tbuckley/cabot-search huggingface dataset:
The Genetic Evolution of Melanoma from Precursor Lesions
Authors: A. Hunter Shain, Iwei Yeh, Ivanka Kovalyshyn, Aravindhan Sriharan, Eric Talevich, Alexander Gagnon, Reinhard Dummer, Jeffrey North, Laura Pincus, Beth Ruben, William Rickaby, Corrado D’Arrigo, Alistair Robson, Boris C. Bastian
Journal: New England Journal of Medicine (2015)

The pathogenic mutations in melanoma have been largely catalogued; however, the order of their occurrence is not known.We sequenced 293 cancer-relevant genes in 150 areas of 37 primary melanomas and their adjacent precursor lesions. The histopathological spectrum of these areas included unequivocally benign lesions, intermediate lesions, and intraepidermal or invasive melanomas.Precursor lesions were initiated by mutations of genes that are known to activate the mitogen-activated protein kinase pathway. Unequivocally benign lesions harbored BRAF V600E mutations exclusively, whereas those categorized as intermediate were enriched for NRAS mutations and additional driver mutations. A total of 77% of areas of intermediate lesions and melanomas in situ harbored TERT promoter mutations, a finding that indicates that these mutations are selected at an unexpectedly early stage of the neoplastic progression. Biallelic inactivation of CDKN2A emerged exclusively in invasive melanomas. PTEN and TP53 mutations were found only in advanced primary melanomas. The point-mutation burden increased from benign through intermediate lesions to melanoma, with a strong signature of the effects of ultraviolet radiation detectable at all evolutionary stages. Copy-number alterations became prevalent only in invasive melanomas. Tumor heterogeneity became apparent in the form of genetically distinct subpopulations as melanomas progressed.Our study defined the succession of genetic alterations during melanoma progression, showing distinct evolutionary trajectories for different melanoma subtypes. It identified an intermediate category of melanocytic neoplasia, characterized by the presence of more than one pathogenic genetic alteration and distinctive histopathological features. Finally, our study implicated ultraviolet radiation as a major factor in both the initiation and progression of melanoma. (Funded by the National Institutes of Health and others.).
Cullin-3 is a potential novel target for breast cancer chemoprevention and treatment
Authors: W. Miao, M. Loignon, L. Hu, M. Basik, G. Batist
Journal: Journal of Clinical Oncology (2006)

13070 Background: Nrf2 is a master transcription factor regulating multiple phase II carcinogen-detoxifying enzymes. Modulating Nrf2 is a current chemoprevention strategy under investigation. Nrf2 levels are regulated by the Keap1, which functions as a substrate adaptor protein targeting Nrf2 to the Cullin-3 (Cul3)-dependent ubiquitin E3 ligase complex. Methods: We used RT-PCR and Western blot to measure the mRNA and protein levels of Nrf2, Keap1 and Cul3 in human breast cancer cell lines. SiRNA and retrovectors were used to construct stable Cul3 silenced breast cancer cell lines. Agilent DNA microarray analysis was used to study the Cul3-slienced cells. Results: We discovered that Nrf2 protein levels in both nucleus and cytoplasm are significantly decreased in all breast cancer cell lines examined compared to normal human mammary epithelial cells (HMEC). This was confirmed with IHC analysis in 8 out of 10 breast cancer specimens containing normal mammary tissues for comparison. Since RT-PCR showed no change in Nrf2 mRNA levels in the breast cancer cell lines, we examined the degradation pathway of Nrf2, and we found that Cul3 is significantly overexpressed in all three breast cancer cell lines studied compared to HMEC. Silencing Cul3 using siRNA results in restoration of Nrf2 protein level, along with multiple carcinogen-detoxifying enzymes, such as GCS. The Cul3 silenced cells showed remarkable growth retardation compared to the wild type MCF-7 cell line both in vitro and in vivo in a mouse mammary fat pad cancer xenograft model. Microarray analyses of Cul3 siRNA-slinced cells demonstrated upregulation of several detoxifying genes, altered cell cycle markers and several upregulated tumor suppressor genes. Conclusions: Nrf2 is significantly downregulated in breast cancer cells, which is related to the overexpression of Cul3, and may represent sensitivity of these cells to carcinogenic transformation. Knocking down Cul3 constitutively upregulates the Nrf2 as well as multiple carcinogen-detoxifying genes. Moreover, it significantly suppressess the proliferation of cancer cells in vitro and growth of xenograft tumors in vivo. These data suggest that Cul-3 is a potential new target for breast cancer chemoprevention and treatment. No significant financial relationships to disclose.
Online feedback from patients is succeeding in improving services, says report
Authors: J. Wise
Journal: BMJ (2015)

The voices of patients and carers have become increasingly heard by NHS services over the past decade, says a report by the organisation Patient Opinion produced to celebrate the 10th anniversary of its feedback website.

The independent website allows patients, other users of health or social care services, and carers to share their experiences. When a story is published an alert is sent to relevant staff in the relevant organisation, including care providers, commissioning and health boards, regulators, patients’ organisations, and other local or national bodies. Staff can then respond to the story, and …
Evaluating the Adequacy of Molecular Clock Models Using Posterior Predictive Simulations
Authors: David A. Duchêne, Sebastian Duchêne, Edward C. Holmes, Simon Y.W. Ho
Journal: Molecular Biology and Evolution (2015)

Molecular clock models are commonly used to estimate evolutionary rates and timescales from nucleotide sequences. The goal of these models is to account for rate variation among lineages, such that they are assumed to be adequate descriptions of the processes that generated the data. A common approach for selecting a clock model for a data set of interest is to examine a set of candidates and to select the model that provides the best statistical fit. However, this can lead to unreliable estimates if all the candidate models are actually inadequate. For this reason, a method of evaluating absolute model performance is critical. We describe a method that uses posterior predictive simulations to assess the adequacy of clock models. We test the power of this approach using simulated data and find that the method is sensitive to bias in the estimates of branch lengths, which tends to occur when using underparameterized clock models. We also compare the performance of the multinomial test statistic, originally developed to assess the adequacy of substitution models, but find that it has low power in identifying the adequacy of clock models. We illustrate the performance of our method using empirical data sets from coronaviruses, simian immunodeficiency virus, killer whales, and marine turtles. Our results indicate that methods of investigating model adequacy, including the one proposed here, should be routinely used in combination with traditional model selection in evolutionary studies. This will reveal whether a broader range of clock models to be considered in phylogenetic analysis.
Any Need for Preoperative Cardiac Testing in Intermediate-Risk Patients With Tight Beta-Adrenergic Blockade?⁎⁎Editorials published in the Journal of American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Kim A. Eagle, Wei C. Lau
Journal: Journal of the American College of Cardiology (2006)
Magnetic resonance imaging-guided transcatheter implantation of a prosthetic valve in aortic valve position:
Authors: Titus Kuehne, Sevim Yilmaz, Carolin Meinus, Phillip Moore, Maythem Saeed, Oliver Weber, Charles B. Higgins, Thiemo Blank, Erhard Elsaesser, Bernhard Schnackenburg, Peter Ewert, Peter E. Lange, Eike Nagel
Journal: Journal of the American College of Cardiology (2004)
Chemoprevention of colon cancer by diosgenin, a steroidal saponin constituent of fenugreek
Authors: Venkat Swamy Malisetty, Jagan M. R. Patlolla, Jayadev Raju, Lee Ann Marcus, Chang-In Choi, Chinthalapally V. Rao
Journal: Cancer Research (2005)

2473    Trigonella foenum graecum  (fenugreek) is traditionally used to treat disorders such as high cholesterol, diabetes, wounds, inflammation, and gastrointestinal ailments. Recently we have shown that diosgenin a major constituent of fenugreek inhibit human colon cancer cell growth and induce apoptosis and suppress the carcinogen-induced colonic aberrant crypt foci in rats (CEBP, 13: 1-7, 2004). However, there are no studies indicating disogenin indeed inhibits carcinoma formation in established animal models of colon cancer. The present double-blind study was designed to assess the potential chemopreventive properties of diosgenin on azoxymethane (AOM)-induced rat colon carcinogenesis. Colonic adenocarcinomas were chosen as chemopreventive efficacy end point. In addition, we assessed the markers of proliferation and apoptosis in colonic tumors and normal appearing crypt to understand the mechanism of tumor growth inhibition of diosgenin. Male F344 rats at 7-weeks of age were fed the control (AIN-76A diet) and one week later, rats received  s.c.  injections of AOM (15 mg/kg body wt., once weekly for 2 weeks) or equal volume of normal saline (vehicle). One week after the carcinogen treatment groups of rats fed experimental diets containing 0 or 0.1% of diosgenin and continued on the experimental diets for 48 weeks and sacrificed. Colon tumors were evaluated histopathologically and expression levels of markers associated with proliferation and apoptosis were determined in colon tumors and normal appearing colon. Administration of diosgenin significantly suppressed both invasive and non-invasive colon tumor incidence up to 60% (p
Palliative care screening tool: Does utilization promote early integration of palliative care for inpatient oncology patients?
Authors: Michelle Farnan, Erica Smeltz, Susan Glod, Nancy Parson, Margaret Kreher
Journal: Journal of Clinical Oncology (2014)

43 Background: Early integration of specialty Palliative Care (PC) in cancer patients improves quality of life and lowers medical costs. Engaging cancer patients early remains challenging. A checklist approach that evaluates type of malignancy, comorbidities, functional status, uncontrolled symptoms, readmission rates, and psychosocial/spiritual distress may prompt consultation to the PC team. We evaluated a palliative care screening tool’s (PCST) effect on promoting early PC consultation for oncology inpatients. Methods: A modified version of the Center to Advance Palliative Care screening tool was utilized by our hospital as part of the admission assessment. Registered nurses completed the PCST within 24 hours of admission for all adults. A PCST score of 3 or higher prompted staff to suggest a PC consult. A retrospective chart review of oncology patients who received a PC consult was performed to assess whether the screening tool score within 24 hours of admission impacted timing of a consult order. Effective tool utilization was considered to be a consult order within 36 hours of a high risk screen score. Results: From January through March 2014, 215 cancer patients screened with the PCST were found to have a score of 3 or higher. Seventy seven percent scored a 3 or higher, and PC consultation occurred in 16% of that patient cohort. Twenty three percent of PC consults occurred in patients scoring less than 3. The average number of days from admission to PC consult was 6 days. Conclusions: Using a PCST did not trigger PC consultation for inpatient cancer patients. Thirty four percent of the screened patients died during that admission, indicating a dramatic change in status from admission or ineffective prognostication, both barriers to early integration of PC. Our work suggests that a screening tool alone, even in a center with a well-embedded PC program, is not a sufficient means of effectively integrating PC into a patient’s hospital stay. Further work to identify patient characteristics that lead to consultation in both high and low risk patients is necessary.
Nasal potential difference of carriers of the W493R ENaC variant with non-cystic fibrosis bronchiectasis
Authors: Jessica Rademacher, Angela Schulz, Silke Hedtfeld, Frauke Stanke, Felix Ringshausen, Tobias Welte, Burkhard Tümmler
Journal: European Respiratory Journal (2015)

Common underlying conditions leading to bronchiectasis are infection, immune deficiency or cystic fibrosis (CF) [1]. Transgenic mice that overexpress the amiloride-sensitive epithelial sodium channel ENaC mimic the typical features of CF lung disease [2], and correspondingly, it has been proposed that ENaC hyperactivity may predispose to bronchiectasis [3]. The ENaC ion channel consists of three subunits which are encoded by the genes SCNN1A , SCNN1B and SCNN1G. Sequencing of these three genes in 71 subjects with CF-like disease in whom a mutation could not be identified on both CFTR (cystic fibrosis transmembrane conductance regulator) genes uncovered singular cases of disease caused by mutations in SCNN1A [3] and SCNNB [4], and a higher incidence of ENaC polymorphisms [3]. Of nine identified amino acid sequence polymorphisms, one variant in the alpha subunit, named p.W493R- SCNN1A , encoded a hyperactive ENaC channel when tested in a heterologous expression system [3]. Hence Azad et al. [3] proposed that the p.W493R- SCNN1A ENaC variant could be a global risk factor for the development of lung diseases. ENaC polymorphism p.W493R is associated with bronchiectasis but does not necessarily lead to aberrant ion conductance <http://ow.ly/S5Mwj> We thank Rabea Gatzke (Dept of Respiratory Medicine, Hannover Medical School, Hannover, Germany) for organisational support.
The Urgent Need for Clinical Research Reform to Permit Faster, Less Expensive Access to New Therapies for Lethal Diseases
Authors: David J. Stewart, Gerald Batist, Hagop M. Kantarjian, John-Peter Bradford, Joan H. Schiller, Razelle Kurzrock
Journal: Clinical Cancer Research (2015)

Abstract High costs of complying with drug development regulations slow progress and contribute to high drug prices and, hence, mounting health care costs. If it is exorbitantly expensive to bring new therapies to approval, fewer agents can be developed with available resources, impeding the emergence of urgently needed treatments and escalating prices by limiting competition. Excessive regulation produces numerous speed bumps on the road to drug authorization. Although an explosion of knowledge could fuel rapid advances, progress has been slowed worldwide by inefficient regulatory and clinical research systems that limit access to therapies that prolong life and relieve suffering. We must replace current compliance-centered regulation (appropriate for nonlethal diseases like acne) with “progress-centered regulation” in lethal diseases, where the overarching objective must be rapid, inexpensive development of effective new therapies. We need to (i) reduce expensive, time-consuming preclinical toxicology and pharmacology assessments, which add little value; (ii) revamp the clinical trial approval process to make it fast and efficient; (iii) permit immediate multiple-site trial activation when an eligible patient is identified (“just-in-time” activation); (iv) reduce the requirement for excessive, low-value documentation; (v) replace this excessive documentation with sensible postmarketing surveillance; (vi) develop pragmatic investigator accreditation; (vii) where it is to the benefit of the patient, permit investigators latitude in deviating from protocols, without requiring approved amendments; (viii) confirm the value of predictive biomarkers before requiring the high costs of IDE/CLIA compliance; and (ix) approve agents based on high phase I–II response rates in defined subpopulations, rather than mandating expensive, time-consuming phase III trials. Clin Cancer Res; 21(20); 4561–8. ©2015 AACR. See all articles in this CCR Focus section, “Innovations to Speed Drug Development.”
Detection of antibody therapy-induced anti-tumor immune responses using anti-CD8 immuno-pet
Authors: Richard Tavare, Helena Escuin-Ordinas, Melissa McCracken, Kirstin Zettlitz, Felix Salazar, Owen Witte, Antoni Ribas, Anna Wu
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Tumor heterogeneity and the dynamic tumor immune microenvironment have become important topics in the field of cancer immunotherapy. The ability to noninvasively monitor immune cells in vivo via surface markers on immune cell subsets using immuno-positron emission tomography (
Targeting the indoleamine 2,3-dioxygenase pathway in cancer
Authors: Yong Wha Moon, Joud Hajjar, Patrick Hwu, Aung Naing
Journal: Journal for ImmunoTherapy of Cancer (2015)

Tumor cells escape the immune surveillance system of the host through a process called immune tolerance. Immunotherapy targets molecules that serve as checks and balances in the regulation of immune response. Indoleamine-2,3-dioxygenase (IDO) is an intracellular enzyme, which through the process of tryptophan depletion exerts an immunosuppressive effect, facilitating immune escape of tumors. This review summarizes our current knowledge on IDO expression in malignancies, the IDO inhibitors that are currently available and those under clinical development.
Towards operative in vivo fluorescence imaging of c-Met proto-oncogene for personalization of therapy in ovarian cancer
Authors: S Liu, Y Zheng, D Volpi, M El-Kasti, D Klotz, I Tullis, A Henricks, L Campo, K Myers, A Laios, P Thomas, T Ng, S Dhar, C Becker, B Vojnovic, A A Ahmed
Journal: Cancer Research (2014)
Lung biopsy predicts outcome in bronchiolitis obliterans following allogeneic stemcell transplantation
Authors: Andreas Holbro, Jörg Halter, Spasenija Savic, Lukas Bubendorf, Dominik Heim, Martin Stern, Christoph Bucher, Jakob Passweg, Didier Lardinois, Michael Tamm
Journal: European Respiratory Journal (2011)

Graft versus Host Disease (GvHD) is a serious complication following allogeneic stemcell transplantation. Lung involvement with a decline in FEV1 is a pulmonary manifestation of GvHD which occurs in 5 to 8% of SCT recipients. Early studies showed that bronchiolitis obliterans (BO) is the histological correlate of pulmonary GvHD and associated with a high mortality. In our institution VATS biopsy is still considered the gold standard to diagnose bronchiolitis obliterans, after pulmonary infection has been excluded by BAL. In this study we analysed the histological pattern and outcome of 22 patients with biopsy proven bronchiolitis obliterans. There were no major surgical complications of VATS in this immunocompromised patient group. Twelve patients showed constrictive bronchiolitis obliterans (CBO) on biopsy whereas there was lymphocytic bronchiolitis in 10 cases (LBO). Median FEV1 was 43.6% in CBO and 62.6% in LBO. There was no difference in age, underlying hematologic disease or pretreatment between the two groups. Almost all patients suffered from chronic GvHD. Median time to the diagnosis of bronchiolitis obliterans after allogeneic SCT was 558 days in CBO as compared to 703 days in LBO. FEV1 markedly improved in the majority of cases with LBO whereas FEV only partly improved in patients with CBO. Six patients died in the CBO group as compared to only one death in the LBO group.   Conclusion:  The histological pattern of lymphocytic bronchiolitis obliterans is associated with a much better prognosis as compared to constrictive bronchiolitis obliterans following allogeneic stemcell transplantation. We recommend to perform VATS in patients with suspected bronchiolitis obliterans.
Erratum. Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations. Diabetes Care 2015;38:2033–2041
Authors: Jacques Beltrand, Caroline Elie, Kanetee Busiah, Emmanuel Fournier, Nathalie Boddaert, Nadia Bahi-Buisson, Miriam Vera, Emmanuel Bui-Quoc, Isabelle Ingster-Moati, Marianne Berdugo, Albane Simon, Claire Gozalo, Zoubir Djerada, Isabelle Flechtner, Jean-Marc Treluyer, Raphael Scharfmann, Helene Cavé, Laurence Vaivre-Douret, Michel Polak
Journal: Diabetes Care (2015)
Disease-modifying antirheumatic drug-free sustained remission in rheumatoid arthritis: an increasingly achievable outcome with subsidence of disease symptoms
Authors: S Ajeganova, H W van Steenbergen, J A B van Nies, L E Burgers, T W J Huizinga, A H M van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objective</h3> Disease-modifying antirheumatic drug (DMARD)-free sustained remission, the sustained absence of synovitis after cessation of DMARD therapy, is a relevant long-term outcome of rheumatoid arthritis (RA) if (1) its occurrence is promoted by treatment and (2) this status reflects resolution of symptoms and disability. This study investigated both items. <h3>Methods</h3> 1007 patients with RA diagnosed between 1993 and 2011, included in the Leiden Early Arthritis Clinic, were studied on achieving DMARD-free sustained remission. Patients included in 1993–1995 were initially treated with non-steroidal anti-inflammatory drugs, in 1996–1998 mild DMARDs were started early, from 1999 onwards methotrexate was initiated promptly and from 2005 onwards disease activity score (DAS)-steered treatment was common. Remission rates were compared using Kaplan–Meier curves and Cox proportional regression. <h3>Results</h3> In total, 155 patients achieved DMARD-free sustained remission. Specific treatment strategies were significantly associated with achieving remission (p&lt;0.001). Cox regression adjusted for anticitrullinated protein antibody/rheumatoid factor, swollen joint count, erythrocyte sedimentation rate, C-reactive protein revealed HRs for DMARD-free sustained remission of 1.13 (95% CI 0.48 to 2.64) in patients diagnosed in 1996–1998, 2.39 (1.07 to 5.32) in patients treated with early methotrexate (inclusion 1999–2004) and 3.72 (1.60 to 8.62) in those treated early with methotrexate and DAS-steered therapy (inclusion 2005–2011). At the time of remission, the Health Assessment Questionnaire was at the level of the general population (median 0.13, IQR 0–0.63). Also, patient-rated visual analogue scale (VAS) morning stiffness, fatigue, pain and disease activity were low (median (IQR) mm, 14 (2–27), 10 (0–47), 6 (0–20), 7 (0–20), respectively). <h3>Conclusions</h3> More intensive treatment strategies increased the chance for DMARD-free sustained remission, indicating that RA chronicity can be influenced. Patients with RA achieving DMARD-free sustained remission have a normalised functional status.
Eradication of the infection on grounds of cardiovascular risk is not supported by current evidence
Authors: B. C Delaney, F D R. Hobbs, R. Holder
Journal: BMJ (1996)

significant difference in the prevalence of the antibodies between the sexes (51/61 (84%) in the men versus 55/63 (87%) in the women respectively; x2=0 341) or between the patients with and without left ventricular hypertrophy (defined as a left ventricular mass index >134 g/m2 in men and > 1 10 g/m2 in women on echocardiography) (65/78 (83%) versus 41/46 (89%) respectively; X2=0-784).This preliminary study suggests a relation between H pyloni infection and hypertension.We did not, however, find any associations with cardiovascular risk factors (including the presence of left ventricular hypertrophy) except for a weak relation with body mass index.Our findings are consistent with a study from a general practice in Gloucester, which showed a significant relation between H pylori infection and hypertension.2Our group has also reported data suggesting an association between the presence of antibodies to C pneumoniae and hypertension.3Thus our study and that of Barnes et aP are at variance with that of Patel and colleagues as there seem to be significant relations between both H pylon and C pneumoniae infections and hypertension.