutions, e.g. those of Uganda and Nigeria, which in the 19509s and 19609s contributed significantly in the evolving global cancer epidemiology and chemotherapeutic intervention. The remarkable achievements of the period in cancer research and unprecedented biotechnological advances that have made impressive in-roads in cancer CC globally have bypassed AF. Demoralized by its incapacitation, the meager cadre of HC professionals and scientists was further decimated by exodus of its members to developed countries (DC), thus further aggravating the situation. The response of the international community to the AF HC dilemma has been haphazard, uncoordinated and often inappropriate and self-centered. Faced with the challenges of developing appropriate research and management machinery for its HC and academic institution, Subsahara AF needs to acquire new directions. Recent developments, including the demise of apartheid and its inhibition of growth in a critical AF region, elections of political leadership vis-a-vis military dictatorship, enhancement of transcontinental economic cooperation and replacement of corrupt practices with probity and effective governance, are encouraging. The creation of the Africa Union, emergence of regional collaborative units, e.g. Economic Council of the West African States (ECOWAS), New Partnership for Africa9s Development (NEPAD) etc are indicative of AF renaissance, and the will to free itself from poverty and disease. The African Organisation (O) for Research and Training in Cancer (AORTIC), founded in Lome, Togo, in 1983, demonstrated that meaningful CC research was achievable in spite of inundation of the HC system by more preventable HC challenges, until it lapsed into inactivity in the early 19909s, victim of economic challenges of the period. In 2000, expatriate African CC professionals and scientists and friends in institutions of North America and Europe constituted themselves into AORTIC International (AI), which dedicated itself to the objectives of reactivating AORTIC as an AF-based (AFB) O and the resumption of its CC objectives as enunciated at its inception. Reactivation of AORTIC occurred in 2003 with the election of AFB AORTIC leadership. AI promotes linkages of AFB with major international CC O, e.g. American Association for Cancer Research (AACR), American Society of Clinical Oncology (ASCO), and similar O in DC. CC in AF requires models of strategic alliances, including intra-continental initiatives and international collaborative designs with governmental and non-governmental O for mutually beneficial programs.
Blood cholesterol in late-life and cognitive decline: a longitudinal study of the Chinese elderly
Authors: Chaoran Ma, Zhaoxue Yin, Pengfei Zhu, Jiesi Luo, Xiaoming Shi, Xiang Gao
Journal: Molecular Neurodegeneration (2017)

Previous studies regarding the lipid-cognition relation in older adults are limited and have generated mixed results. We thus examined whether higher blood cholesterol concentrations were associated with faster cognitive decline in a community-based longitudinal study of Chinese elderly.The study included 1,159 Chinese adults aged over 60 years (women: 48.7%, mean age: 79.4 years), who were free of dementia, Parkinson disease and stroke at the baseline. Blood concentrations of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG), were assessed at the baseline. Global cognitive functions were assessed using the Chinese Mini-Mental State Examination (MMSE) at in 2009, 2012 and 2014. Association between blood cholesterol and repeated cognitive function was analyzed with linear mixed models, adjusting for sociodemographic information, behavior and lifestyle, depression symptoms, physical examination, hypertension, and laboratory indexes.Higher baseline TC and LDL-C concentrations were significantly associated with greater cognitive decline. Adjusted mean difference in cognitive decline rate, comparing two extreme quartiles, was 0.28 points (MMSE score) per year (95% confident interval (CI): -0.54,-0.02; P-trend = 0.005) for TC and 0.42 points per year (95% CI: -0.69, -0.16; P-trend = 0.006) for LDL-C. In a subgroup analysis, the associations between all lipids and cognitive decline appeared to be more pronounced among individuals aged 100 years or older (n = 90), relative to others.Higher blood concentrations of TC and LDL-C in late-life were associated with faster global cognitive decline.
Improved median overall survival (OS) in patients with metastatic melanoma (mM) treated with high-dose (HD) IL-2: Analysis of the PROCLAIM 2007-2012 national registry.
Authors: Gregory A. Daniels, Michael Morse, Michael K.K. Wong, Howard Kaufman, David F. McDermott, Sandra Aung, James N. Lowder
Journal: Journal of Clinical Oncology (2014)

9054 Background: HD IL-2 has been reported to have a overall response rate (ORR) for mM of 16% and a median OS 11.4 months (Atkins,1999), however, the studies that led to its regulatory approval are >15 years old and were performed in an era predating checkpoint inhibition and targeted therapies. Methods: The PROCLAIM registry (www.proclaimregistry.com), a HD IL-2 observational database currently with over 30 participating sites, consists of a retrospective cohort (treated 2007-2012) informing an ongoing prospective cohort (~600 patients). We report on the retrospective mM subjects (n=170, 11 sites) with survival status determined as of 11/2013 and a median follow-up of 30.5 months. Sites were encouraged to enroll patients sequentially. Inclusion criteria required that patients have received at least one dose of HD IL-2. Results: The ORR for mM in the database was similar to the historical rates. All 170 subjects were accounted for, 98 were deceased and 72 were known to be alive. Median OS was 21 months for mM compared to a median OS range of 6.4-13.6 months for other single agent FDA-approved drugs (Bhatia, 2009; Kaufman, 2005; Hodi, 2010; Chapman, 2012). Among patients with stable disease (SD), median OS was 36.6 months compared to 15.4 months in patients with progressive disease (PD). Median OS has not been reached for patients with complete response (CR) or partial response (PR). Comparison of patients who received HD IL-2 as 1st or 2ndline (n=138, 32, respectively) showed no significant difference in OS between these patients. No deaths due to IL-2 related toxicity were reported in the retrospective cohort. Conclusions: The PROCLAIM registry documents an improvement in OS for patients treated with HD IL-2 as compared to the historical reference standards. Response to HD IL-2 traditionally defined as CR or PR and, according to this data, should also include SD, which can be very durable. The observation that 1st and 2nd line HD IL-2 possessed similar OS raises intriguing hypotheses about the sequencing of immunotherapy and targeted therapy in mM, and the utility of IL-2 as a salvage option - all of which are currently under examination in the prospective database.
Ultra Rapid, One Step Molecular Detection of BCR-ABL Major and Minor Transcripts by Isothermal RT-Loop Mediated Amplification Reaction.
Authors: Elena D'agostini, Giulia Minnucci, Giulia Amicarelli, Cinzia Pultrone, Veronica Tettamanzi, Chiara Boroni, Silvia Salmoiraghi, Orietta Spinelli, Francesco Colotta, Alessandro Rambaldi
Journal: Blood (2012)
Comparison of Clinical Outcomes Between Pediatric Aplastic Anemia and Refractory Cytopenia of Childhood
Authors: Asahito Hama, Atsushi Manabe, Daisuke Hasegawa, Kazue Nozawa, Atsushi Narita, Hideki Muramatsu, Yoshiyuki Takahashi, Kenichiro Watanabe, Akira Ohara, Masafumi Ito, Seiji Kojima
Journal: Blood (2016)
Subjective cognitive complaints one year after ceasing adjuvant endocrine therapy for early-stage breast cancer: Findings from the Breast International Group (BIG) 1-98 trial.
Authors: Kelly-Anne Phillips, Karin Ribi, Julie Aldridge, Alastair Mark Thompson, Vernon J. Harvey, Beat J. K. Thurlimann, Fatima Cardoso, Olivia Pagani, Alan Stuart Coates, Aron Goldhirsch, Karen N. Price, Richard D. Gelber, Juerg Bernhard
Journal: Journal of Clinical Oncology (2012)

9022 Background: We have previously reported that, in the BIG 1-98 trial, objective cognitive function improved in postmenopausal women one year after cessation of adjuvant endocrine therapy for breast cancer. Here we evaluate changes in subjective cognitive function (SCF). Methods: One hundred postmenopausal women, randomized to receive five years of adjuvant tamoxifen, letrozole, or sequences of both, completed self-reported measures on SCF, psychological distress, fatigue and quality of life during the fifth year of trial treatment (year 5) and one year after treatment completion (year 6). Changes between years 5 and 6 were evaluated using the Wilcoxon signed-rank test. SCF and its correlates were explored. Results: Mean age of participants was 63.9 years [SD=7.1 years]. SCF and the other patient-reported outcomes did not change significantly after cessation of endocrine therapy with the exception of improvement in hot flushes (p=0.0005). No difference in changes was found between women who were taking tamoxifen or letrozole at year 5. SCF was the only psychosocial outcome with a substantial correlation between year 5 and 6 (Spearman’s R=0.80). Correlations between SCF and the other patient-reported outcomes were generally low. Conclusions: Although objective cognitive function improved after cessation of adjuvant endocrine therapy in the BIG 1-98 trial, improvement in SCF was not evident. The underlying reason for the clear disconnect between objective and subjective cognitive function seen in this and most other studies, is a crucial issue. It should be a research priority in order to effectively tackle the concerns of women about their cognition during and after breast cancer treatment.
Specific Inhibition of Syk Suppresses Leukocyte Immune Function and Alleviates Inflammation In Rodent Models of Rheumatoid Arthritis
Authors: Greg Coffey, DeGuzman Francis, Mayuko Inagaki, Yvonne Pak, Suzanne Delaney, Andreas Betz, Zhaozhong J Jia, Qing Xu, Shawn Bauer, Yonghong Song, Anjali Pandey, Dale Baker, Stanley Hollenbach, David R. Phillips, Uma Sinha
Journal: Blood (2010)
A Multicenter Phase II Study of Perifosine (KRX-0401) Alone and in Combination with Dexamethasone (Dex) for Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM).
Authors: Paul Richardson, S. Lonial, A. Jakubowiak, J. Wolf, A. Krishnan, J. Densmore, S. Singhal, I. Ghobrial, L. Schwartzberg, K. Colson, J. Harris, T. Kendall, B. Martineau, N. Obadike, K. Sullivan, S. Pearson, T. Hideshima, L. Lai, P. Sportelli, L. Gardner, R. Birch, I.C. Henderson, K.C. Anderson
Journal: Blood (2006)
Maintaining Imatinib ≥600 Mg Daily in the First 12 Months of Chronic Phase CML Treatment Is Associated with Superior Event-Free Survival at 5 Years.
Authors: Michael P Osborn, Susan Branford, Deborah L White, John F Seymour, Ruth Columbus, Kerry Taylor, Christopher Arthur, Anthony Schwarer, Julian Cooney, Michael F Leahy, Philip Rowlings, John Catalano, Mark S Hertzberg, Robin Filshie, Anthony K Mills, Keith Fay, Simon Durrant, Henry Januszewicz, David Joske, Craig Underhill, Scott Dunkley, Andrew Grigg, Timothy P Hughes
Journal: Blood (2009)
Everolimus-Eluting Versus Sirolimus-Eluting Stents in Patients Undergoing Percutaneous Coronary Intervention
Authors: Kyung Woo Park, In-Ho Chae, Do-Sun Lim, Kyoo-Rok Han, Han-Mo Yang, Hae-Young Lee, Hyun-Jae Kang, Bon-Kwon Koo, Taehoon Ahn, Jung-Han Yoon, Myung-Ho Jeong, Taek-Jong Hong, Woo-Young Chung, Sang-Ho Jo, Young-Jin Choi, Seung-Ho Hur, Hyuck-Moon Kwon, Dong-Woon Jeon, Byung-Ok Kim, Si-Hoon Park, Nam-Ho Lee, Hui-Kyung Jeon, Hyeon-Cheol Gwon, Yang-Soo Jang, Hyo-Soo Kim
Journal: Journal of the American College of Cardiology (2011)
Traitement endoscopique des petites tumeurs neuroendocrines duodénales et ampullaires
Authors: E. Coron
Journal: Endoscopy (2016)

Les tumeurs neuroendocrines (TNE) à localisation duodénale ou ampullaire sont rares puisqu’elles représentent seulement 1 à 3 % des TNE digestives. Le traitement optimal des petites TNE est encore à définir. En effet, si la chirurgie est recommandée par la Société Européenne des TNE (ENETS) pour les lésions duodénales de plus de 20mm et/ou métastatiques et pour les TNE ampullaires et péri-ampullaire, la place du traitement endoscopique est encore mal évaluée, en particulier pour les lésions mesurant entre 10 et 20 mm.
Role of Stromal Microenvironment In Non-Pharmacological Resistance of CML to Tyrosine Kinase Inhibitors through Lyn/CXCR4 Interactions In Lipid Rafts.
Authors: Yoko Tabe, Linhua Jin, Zhou Yixin, Naoki Ichikawa, Kazuhisa Iwabuchi, Takashi Miida, Jorge Cortes, Michael Andreeff, Marina Konopleva
Journal: Blood (2010)
Exploration of haplotype research consortium imputation for genome-wide association studies in 20,032 Generation Scotland participants
Authors: Reka Nagy, Thibaud S. Boutin, Jonathan Marten, Jennifer E. Huffman, Shona M. Kerr, Archie Campbell, Louise Evenden, Jude Gibson, Carmen Amador, David M. Howard, Pau Navarro, Andrew Morris, Ian J. Deary, Lynne J. Hocking, Sandosh Padmanabhan, Blair H. Smith, Peter Joshi, James F. Wilson, Nicholas D. Hastie, Alan F. Wright, Andrew M. McIntosh, David J. Porteous, Chris S. Haley, Veronique Vitart, Caroline Hayward
Journal: Genome Medicine (2017)

The Generation Scotland: Scottish Family Health Study (GS:SFHS) is a family-based population cohort with DNA, biological samples, socio-demographic, psychological and clinical data from approximately 24,000 adult volunteers across Scotland. Although data collection was cross-sectional, GS:SFHS became a prospective cohort due to of the ability to link to routine Electronic Health Record (EHR) data. Over 20,000 participants were selected for genotyping using a large genome-wide array. GS:SFHS was analysed using genome-wide association studies (GWAS) to test the effects of a large spectrum of variants, imputed using the Haplotype Research Consortium (HRC) dataset, on medically relevant traits measured directly or obtained from EHRs. The HRC dataset is the largest available haplotype reference panel for imputation of variants in populations of European ancestry and allows investigation of variants with low minor allele frequencies within the entire GS:SFHS genotyped cohort. Genome-wide associations were run on 20,032 individuals using both genotyped and HRC imputed data. We present results for a range of well-studied quantitative traits obtained from clinic visits and for serum urate measures obtained from data linkage to EHRs collected by the Scottish National Health Service. Results replicated known associations and additionally reveal novel findings, mainly with rare variants, validating the use of the HRC imputation panel. For example, we identified two new associations with fasting glucose at variants near to Y_RNA and WDR4 and four new associations with heart rate at SNPs within CSMD1 and ASPH, upstream of HTR1F and between PROKR2 and GPCPD1. All were driven by rare variants (minor allele frequencies in the range of 0.08–1%). Proof of principle for use of EHRs was verification of the highly significant association of urate levels with the well-established urate transporter SLC2A9. GS:SFHS provides genetic data on over 20,000 participants alongside a range of phenotypes as well as linkage to National Health Service laboratory and clinical records. We have shown that the combination of deeper genotype imputation and extended phenotype availability make GS:SFHS an attractive resource to carry out association studies to gain insight into the genetic architecture of complex traits.