tbuckley/cabot-search huggingface dataset:
Abstract #5382: Synthesis of sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate and pharmacologic tests in vitro and in vivo
Authors: Claudete Valduga, Durvanei Maria, Gilvan Leonardo, Fernanda Flores, Reginaldo Santos, Paulo Pardi, Daniela Rando, José Quincoces
Journal: Cancer Research (2009)

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

Introduction and Objective: Our group have been focused on the sythesis of 1,5-bis(4-hidroxy-3-methoxyphenyl)penta-1,4-dien-3-one (HB1) and derivatives. These compounds showed an interesting antitumor, antiparasite and other biological activities and low toxicity, but are poor water-soluble. Here we transformed HB1 in a water-soluble salt and evaluated its cytotoxicity against B16F10 murine melanoma cells, tumor regression in B16F10 melanoma-bearing mice, as well pharmacokinetic and biodistribution in mice. Materials and Methods: HB1 was transformed in its respective sodium salt by the reaction with metallic alcoxyde in a 1:1 molar ratio. MTT method was use to find IC50 value of DM1. Lethal dose (DL50) was determined in mice. To evaluate tumoral regression B16F10 tumor-bearing mice were intraperitonially injected with 0.71mg/kg of DM1 at day 11th to day 31st after tumor inoculation. This group was compared with a control without treatment. A high-performance liquid chromatographic (HPLC) method was developed and validated to determine the pharmacokinetic parameters and analyze metabolites in plasma, heart, liver, spleen, brain, lymph node, kidney and lung, of DM1 in healthy mice. Nine groups of four mice were injected in bolus with 50mg/Kg. Blood samples were collected from orbital vein at time 5, 10 and 15 min., and 1, 2, 4, 8 and 24h. DM1, HB1 and/or their metabolites were extracted from plasma and organs with methanol and methanol/chloroform 1:2, respectively. Solvents were concentrated under nitrogen flow, reconstituted and analyzed in HPLC and LC-MS. Results: DM1 was obtained with 100 % yield and >99% purity, assayed by HPLC. Its IC50 against B16F10 was 5.3\#956;M. Regarding the animal toxicity performed in female C57BL/6J mice, it was found a low toxicity (LD50 = 14mg/kg). Antitumoral activity evaluated in B16F10 melanoma-bearing mice show 84% regression compared to the control group. Regarding pharmacokinetic, the sodium salt or its neutral form disappear from plasma fifteen minutes after injection, and it is not found in analyzed organs. The half-life is very short although its neutral form shows a half-life around of 6h. The main metabolite found in all analyzed tissue, except kidney, was the O-desmethylated compound and O-glucuronide in all organs. Conclusion: The great advantage of use the salt form of the HB1 is the high water-soluble avoiding toxic organic solvents, solving problems related to its administration. Additionally, the increasing of the bioavailability found for DM1 can be very interesting pharmacologically.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5382.
Integrated Evaluation of Results from Genome-Wide Association Studies and Crispr/Cas9-Based Functional Genomics in Myeloma: Implications for Cell-Autonomous Vs. Non-Autonomous Role of Candidate Genes in Myeloma Pathophysiology
Authors: Ricardo De Matos Simoes, Geoffrey M. Matthews, Yiguo Hu, Brian Glassner, Megan A. Bariteau, Michal Sheffer, Ryosuke Shirasaki, Constantine S Mitsiades
Journal: Blood (2016)
A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis
Authors: Thuy Le, Nguyen Van Kinh, Ngo T.K. Cuc, Nguyen L.N. Tung, Nguyen T. Lam, Pham T.T. Thuy, Do D. Cuong, Pham T.H. Phuc, Vu H. Vinh, Doan T.H. Hanh, Vu Van Tam, Nguyen T. Thanh, Tran P. Thuy, Nguyen T. Hang, Hoang B. Long, Ho T. Nhan, Heiman F.L. Wertheim, Laura Merson, Cecilia Shikuma, Jeremy N. Day, Nguyen V.V. Chau, Jeremy Farrar, Guy Thwaites, Marcel Wolbers
Journal: New England Journal of Medicine (2017)

Talaromyces marneffei infection is a major cause of human immunodeficiency virus (HIV)-related death in South and Southeast Asia. Guidelines recommend initial treatment with amphotericin B deoxycholate, but this drug has substantial side effects, a high cost, and limited availability. Itraconazole is available in oral form, is associated with fewer unacceptable side effects than amphotericin, and is widely used in place of amphotericin; however, clinical trials comparing these two treatments are lacking.In this open-label, noninferiority trial, we randomly assigned 440 HIV-infected adults who had talaromycosis, confirmed by either microscopy or culture, to receive either intravenous amphotericin B deoxycholate (amphotericin) (219 patients), at a dose of 0.7 to 1.0 mg per kilogram of body weight per day, or itraconazole capsules (221 patients), at a dose of 600 mg per day for 3 days, followed by 400 mg per day, for 11 days; thereafter, all the patients received maintenance therapy with itraconazole. The primary outcome was all-cause mortality at week 2. Secondary outcomes included all-cause mortality at week 24, the time to clinical resolution of talaromycosis, early fungicidal activity, relapse of talaromycosis, development of the immune reconstitution inflammatory syndrome (IRIS), and the side-effect profile.The risk of death at week 2 was 6.5% in the amphotericin group and 7.4% in the itraconazole group (absolute risk difference, 0.9 percentage points; 95% confidence interval [CI], -3.9 to 5.6; P<0.001 for noninferiority); however, the risk of death at week 24 was 11.3% in the amphotericin group and 21.0% in the itraconazole group (absolute risk difference, 9.7 percentage points; 95% CI, 2.8 to 16.6; P=0.006). Treatment with amphotericin was associated with significantly faster clinical resolution and fungal clearance and significantly lower rates of relapse and IRIS than itraconazole. The patients who received amphotericin had significantly higher rates of infusion-related reactions, renal failure, hypokalemia, hypomagnesemia, and anemia than patients in the itraconazole group.Amphotericin was superior to itraconazole as initial treatment for talaromycosis with respect to 6-month mortality, clinical response, and fungicidal activity. (Funded by the Medical Research Council and others; IVAP Current Controlled Trials number, ISRCTN59144167 .).
Reversible Cardiotoxicity Associated with Carfilzomib Use in Patients with Multiple Myeloma
Authors: Tania Jain, Hemalatha Narayanasamy, Joseph Mikhael, Craig B. Reeder, P. Leif Bergsagel, Angela Mayo, A. Keith Stewart, Farouk Mookadam, Rafael Fonseca
Journal: Blood (2016)
Early vestibular and visual dysfunction predicts prolonged symptomatology following paediatricpediatric concussion
Authors: Christina L Master, Matthew F Grady, Eileen Storey, Olivia Podolak, Julia Lockyer, Douglas Wiebe
Journal: British Journal of Sports Medicine (2017)

Objective Vestibular and visual dysfunction, including accommodation disorder, symptoms with vestibular ocular reflex (VOR) testing, or receded near point of convergence, are common following concussion and have been associated with prolonged concussion symptomatology. The objective of this study was to determine whether vestibular and visual information contributed significantly to a model predicting the likelihood of having persistent concussion symptoms at 28 days after injury. Design Retrospective cohort study Setting Sports medicine concussion program within a large regional paediatric healthcare network. Participants 274 consecutive patients aged 3-18 years with the diagnosis of concussion seen in the concussion program Independent Variables Standard demographic and clinical data, as well as vestibular and visual examination findings at presentation Outcome measures Symptom recovery from concussion, defined as a symptom score=0 on the Post Concussion Symptom Scale at 28 days Main results Study subjects were 3–18 years (median=14), presenting a median of 14 days from injury. Applying a stepwise regression approach using traditional demographic and clinical variables (age, gender, past medical history, symptoms and balance testing) as well as information from vestibular and visual testing, we found that VOR testing is a statistically significant component (p=0.02) of the final predictive model. Furthermore, in the subset of patients presenting within 14 days of injury, positive VOR testing (p=0.02) and vision problems (p=0.01) significantly contribute to predicting ongoing symptoms at 28 days. Conclusions Symptoms with VOR testing and vision problems upon presentation within 14 days of injury contributed significantly to the prediction model for prolonged symptoms following concussion and warrant further study. Competing interests None.
Abstract 114: System’s Biology Approach to Non-Invasive Integrative Analysis of Cardiac Energetics
Authors: Philippe Diolez, Véronique Deschodt-Arsac, Laurent Arsac, Pierre dos Santos, Mélèze Hocini, Pierre Jais, Michel Haissaguerre
Journal: Circulation Research (2013)

Our aim is to propose an inovative non-invasive analysis of heart contraction energetics, to be used for diagnosis and therapeutics follow-up in human heart pathologies. The analysis is based on the combination of non-invasive 31P-NMR and IRM techniques and the analytical background of metabolic modular control analysis (MoCA). Metabolic control analysis’ based approaches have been used by us and others to overcome the complexity of intra-cellular regulations and to describe and quantify controls and regulations in complex systems. We previously demonstrated that MoCA does bring new informations on the interplay between ATP demand and supply in heart contraction energetics. In the present study, MoCA was applied to beating Langendorff perfused guinea pig heart to describe qualitatively and quantitatively the global action of various inotropic effectors effector modifying (Adrenaline) or not (Levosimendan, a calcium-sensitizer; Frank-Starling effect) cytosolic calcium transients. MoCA allows to describe the relative importance of the different routes within the heart by which the inotropic effects are transmitted. The results show that in the absence of calcium transient changes, an energetic feed-back control occurs at the expense of total energy, like in skeletal muscle, while parallel activation of both supply and demand occurs after adrenaline addition, maintaining energy homeostasis (heart energetic paradigm). In conclusion, clinical application of System’s biology to the study of contraction energetics in patients may help to the understanding of the links between molecular events in pathologies and whole organ function / dysfunction.
Combined DNA and Transcriptome Sequencing Reveals Discrete Subtypes of Myelodysplasia
Authors: Yusuke Shiozawa, Luca Malcovati, Anna Gallì, Andrea Pellagatti, Hiromichi Suzuki, Tetsuichi Yoshizato, Yusuke Sato, Keisuke Kataoka, Kenichi Yoshida, Kenichi Yoshida, Masashi Sanada, Hideki Makishima, Yuichi Shiraishi, Kenichi Chiba, Satoru Miyano, Jacqueline Boultwood, Eva Hellström-Lindberg, Seishi Ogawa, Mario Cazzola
Journal: Blood (2016)
Association between concussion history and knowledge among italian youth soccer athletes
Authors: Naji Filali, Tamara Valovich McLeod, Cailee Welch Bacon, Gianandrea Bellini, Paolo Amaddeo, Claudio Cornali
Journal: British Journal of Sports Medicine (2017)

Objective To compare concussion-based knowledge between Italian youth soccer athletes who reported a previously diagnosed concussion or concussion-like symptoms and those without prior concussion history. Design Cross sectional. Setting Self-reported survey. Subjects Male soccer athletes (n=766, age=16.9 ± 1.3 years, experience=6.6 ± 3.9 years) from 25 club teams across three professional leagues in Italy. Intervention The independent variables studied were diagnosed concussion group (prior diagnosed concussion vs. no diagnosed concussion) and self-reported concussion symptom group (experienced concussion-like symptoms vs. no concussion-like symptoms). Outcome measures The dependent variables were total knowledge scores, measured through accurate endorsement of symptoms and responses to true and false prompts. Independent t-tests were used to determine group differences. Results 45 (6%) respondents indicated they sustained a physician-diagnosed concussion. The mean number of diagnosed concussions was 0.065±0.3 (range 0–3). 198 (26.2%) respondents indicated they had experienced concussion-like symptoms. The mean frequency of self-reported concussion-like symptoms was 0.54±1.3 (range: 0–15). There were no significant differences in concussion symptom knowledge ( P =0.616, 13.9±2.0 vs. 14.1±2.2) or true and false knowledge ( P =0.390, 10.7±1.8 vs. 10.4±1.7) between the group with a previously diagnosed concussion compared to the one without. There were also no significant differences in concussion symptom knowledge ( P =0.499, 14.2±2.1 vs 14.1±2.2) or true and false knowledge ( P =0.256, 10.5±1.6 vs. 10.4±1.8) between the group that had experienced concussion-like symptoms compared to the group that had not. Conclusions These results suggest the necessity for targeted knowledge-based interventions for youth athletes, especially for those who sustain and report concussions. Competing interests None.
A Phase 1 Study Of The Selective PI3Kδ Inhibitor Idelalisib (GS-1101) In Combination With Therapeutic Anti-CD20 Antibodies (Rituximab or Ofatumumab) In Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia
Authors: Richard R. Furman, Sven De Vos, John P. Leonard, Jacqueline C. Barrientos, Marshall T. Schreeder, Ian W. Flinn, Jeff P. Sharman, Thomas Boyd, Nathan Fowler, Kanti R. Rai, Yeonhee Kim, Leanne M. Holes, Roger Dansey, Thomas M. Jahn, Steven E. Coutre
Journal: Blood (2013)
The Dying Process: Experiences of Patients in Palliative Care
Authors: Esther Waterhouse
Journal: BMJ (2001)

Julia Lawton 

Routledge, £14.99, pp 240

ISBN 0 415 22679 1

Rating: ![Graphic][1] ![Graphic][2] ![Graphic][3] 

This is a book that can—and will—be read on many different levels. To patients, or their families, it may truly reflect some of the distress that they have experienced. To the medical sociologist it is no doubt an interesting academic discourse on the concept of “self” in contemporary England, and the changes that the “self” goes through when faced with impending death. To a doctor, particularly one working in palliative medicine, it throws up many …

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Recovery from community acquired pneumonia: the view from the top of the iceberg
Authors: Grant Waterer
Journal: European Respiratory Journal (2017)

A very common question patients with pneumonia ask is, "When will I be better?" My usual response is a mixture of educated guess and anecdotal experience: "Probably not for 6–8 weeks at least – and it may be longer", mentally reducing that time frame for younger patients and increasing it for the elderly. Given how fundamentally important this question is for our patients, the study in this issue of the journal by Wootton et al . [1] is particularly welcome. What I am not sure of is whether the study conducted has really answered the question. Recovery from pneumonia is much more complicated than the paper in this issue of the ERJ suggests <http://ow.ly/1UlC30bFNLS>
Abstract 292: Isoform-Specific Expression of Estrogen-Related Receptors Regulates Cardiomyocyte Metabolic Adaptation to Oxidative Stress
Authors: Kathryn Cribben, Paul McDermott
Journal: Circulation Research (2012)

In the ischemic heart, metabolic adaptation of cardiomyocytes exposed to prolonged hypoxia is critical to sustain myocardial energy production. Metabolic gene expression is regulated by Estrogen-Related Receptor (ERR) transcription factors and Peroxisome Proliferator-Activated Receptor γ Coactivator-1 (PGC-1) co-activators. ERRs do not require ligand to achieve an active conformation and regulate an array of target genes involved in myocardial energy metabolism. These studies aim to determine the regulatory mechanisms governing expression of ERR isoforms (ERRα and ERRβ) in cardiomyocytes undergoing oxidative stress. We hypothesize that metabolic energy production in myocardium initially adapts to hypoxia by inducing transient ERRβ expression, and maintains this compensatory expression through induction of sustained ERRα expression. Adult feline cardiomyocytes in primary culture were electrically stimulated to contract continuously at 1 Hz under normoxia (21% [O2]), hypoxia (0.5% [O2]), or hypoxia followed by reoxygenation. Expression of ERR, PGC-1 and target genes was measured by QRT-PCR (n≥5). QRT-PCR arrays were used to screen for prospective target genes. In response to 24 hours of hypoxia, mRNA levels increased for ERRα (3-fold by 24 hours), ERRβ (11-fold by 12 hours), PGC-1α (16-fold by 24 hours) and PGC-1β (8-fold by 24 hours). Subsequent reoxygenation for 24 hours decreased ERRβ, PGC-1α and PGC-1β mRNA levels to that of normoxia controls. However, reoxygenation did not markedly decrease (∼25%; 0.7 of 3.0-fold) ERRα mRNA levels. Cytochrome C Oxidase Subunit VIc (Cox6c) and Fatty Acid Binding Protein 3 (Fabp3) were identified as potential ERRα target genes in adult cardiomyocytes based on correlation of expression. Moreover, hypoxia-induced increases in Cox6c and Fabp3 mRNA levels were partially blocked by treatment with XCT-790, an inhibitor of ERRα activity. We conclude that hypoxia and subsequent reoxygenation elicit isoform-specific changes in ERR and PGC-1 mRNA expression in adult cardiomyocytes. This observed regulation of expression for ERR isoforms and their target genes may play a critical role in metabolic adaptation to oxidative stress.
Experience of Day-Case Transcutaneous Liver Biopsies Performed in a Single Unit
Authors: J Leyden, G Bennett, C Walsh, S Looby, P MacMathuna, J Crowe
Journal: Endoscopy (2004)

Background: Though an accepted procedure internationally, day-case liver biopsy is not widely practiced in Ireland. Since January 2003 we have been performing day-case liver biopsies in our Unit. We report on our experience to date.
Immunoparesis in newly diagnosed AL amyloidosis as a marker for response and survival.
Authors: Eli Muchtar, Angela Dispenzieri, Shaji Kumar, Francis Buadi, Martha Lacy, Steven R. Zeldenrust, Suzanne R. Hayman, Nelson Leung, Taxiarchis Kourelis, Wilson I. Gonsalves, Rajshekhar Chakraborty, Stephen J. Russell, David Dingli, John Anthony Lust, Yi Lin, Prashant Kapoor, Ronald S. Go, Robert A. Kyle, S.Vincent Rajkumar, Morie A. Gertz
Journal: Journal of Clinical Oncology (2016)

8016 Background: Immunoparesis is a marker for progression and survival in plasma cell disorders. Its impact in AL amyloidosis has not been explored in depth. Methods: Nine hundred and ninety eight AL amyloidosis patients were evaluated for immunoparesis at presentation by two methods. The first method was qualitative, considering the number of suppressed uninvolved immunoglobulins below the lower limit of normal (none, partial, all). The second method was quantitative, assessing the average relative difference (ARD) of the uninvolved immunoglobulins from the lower limit of normal. Results: Patients with suppression of all the uninvolved immunoglobulins (23% of patients) were less likely to have achieved a VGPR or better to first line treatment (44%) compared to patients with partial suppression (68%) or preserved uninvolved immunoglobulins (64%; p < .0001). Additionally, patients with suppression of all the uninvolved immunoglobulins had a shorter survival compared to the respective comparators (18 vs. 54 vs. 52 months; p < .0001). In the quantitative method, patients with negative ARD values (36% of patients) were less likely to achieve VGPR or better (48%) and had a shorter survival (24 months) compared to patients with positive ARD (69%, 57 months, respectively; p < .0001). The negative impact of immunoparesis on survival was maintained in several selected sub-groups of patients, including landmark analysis at 6 months from diagnosis, translocation (11;14) at presentation, more than 2 viscera involved and those with an intact immunoglobulin on serum immunofixation. However, in patients who underwent ASCT at first line the effect of immunoparesis on survival was not significant. In a multivariate analysis, both immunoparesis assessment methods retained an independent impact on survival, after adjusting for age, number of involved organs, revised Mayo staging system, AL-MM/AL-CRAB and stem cell transplant at first line. Conclusions: Significant immunoparesis, assessed by two different methods, has a negative impact on response and survival in newly diagnosed AL amyloidosis. The quantitative method of immunoparesis has a better response and survival discrimination than the qualitative method.
Phase II study of oral ENMD-2076 administered to patients with ovarian clear cell carcinoma: A trial of the Princess Margaret Phase II Consortium.
Authors: Cristina Martin-Lorente, David SP Tan, Neesha Dhani, Marcus Butler, Helen Mackay, Michelle Wilson, Stephanie Lheureux, Hal W. Hirte, Stephen Welch, Johanne Ingrid Weberpals, Ghatage Prafullg, Katia Tonkin, Lisa Wang, Anna Haley, Stephanie Capobianco, Amit M. Oza
Journal: Journal of Clinical Oncology (2014)

TPS5620 Background: Ovarian clear cell carcinoma (OCCC) represents nearly 15% of all epithelial ovarian carcinomas (EOC). This histology is associated with resistance to chemotherapy and a worse prognosis. VEGF has been found to be strongly expressed in OCCC. Somatic mutations in the ARID1A (the AT-rich interactive domain 1A gene that encodes BAF250a, a key component of the SWI/SNF chromatin remodeling complex) has also been demonstrated in 46-57% of OCCCs. Alteration of this chromatin remodeling complex may result in upregulation and overexpression of Aurora A. ENMD-2076 is a multi-target kinase inhibitor, which has selective activity against Aurora A and multiple antiangiogenesis and lymphangiogenesis targets. In a Phase II study in platinum-resistant EOC, 58% of the patients treated with single agent ENMD-2076 showed partial response or stable disease, the PFS at 6 month was 22% with a median time to progression of 3.6 months. Two out of 3 patients with OCCC who were enrolled had a longer PFS than the median. Methods: This is a multi-center, Phase II study, in patients with recurrent OCCC to assess response rate and progression free survival rate, as primary endpoints, and duration of overall response, as a secondary endpoint, of single agent ENMD-2076 275 mg/day. Exploratory endpoints include association of somatic mutations in PI3KCA, ARID1A and PTEN, and ARID1A and PTEN expression with outcome and response. Patients ECOG ≤2, with histologically documented diagnosis of recurrence OCCC, any number of prior treatment regimens (chemotherapy, biologics or other target therapies except for Aurora A targeted therapies), and measurable disease (RECIST criteria 1.1) are eligible. Based on data from previous studies, a sample size of 36 patients will provide 95% power to detect an improvement in response rate from 10 to 30% and 90% power to detect an increase in 6 month PFS from 20 to 40%. Since September 2013, 6 patien Clinical trial information: NCT01914510.
The External Validity of Prediction Models for the Diagnosis of Obstructive Coronary Artery Disease in Patients With Stable Chest Pain
Authors: Tessa S.S. Genders, Adrian Coles, Udo Hoffmann, Manesh R. Patel, Daniel B. Mark, Kerry L. Lee, Ewout W. Steyerberg, M.G. Myriam Hunink, Pamela S. Douglas
Journal: JACC. Cardiovascular imaging (2017)