tbuckley/cabot-search huggingface dataset:
Insights from Empirical Analyses and Simulations on Using Multiple Fossil Calibrations with Relaxed Clocks to Estimate Divergence Times
Authors: Tom Carruthers, Robert W Scotland
Journal: Molecular Biology and Evolution (2019)

Abstract Relaxed clock methods account for among-branch-rate-variation when estimating divergence times by inferring different rates for individual branches. In order to infer different rates for individual branches, important assumptions are required. This is because molecular sequence data do not provide direct information about rates but instead provide direct information about the total number of substitutions along any branch, which is a product of the rate and time for that branch. Often, the assumptions required for estimating rates for individual branches depend heavily on the implementation of multiple fossil calibrations in a single phylogeny. Here, we show that the basis of these assumptions is often critically undermined. First, we highlight that the temporal distribution of the fossil record often violates key assumptions of methods that use multiple fossil calibrations with relaxed clocks. With respect to “node calibration” methods, this conclusion is based on our inference that different fossil calibrations are unlikely to reflect the relative ages of different clades. With respect to the fossilized birth–death process, this conclusion is based on our inference that the fossil recovery rate is often highly heterogeneous. We then demonstrate that methods of divergence time estimation that use multiple fossil calibrations are highly sensitive to assumptions about the fossil record and among-branch-rate-variation. Given the problems associated with these assumptions, our results highlight that using multiple fossil calibrations with relaxed clocks often does little to improve the accuracy of divergence time estimates.
Clinical outcome (CO) evaluation of very old (≥ 80 years) castration resistant prostate cancer (CRPC) patients (pts) treated with docetaxel (DOC): Preliminary results of an Italian multicenter retrospective study (DELPHI study).
Authors: Francesca Maines, Salvatore Luca Burgio, Giuseppe Di Lorenzo, Florinda Scognamiglio, Fable Zustovich, Gaetano Facchini, Teresa Gamucci, Giuseppe Procopio, Roberto Bortolus, Giovanni Lo Re, Francesca La Russa, Andrea Bonetti, Caterina Messina, Michele Lodde, Alessandra Perin, Roberto Iacovelli, Giovanni L. Pappagallo, Antonello Veccia, Orazio Caffo, Enzo Galligioni
Journal: Journal of Clinical Oncology (2013)

5050 Background: Since prostate cancer is mainly diagnosed in pts over 65 yrs of age, castration resistance is usually observed in older pts. In the case of very old pts (≥ 80 years), fear of high toxicity degree limit chemotherapy use due to both pts frailty and several comorbidities occurrence. Moreover, if treated these pts usually receive an adapted chemotherapy, often with a weekly schedule, which in TAX327 trial failed to show survival advantage compared to mitoxantrone. The present retrospective study is aimed to assess CO in this very elderly CRPC population. Methods: In this multicentric retrospective study, after Ethical Committee approval, we have reviewed the clinical records of all ≥ 80 yrs CRPC pts from participating institutions, treated with DOC in clinical practice, recording the pre and post-DOC clinical history, the DOC treatment details and outcomes. Results: To date we collected a consecutive series of 81 pts from 17 Italian hospitals. The median age was 82 yrs (range 80-90). The median baseline PSA was 107 ng/ml (range 3-1597); 81% of the pts had bone metastases, while nodal, lung and liver metastases were observed in 37%, 6%, and 6% of the pts, respectively. Median Cumulative Illness Rating Scale score was 3 (range 0-11), median Activity Daily Living index score was 0 (range 0-5), median Instrumental Activities of Daily Living score was 0 (range 0-5). The DOC was administered on 3-week or weekly schedule basis (41%/59%). A PSA reduction &gt; 50% and an objective response were observed in 74% and 11% of the pts, respectively. Grade 3-4 toxicities were: neutropenia (11%) , fatigue (8%), diarrhea (1%), renal (2%), and febrile neutropenia (1%). The median PFS and OS were 7 mos and 22 mos, while the 1-year PFS and OS rates were 17.3% and 43.9%, respectively. Conclusions: This data suggests that DOC treatment, both on 3-week or weekly schedule, is able to produce good survival outcomes, comparable to pivotal trials (18 mos), also in highly selected very older (≥ 80 yrs) CRPC pts.
Effect of Exercise Intensity and Duration on Cardiac Troponin Release
Authors: Lucy Marshall, Kuan Ken Lee, Stacey D. Stewart, Adam Wild, Takeshi Fujisawa, Amy V. Ferry, Catherine L. Stables, Hannah Lithgow, Andrew R. Chapman, Atul Anand, Anoop S.V. Shah, Neeraj Dhaun, Fiona E. Strachan, Nicholas L. Mills, Mark D. Ross
Journal: Circulation (2019)
Occurrence of Selected Organic Contaminants in Edible Insects and Assessment of Their Chemical Safety
Authors: Giulia Poma, Shanshan Yin, Bin Tang, Yukiko Fujii, Matthias Cuykx, Adrian Covaci
Journal: Environmental Health Perspectives (2019)

Feeding the continuously growing world population is challenging, and edible insects offer a sustainable alternative to conventional sources of animal proteins. As with any food source, the potential presence of hazardous organic chemicals, such as persistent organic pollutants (POPs), plasticizers and flame retardants (FRs), must be investigated to guarantee consumer chemical safety.Here, we have investigated the contamination levels of several classes of organic compounds in edible insects. To evaluate their chemical safety, a dietary exposure risk assessment was then performed by combining the measured chemical contamination with the most recent food consumption data from local surveys.Insect samples, belonging to six orders (Orthoptera, Coleoptera, Lepidoptera, Hemiptera, Odonata, Hymenoptera) were purchased from five European and three Asian countries. POPs and halogenated FRs were analyzed by gas chromatography-mass spectrometry (GC/MS) and organophosphorus FRs and plasticizers were quantified by liquid chromatography-MS/MS, according to validated protocols.The overall levels of chemical contamination varied greatly among the insect orders and country of purchase, but they were generally low and comparable with other commonly consumed animal products.Here we show that, besides the activities during rearing, the industrial post-harvesting handling and addition of ingredients are supplementary factors influencing the chemical load of the final insect food-product. The total estimated dietary intakes of the considered classes of compounds through insect consumption are comparable with those generally assessed in common food of animal origin worldwide and, when compared with existing reference dose values, suggest that the risk of adverse health effects from exposure to the targeted organic compounds via insect consumption is unlikely. https://doi.org/10.1289/EHP5782.
Persistent Proarrhythmic Neural Remodeling Despite Recovery From Premature Ventricular Contraction-Induced Cardiomyopathy
Authors: Alex Y. Tan, Khalid Elharrif, Ricardo Cardona-Guarache, Pranav Mankad, Owen Ayers, Martha Joslyn, Anindita Das, Karoly Kaszala, Shien-Fong Lin, Kenneth A. Ellenbogen, Anthony J. Minisi, Jose F. Huizar
Journal: Journal of the American College of Cardiology (2020)
Molecular characterization of circulating tumor cells in human metastatic colorectal cancer.
Authors: Jorge Barbazan, Lorena Alonso-Alconada, Laura Muinelo-Romay, Maria Vieito, Alicia Abalo, Marta Alonso-Nocelo, Sonia Candamio, Francisca Vazquez, Yolanda Vidal, Beatriz Fernandez, Ihab Abdulkader, Maria de los Angeles Casares, Antonio Gomez-Tato, Miguel Abal, Rafael Lopez
Journal: Journal of Clinical Oncology (2012)

10534 Background: Metastatic colorectal cancer (mCRC) relies on the detachment of aggressive malignant cells from the primary tumor into the bloodstream, being this Circulating Tumor Cells (CTC) the principal source of the further metastasis. Clinically, the presence of CTC is associated with poor prognosis and there exists a clear necessity for more specific and efficient chemotherapies in the treatment of mCRC. Our aim was to overcome this adverse scenario through the massive molecular profiling of the CTC population isolated from mCRC patients. Methods: CTC’s were magnetically isolated by using anti-EpCAM coupled magnetic beads from 6 mCRC patients and 3 healthy controls. The presence of CTCs was evaluated by citokeratins 8, 18 and 19 staining. RNA from CTCs was amplified by a whole transcriptome amplification system (WTA) and resulting material was hybridized onto gene expression arrays. Bioinformatics were used to array analysis. Selected genes were validated by RT-qPCR. Results: 410 transcripts were found to specifically characterise the CTC population after array signals comparison between mCRC patients and controls. Gene-gene interaction analysis generated networks related with cell migration, adhesion or apoptosis resistance. Gene ontology revealed similar functions. Signalling pathways such as RhoA, PKA, ILK, integrins or actin cytoskeleton signalling were found as relevant in CTCs. Eleven genes (TGFB1, APP, TIMP1, CD9, CLU, ITGB5, LIMS1, RSU1, VCL, BMP6 and TLN1) were validated by real-time PCR in 20 mCRC patient and 10 control samples. All genes showed a significantly higher expression in patients (p&lt;0.0001). Except from TLN1 and CD9, all genes had a prognostic value in terms of progression free survival (p&lt;0.05). Conclusions: We described the molecular profiling of CTCs in stage IV CRC patients, characterized by a migratory and invasive phenotype. Specific and sensitive diagnostic/prognostic markers were obtained. Our strategy represents an innovative and promising approach in the clinical management of mCRC patients.
PDCT-03. CHEMOTHERAPY STRATEGIES FOR YOUNG CHILDREN NEWLY DIAGNOSED WITH MEDULLOBLASTOMA UP TO THE ERA OF MOLECULAR PROFILING – A COMPARATIVE OUTCOMES ANALYSIS
Authors: Jonathan Finlay, Martin Mynarek, Girish Dhall, Lucie Lafay-Cousin, Claire Mazewski, David Ashley, Sarah Leary, Andre von Bueren, Nicolas Gerber, Bruce Cohen, Giles Robinson, J Russell Geyer, Diana Tait, Joseph Stanek, Amar Gajjar, Stefan Rutkowski
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND/OBJECTIVE Survival had been poor in several multi-center/national studies since the 1980s attempting to delay, avoid or minimize brain irradiation in young children with medulloblastoma. The introduction of regimens in Germany incorporating both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, as well as regimens in North America incorporating marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), have reported encouraging outcomes. The objective of this report is to perform a comparative outcomes analysis of these differing strategies. METHODS Data from 17 prospective multi-center trials published between 1990 and 2018 for children under six years old with medulloblastoma were reviewed; event-free (EFS) and overall survivals (OS) were compared. RESULTS Two trials using full-dose cranio-spinal irradiation with or without chemotherapy reported 5-year survivals of 32–38%. Three trials using standard chemotherapy with delayed irradiation reported 2-4-year EFS and OS of 23–34% and 31–46%. Two trials employing standard chemotherapy without irradiation reported 3-5-year EFS and OS of 22–33% and 34–43%. Four trials incorporating HD-MTX with or without IVENT-MTX reported 5-10-year EFS and OS of 56–59% and 67–80%, and 31% and 59% respectively; one trial with HD-MTX without IVENT-MTX for localized desmoplastic/nodular medulloblastoma (DN-MB) reported 2-year EFS and OS of 52% and 92%. Finally, five trials employing induction chemotherapy, with or without HD-MTX, followed by single or tandem HDCx+AuHCR have reported 3-5-year EFS and OS of 45–60% and 60–70%. CONCLUSIONS The best survivals are observed in trials including HD-MTX and IVENT-MTX or including HD-MTX during induction followed by HDCx+AuHCR. Because histology/biology (classic and large cell/anaplastic versus DN-MB; SHH versus non-SHH subtypes) have crucial prognostic roles, EFS and irradiation-free survival advantages require analysis in these settings. The benefit of these trials appears true for all young children with medulloblastoma. Risk-adapted treatment stratification for young children may be improved by molecular profiling of SHH- and non-SHH medulloblastoma.
Correlating Cardiac Origin Neurohormonal Stress Levels With Heart Failure Outcomes
Authors: Robin M. Shaw
Journal: JAMA Cardiology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
There is more to memory than recollection and familiarity
Authors: John F. Kihlstrom
Journal: Behavioral and Brain Sciences (2019)

Abstract Theoretical models of memory retrieval have focused on processes of recollection and familiarity. Research suggests that there are still other processes involved in memory reconstruction, leading to experiences of knowing and inferring the past. Understanding these experiences, and the cognitive processes that give rise to them, seems likely to further expand our understanding of the neural substrates of memory.
Diminished asparaginase turnover due to a germ-line mutation in cathepsin B.
Authors: Dunja Maroeslea W.M. Te Loo, Marloes Levers, Esme Waanders, Hanka Venselaar, Peter Hoogerbrugge, Frank van Leeuwen, Laurens van der Meer
Journal: Journal of Clinical Oncology (2012)

9550 Background: ASNase is a key component of multi-agent chemotherapy protocols used in the treatment of pediatric as well as adult acute lymphoblastic leukemia (ALL). Patients that are treated according to fixed shedules show a strong inter individual variation in serum ASNase levels. While underexposure may compromise therapeutic benefits, strongly elevated serum levels may lead to serious adverse effects. In at least 10% of the patients the desired ASNase levels are either not reached or exceeded. Therefore our understanding of ASNase dynamics in vivo needs to be improved. Here we describe the identification of a novel mutation in the gene encoding Cathepsin B to diminished ASNase turnover in a pediatric patient with ALL. Methods: Sequencing, biochemical experiments and immunofluorescence. Results: A 3-year-old girl diagnosed with ALL experienced serious toxicity in the form of hyperammonemic encephalopathy during treatment with ASNase derived from Erwinia chrysantemi. Pharmacokinetic data showed a strongly delayed clearance of the ASNase, which with the standard treatment protocol resulted in extremely high serum ASNase levels. Plasmapheresis was performed and dosage frequencies were adjusted to improve the clinical status of the patient. No underlying metabolic disorder could be diagnosed. Based on a previous report describing the role of proteases in degradation of ASNase in vitro, we hypothesized that the cysteine protease Cathepsin B might be implicated in the strongly reduced clearance of ASNase in this patient. Sequencing of the open reading frame of the Cathepsin B gene (CTSB) revealed a single codon deletion in the germline of the patient, affecting a lysine residue in the carboxy terminus of the protein. Immunofluorescence and biochemical experiments show that this single amino acid deletion leads to a protein product that is retained in the endoplasmic reticulum and is inefficiently processed. Conclusions: ASNase degradation assays show that the mutant Cathepsin B has lost its ability to efficiently degrade ASNase which could explain the high levels of ASNase as observed in our patient.Together, these findings suggest that variations in Cathepsin B activity may influence serum ASNase levels in the patients.
Neurocysticercosis
Authors: J. Sotelo
Journal: BMJ (2003)

Neurocysticercosis is a disease of large proportions; in most developing countries, with the exception of the Muslim world, neurocysticercosis is by far the main cause of epilepsy with a late onset and of hydrocephalus in adults.1 In the past 20 years two developments have drastically improved the gloomy picture that was associated with neurocysticercosis in the past: neuroimaging studies and the advent of effective cysticidal drugs. Computed tomography and magnetic resonance are now the cornerstone tools for diagnosing neurocysticercosis, and two drugs, albendazole and praziquantel, are inexpensive, effective cysticidals and are not toxic.2 Pharmacological treatment is now widely accessible and effective even in cases of giant cysticerci or ventricular cysts, which used to be the exclusive domain of neurosurgery.3

However, a new paradox has emerged. Although drug treatment is inexpensive, neuroimaging is unaffordable for many patients in endemic areas. Immunodiagnostic tests using serum, which theoretically would represent a logical alternative for screening and diagnosis, have been abandoned in many neurological centres because of their poor reliability.4 Currently they …
Can animal models really teach us anything about pneumonia? Con
Authors: Mark Metersky, Grant Waterer
Journal: European Respiratory Journal (2020)

In their 1987 community-acquired pneumonia (CAP) guidelines, the British Thoracic Society recommended amoxicillin with or without erythromycin (or tetracycline) in all admitted patients, with the coverage for Legionella being mandatory in seriously ill patients [1]. They also recommended intravenous flucloxacillin when Staphylococcus aureus was suspected and gentamicin or ceftazidime if a Gram-negative agent was suspected. This guideline, now more than 30 years old, also emphasised the need to identify critically ill patients based on objective physiological criteria so they could receive intensive care support, recommended obtaining culture specimens when possible and stated that antibiotics should be started immediately upon diagnosis. All of these 1987 recommendations were based on clinical studies on the aetiology of pneumonia, analysis of the predictors of outcome from pneumonia from clinical studies and a series of observational studies comparing outcomes of different antibiotic regimens in the prior three decades. Animal models of pneumonia are severely flawed and need to change if they are going to help us with new therapies <http://bit.ly/2B1d7tD>
Nanocarrier-based drug combination therapy for glioblastoma
Authors: Mengnan Zhao, Demian van Straten, Marike L.D. Broekman, Véronique Préat, Raymond M. Schiffelers
Journal: Theranostics (2020)

The current achievements in treating glioblastoma (GBM) patients are not sufficient because many challenges exist, such as tumor heterogeneity, the blood brain barrier, glioma stem cells, drug efflux pumps and DNA damage repair mechanisms.Drug combination therapies have shown increasing benefits against those challenges.With the help of nanocarriers, enhancement of the efficacy and safety could be gained using synergistic combinations of different therapeutic agents.In this review, we will discuss the major issues for GBM treatment, the rationales of drug combinations with or without nanocarriers and the principle of enhanced permeability and retention effect involved in nanomedicine-based tumor targeting and promising nanodiagnostics or -therapeutics.We will also summarize the recent progress and discuss the clinical perspectives of nanocarrier-based combination therapies.The goal of this article was to provide better understanding and key considerations to develop new nanomedicine combinations and nanotheranostics options to fight against GBM.
Characterization of the Severe Phenotype of Pyruvate Kinase Deficiency
Authors: Hanny Al-Samkari, Eduard J. van Beers, D Holmes Morton, Wilma Barcellini, Stefan W. Eber, Bertil Glader, Hassan M. Yaish, Satheesh Chonat, Kevin H. M. Kuo, Nina Kollmar, Jenny M. Despotovic, Dagmar Pospisilova, Christine M. Knoll, Janet L. Kwiatkowski, Yves D. Pastore, Alexis A. Thompson, Marcin W. Wlodarski, Yaddanapudi Ravindranath, Jennifer A. Rothman, Heng Wang, Suzanne Holzhauer, Vicky R. Breakey, Madeleine M. Verhovsek, Joachim B. Kunz, Sujit Sheth, Mukta Sharma, Melissa J. Rose, Heather Bradeen, Melissa A. McNaull, Kathryn Addonizio, Hasan Al-Sayegh, Wendy B. London, Rachael F. Grace
Journal: Blood (2019)
Questioning the Benefit of Statins for Low-Risk Populations—Medical Misinformation or Scientific Evidence?—Reply
Authors: Ann Marie Navar
Journal: JAMA Cardiology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal