tbuckley/cabot-search huggingface dataset:
Phase II trial of tanespimycin (KOS-953), a heat shock protein-90 (Hsp90) inhibitor in patients with metastatic melanoma
Authors: R. Kefford, M. Millward, P. Hersey, B. Brady, M. Graham, R. G. Johnson, A. L. Hannah
Journal: Journal of Clinical Oncology (2007)

8558 Background: Tanespimycin binds to and inhibits the activity of Heat Shock Protein 90 (Hsp90). Hsp90 inhibition results in the degradation of a variety of RAF family proteins, including mutant BRAF. As the majority of melanomas have activation of the BRAF-MAPK pathway, we postulate that tanespimycin will interrupt the MAPK pathway and may lead to clinically significant anti-melanoma effects. Methods: This is a multi-center two-stage Simon design study; continuation to the second stage required at least 1 pt with progression free survival (PFS) of at least 24 weeks (the primary endpoint of this trial). Eligibility: pts with stage M1 melanoma, measurable/unresectable disease, up to 1 prior chemotherapy treatment for metastatic disease and ECOG PS 0 or 1. Tanespimycin (275 mg/m 2 IV) was given D1,4,8,11 q 3/52 until disease progression or toxicity. Where available, assessment of BRAF mutation (V600E) was performed on historical tissue. Results: 14 pts have been enrolled, 3 were non-evaluable. Data are available for the first 11 pts (9 evaluable) completing accrual to the 1 st stage of the Simon design. Demographics: 8 M/6 F; median age 55 years (range 30, 83). A total of 30 treatment cycles were administered (n=11); with relative dose intensity of 89%; 1 pt required a dose reduction. Grade 1–2 toxicity included nausea, vomiting, diarrhoea, anorexia, fatigue, headache, raised alkaline phosphatase/ALT/AST, and back pain. Four pts (29%) experienced Grade 3–4 toxicities: 1) reversible metabolic acidosis with LFT and electrolyte abnormalities; 2) anorexia, dehydration and fatigue; 3) raised gamma-GT; 4) abdominal pain. Two pts withdrew due to toxicity. Of the 4 pts with available tissue: 2 had V600E BRAF positive mutations. One pt achieved a ≥ 24 week PFS, meeting the conditions for accrual of Stage 2. This pt (with V600E mutation) was assessed as having a best response of stable disease as per RECIST, in addition to reduction in size and number of extensive subcutaneous nodules. Conclusions: There is evidence of clinical activity of single-agent tanespimycin in metastatic melanoma. Further accrual with determination of BRAF status to a total of 30 pts will better define the activity of tanespimycin in this population. No significant financial relationships to disclose.
Human epicardial adipose tissue has a specific transcriptomic signature depending on its anatomical peri-atrial, peri-ventricular, or peri-coronary location
Authors: Bénédicte Gaborit, Nicolas Venteclef, Patricia Ancel, Véronique Pelloux, Vlad Gariboldi, Pascal Leprince, Julien Amour, Stéphane N. Hatem, Elisabeth Jouve, Anne Dutour, Karine Clément
Journal: Cardiovascular Research (2015)

Human epicardial adipose tissue (EAT) is a visceral and perivascular fat that has been shown to act locally on myocardium, atria, and coronary arteries. Its abundance has been linked to coronary artery disease (CAD) and atrial fibrillation. However, its physiological function remains highly debated. The aim of this study was to determine a specific EAT transcriptomic signature, depending on its anatomical peri-atrial (PA), peri-ventricular (PV), or peri-coronary location. Samples of EAT and thoracic subcutaneous fat, obtained from 41 patients paired for cardiovascular risk factors, CAD, and atrial fibrillation were analysed using a pangenomic approach. We found 2728 significantly up-regulated genes in the EAT vs. subcutaneous fat with 400 genes being common between PA, PV, and peri-coronary EAT. These common genes were related to extracellular matrix remodelling, inflammation, infection, and thrombosis pathways. Omentin (ITLN1) was the most up-regulated gene and secreted adipokine in EAT (fold-change >12, P < 0.0001). Among EAT-enriched genes, we observed different patterns depending on adipose tissue location. A beige expression phenotype was found in EAT but PV EAT highly expressed uncoupled protein 1 (P = 0.01). Genes overexpressed in peri-coronary EAT were implicated in proliferation, O-N glycan biosynthesis, and sphingolipid metabolism. PA EAT displayed an atypical pattern with genes implicated in cardiac muscle contraction and intracellular calcium signalling pathway. This study opens new perspectives in understanding the physiology of human EAT and its local interaction with neighbouring structures.
Lung Carcinoma of Sheep (Jaagsiekte). III. Lymph Node, Blood, and Immunoglobulin
Authors: I Hod, K Perk, T A Nobel, U Klopfer
Journal: JNCI Journal of the National Cancer Institute (1972)

Pulmonary carcinoma syndrome of sheep, characterized by progressive tumor-cell growth in the lungs and by metastatic involvement of various organs, also had consistent organ and blood effects. The lymph node architecture in diseased animals was destroyed to a varying extent, distinctive by a marked depletion of lymphocytes and germinocytes, by plasma cell hyperplasia with various intracellular inclusion bodies, and by reticulocytosis. Furthermore, an extreme hyperglobulinemia, characterized by increase in the β1- and total γ-globulins and in the amount of slow-moving lipoproteins, was found in sera of diseased sheep. Ultracentrifugal analysis and immunoelectrophoresis indicated that the hyperglobulinemia occurred mainly in the 7S-IgG fraction. A low percentage of lung tumor cells reacted positively with both normal and affected sera in the indirect immunofluorescent antibody test and less frequently when fluorescein isothiocyanate-tagged antisheep globulin antiserum was directly applied on the tumor cell. However, no line of precipitation occurred between the sheep sera and the tumor extract in the gel diffusion test.
Indian endocrinologists start debate on diabetes drug
Authors: Ganapati Mudur
Journal: BMJ (2015)

Two endocrinologists in India have started a debate over whether an Indian drug company launched and is marketing a drug to treat diabetes and dyslipidaemia without adequate safety and efficacy data.

In a commentary published in the Lancet Diabetes and Endocrinology last week, Anoop Misra and Atul Luthra, from the Fortis Centre of Excellence for Diabetes, Metabolic Diseases, and Endocrinology in New Delhi, listed saroglitazar among at least three drugs that were being promoted by drug companies and prescribed by doctors even though “available data are entirely inadequate to show the efficacy and safety of these three drugs.”1

Saroglitazar, marketed as Lipaglyn by Zydus Cadila, was approved after two studies of up to 24 weeks of follow-up with …
Differences in Risk Factors for Local and Distant Recurrence After Breast-Conserving Therapy or Mastectomy for Stage I and II Breast Cancer: Pooled Results of Two Large European Randomized Trials
Authors: Adri C. Voogd, Maja Nielsen, Johannes L. Peterse, Mogens Blichert-Toft, Harry Bartelink, Marie Overgaard, Geertjan van Tienhoven, Knud West Andersen, Richard J. Sylvester, Joop A. van Dongen
Journal: Journal of Clinical Oncology (2001)

PURPOSE: Risk factors for local and distant recurrence after breast-conserving therapy and mastectomy were compared to define guidelines for the decision making between both treatments. PATIENTS AND METHODS: The data of two randomized clinical trials for stage I and II breast cancer patients were pooled. The total number of patients in the study was 1,772, of whom 879 underwent breast conservation, and 893, modified radical mastectomy. Representative slides of the primary tumor were available for histopathologic review in 1,610 cases (91%). RESULTS: There were 79 patients with local recurrence after breast-conservation and 80 after mastectomy, the 10-year rates being 10% (95% confidence interval [CI], 8% to 13%) and 9% (95% CI, 7% to 12%), respectively. Age no more than 35 years (compared with age &gt;60: hazard ratio [HR], 9.24; 95% CI, 3.74 to 22.81) and an extensive intraductal component (HR, 2.52; 95% CI, 1.26 to 5.00) were significantly associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion was predictive of the risk of local recurrence, irrespective of the type of primary treatment (P &lt; .01). Tumor size, nodal status, high histologic grade, and vascular invasion were all highly significant predictors of distant disease after breast-conserving therapy and mastectomy (P &lt; .01). Age no more than 35 years and microscopic involvement of the excision margin were additional independent predictors of distant disease after breast-conserving therapy (P &lt; .01). CONCLUSION: Age no more than 35 years and the presence of an extensive intraductal component are associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion causes a higher risk of local recurrence after mastectomy as well as after breast-conserving therapy and should therefore not be used for deciding between the two treatments.
A phase II trial of weekly one hour paclitaxel as second-line therapy for endometrial and cervical cancer
Authors: H. D. Homesley, L. Vaccarello, G. Lowendowski, A. A. Elbendary
Journal: Journal of Clinical Oncology (2006)

15013 Background: The antitumor activity of other regimens of paclitaxel (from Bristol-Myers Squibb Oncology, Bristol-Myers Squibb Company, Princeton, NJ, U. S. A.) has been identified in both cervical and endometrial cancer. A less toxic and better tolerated regimen for paclitaxel is a one hour infusion every 7 days. The primary aim of this study was to assess the activity of weekly paclitaxel in patients with recurrent or refractory endometrial cancer or squamous cell cancer of the cervix who had failed one prior chemotherapy regimen and had measurable disease. The nature and degree of toxicity of paclitaxel administered in this schedule in this group of patients was assessed. Methods: Eligible patients had initial histologic diagnosis. All patients presented with persistent or recurrent measurable disease with no more than one prior chemotherapeutic regimen and a GOG Performance Status of 2 or better. At entry hematologic and all other labs were within normal limits. Patients received paclitaxel 80 mg/m 2 over one hour every 7 days. One cycle consisted of four weeks and patients had to receive at least two cycles of therapy to be evaluable for response unless progression occurred during the first eight weeks of the trial. Response by measurable disease change and survival were the endpoints of the trial. Results: Forty-three patients were registered. Evaluable for response were 15/16 patients with endometrial cancer and 20/29 patients with advanced cervical cancer. For the endometrial cancer patients 4 of 15 responded. Two of four responders had complete responses with durations of response of 16 to 23 weeks. Stable disease was present in 33%. There were two responders (one a complete response) in the 20 evaluable patients with cervical cancer while 35% had stable disease. Adverse effects were minimal and easily managed with dose adjustments as needed. Conclusions: In this trial, weekly paclitaxel as second line therapy had a response rate of 27% (4/15) in endometrial carcinoma but only 10% in advanced cervical cancer (2/20). Although confirmatory larger trials are needed, weekly paclitaxel appears promising for advanced endometrial carcinoma but not for squamous cell carcinoma of the cervix. [Table: see text]
Abstract 14048: Snf1-related Kinase Improves Cardiac Metabolic Efficiency through a Decrease in Mitochondrial Uncoupling
Authors: Amy K Rines, Rongxue Wu, Arineh Khechaduri, Michael A Burke, Tatsuya Sato, Eltyeb Abdelwahid, Tenley A Rawlings, Gary D Lopaschuk, Paul T Schumacker, E. Dale Abel, Hossein Ardehali
Journal: Circulation (2014)

Introduction: Snf1-related Kinase (SNRK) is a serine/threonine kinase with sequence similarity to AMP-activated protein kinase, but its function is unknown. We found that SNRK is increased in hearts from patients with ischemic cardiomyopathy, and our gene array data suggested that SNRK alters metabolic genes. Here, we assessed the hypothesis that SNRK regulates cardiac metabolic efficiency. Results: Transgenic (TG) mice with cardiac-specific overexpression of SNRK were generated, and displayed decreased glycolysis (1267.66 vs. 1925.60 nmol/min/g, n=6), glucose oxidation (441.73 vs. 602.68 nmol/min/g), and palmitate oxidation (262.39 vs. 385.07 nmol/min/g) compared to wild type littermate controls in perfused working hearts. However, cardiac power, contractility, ATP, and triglyceride and glycogen stores were maintained, while oxygen consumption was reduced, suggesting that SNRK TG mice have increased metabolic efficiency. The hearts also exhibited decreased uncoupling protein 3 (UCP3) expression, mitochondrial uncoupling, and peroxisome proliferator-activated receptor α (PPARα) expression. SNRK homozygous knockout (KO) was embryonic lethal, but hearts from heterozygous SNRK KO mice had increased glucose and fatty acid oxidation and increased expression of UCP3 and PPARα. SNRK knockdown in cardiac cells also increased UCP3, mitochondrial depolarization, and substrate flux, which were all reversed with UCP3 knockdown. The SNRK-mediated changes in UCP3 were PPARα-dependent. To determine the mechanism of PPARα and UCP3 regulation by SNRK, we performed a yeast two hybrid screen and identified Tribbles homolog 3 (Trib3) as a binding partner of SNRK. SNRK transgenic mice had increased Trib3 expression, and Trib3 overexpression reversed the upregulation of PPARα and UCP3 by SNRK knockdown. Finally, SNRK overexpression in mice reduced infarct size compared to area-at-risk (53.01% vs. 37.95%, n=6) in response to myocardial ischemia/reperfusion. Conclusions: Our results demonstrate that SNRK increases cardiac metabolic efficiency and protects against ischemic damage through binding and upregulation of Trib3, leading to PPARα-driven UCP3 downregulation and improved mitochondrial coupling.
Defining the major health modifiers causing atrial fibrillation: a roadmap to underpin personalized prevention and treatment
Authors: Larissa Fabritz, Eduard Guasch, Charalambos Antoniades, Isabel Bardinet, Gerlinde Benninger, Tim R. Betts, Eva Brand, Günter Breithardt, Gabriela Bucklar-Suchankova, A. John Camm, David Cartlidge, Barbara Casadei, Winnie W. L. Chua, Harry J. G. M. Crijns, Jon Deeks, Stéphane Hatem, Françoise Hidden-Lucet, Stefan Kääb, Nikos Maniadakis, Stephan Martin, Lluis Mont, Holger Reinecke, Moritz F. Sinner, Ulrich Schotten, Taunton Southwood, Monika Stoll, Panos Vardas, Reza Wakili, Andy West, André Ziegler, Paulus Kirchhof
Journal: Nature Reviews Cardiology (2015)

To bridge the current gap between the known mechanisms of atrial fibrillation (AF) and the clinical management of patients with this arrhythmia, Fabritz and colleagues propose a roadmap to develop a set of clinical markers that reflect the major causes of AF in patients. A new, mechanism-based classification of AF can provide the basis for personalized prevention and management. Despite remarkable advances in antiarrhythmic drugs, ablation procedures, and stroke-prevention strategies, atrial fibrillation (AF) remains an important cause of death and disability in middle-aged and elderly individuals. Unstructured management of patients with AF sharply contrasts with our detailed, although incomplete, knowledge of the mechanisms that cause AF and its complications. Altered calcium homeostasis, atrial fibrosis and ageing, ion-channel dysfunction, autonomic imbalance, fat-cell infiltration, and oxidative stress, in addition to a susceptible genetic background, contribute to the promotion, maintenance, and progression of AF. However, clinical management of patients with AF is currently guided by stroke risk parameters, AF pattern, and symptoms. In response to this apparent disconnect between the known pathophysiology of AF and clinical management, we propose a roadmap to develop a set of clinical markers that reflect the major causes of AF in patients. Thereby, the insights into the mechanisms causing AF will be transformed into a format that can underpin future personalized strategies to prevent and treat AF, ultimately informing better patient care.
Air quality in European classrooms and inflammatory markers in nasal lavage of school children
Authors: Hanns Moshammer, Dan Norbäck
Journal: European Respiratory Journal (2014)

Within the framework of the European project SINPHONIE (Schools Indoor Pollution and Health Observatory Network in Europe), funded by the European Public Health Agency, indoor air quality in a wide range of European schools from 25 countries was assessed and health of the pupils was determined both by questionnaire and by objective medical examinations.  Here we first report on findings regarding the association between indoor air quality and selected objective health parameters of children. The age of the children differed between countries with some including even children from kindergartens (starting at 3 years), some including pupils from secondary schools (up to 13 years), but most children were from primary schools aged 6 to 10 years.  Ambient monitoring including fine particles (PM2.5), carbon monoxide, carbon dioxide, radon, polycyclic aromatic hydrocarbons, formaldehyde, and various volatile organic compounds displayed high variability, but only few objective health end-points were significantly associated with air quality. Namely the tear-film stability (break-up-time) was significantly affected by several air quality indicators.  Inflammatory markers in nasal lavage (myeloperoxidase, eosinophilic cationic protein, and lysozyme) were negatively associated with various pollutants. This at first sight paradoxical finding could indicate that moderate oxidative stress does not so much enhance production of these inflammatory markers but might lead to a more rapid consumption of these health-protective chemicals.
Preclinical analysis of targeting miR-182 against melanoma liver metastasis.
Authors: C. T. Huynh, M. F. Segura, S. Menendez, F. Darvishian, E. G. Marcusson, E. Hernando
Journal: Journal of Clinical Oncology (2010)

8554 Background: Malignant melanoma is a devastating cancer and the overall survival is extremely poor for stage IV disease. The paucity of effective treatments clearly illustrates the dire need of alternative therapies for metastatic melanoma. Targeting oncogenic microRNAs has the potential to become an important strategy for targeted therapy. Studies from our lab have demonstrated a prometastatic role for miR-182 in melanoma. Moreover, we proved that miR-182 repression in vitro impairs the invasive capacity of melanoma cells and triggers an antiproliferative response. Thus, we hypothesized that the silencing of miR-182 can be of therapeutic benefit in melanoma. Methods: We have tested the effect of anti-miR- 182 oligonucleotides synthesized with a phosphorothioate backbone in a mouse model of liver metastasis after intrasplenic injection of melanoma cells. 1E04 A375 cells stably transduced with the luciferase cDNA were injected into the spleen of NOD/Scid/IL2gR-/- (NOG) mice. Thirty mice received intrasplenic injections of A375 cells, and then were distributed into two groups to either receive anti-miR-182 or a control anti-miR (25 mg/Kg), administered by intraperitoneal injection twice weekly. Mice were monitored using in vivo fluorescence imaging for tumor cell migration from the spleen into the liver. Results: Luciferase imaging performed 4 weeks post-injection showed that mice treated with anti-miR-182 had an appreciably lower burden of macroscopic liver metastases compared to the control. Treatment with anti-miR-182 reduced the number of mice with > 50 macroscopic liver metastases by half. We also confirmed that the anti-miR treated cohort displays lower levels of miR-182 compared to the scrambled treated cohort both in the tumor tissue and in the liver parenchyma. Moroever, we demonstrated that miR-182 targets ADCY6 and FOXO3 were up-regulated in the tumor cells of anti- miR-182 treated mice. Conclusions: These results indicate that in vivo administration of anti-miRs allows for efficient miRNA targeting and concomitant upregulation of target levels. These results suggest that anti-miR-182 is a promising therapeutic strategy for metastatic melanoma. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Regulus Therapeutics Isis Pharmaceuticals
Detection of EGFR mutations in samples with few cancer cells in non-small cell lung cancer (NSCLC) patients (p) and distribution of exon 20 mutations
Authors: N. Reguart, J. Bertrán-Alamillo, M. Molina, E. Carrasco, C. Mayo, C. Queralt, M. Tomàs, L. Layos, M. Tarón, R. Rosell
Journal: Journal of Clinical Oncology (2008)

8073 Background: Detection of EGFR mutations in advanced NSCLC p is very often limited by the small amount of tumor tissue. We developed a protocol to determine EGFR mutations in tumor samples containing less than 150 cancer cells. We also studied the distribution of EGFR mutations throughout tumor samples in p progressing after erlotinib treatment. Methods: Cancer cells were microdissected directly into PCR buffer and amplified by a nested PCR. This preliminary microdissection ensures that only cancer cells are collected. Exon 19 del were subsequently detected by sequencing and Genescan, and exon 20 (T790M) and exon 21 (L858R) mutations by sequencing and TaqMan assay. Results: We examined 268 samples of primary NSCLC having less than 150 cancer cells. EGFR gene status was assessable in 213 samples (79%); 45/45 fresh cytological specimens - pleural effusions, fine-needle aspirates, broncoalveolar lavages, sputum - and 168/223 paraffin-embedded samples. Samples having as little as 8 cancer cells were successfully amplified. Overall, 11.7% of p had exon 19 del and 5.6% exon 21 mutations. The presence of either mutation was predictive of the response to erlotinib. In p progressing to erlotinib, exon 20 mutation was detected in 6/15 p (40%) and was found more frequently in p harboring exon 19 del (5/9) than those with the L858R mutation (1/6). In the 6 p harboring the exon 20 mutation, the original mutation was homogenously present. However, in two cases, the exon 20 mutation could not be detected in some groups of cells or areas within the tumor. Conclusions: The protocol presented allows for detection of EGFR mutations in samples containing few cancer cells, thus widening the range of NSCLC p that can be analyzed. In addition, the distribution of the exon 20 mutation is frequently heterogeneous in mutated tumors from p progressing to erlotinib, suggesting that microdissection of several groups of cancer cells might be the most appropriate way to test for this mutation. E20 wt E20 T790M Primary mutation Del Exon 19 4 5 L858R 5 1 No significant financial relationships to disclose.