tbuckley/cabot-search huggingface dataset:
What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review
Authors: J A B van Nies, A Krabben, J W Schoones, T W J Huizinga, M Kloppenburg, A H M van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> Initiation of DMARD-therapy in the 'window of opportunity' is thought to result in a more effective modification of the processes underlying rheumatoid arthritis (RA). We questioned whether this effect is true or hyped and performed a systematic literature review. <h3>Methods</h3> Medical literature databases up to June 2012 were systematically reviewed for cohort studies and randomised controlled trials reporting outcome data of early RA in relation with symptom duration at treatment initiation. The quality of these studies was assessed by two independent reviewers using a criteria scoring system of 15 items. Studies were dichotomised with the median score (79%) as cut-off. Best-evidence synthesis was applied to determine the level of evidence per outcome category. A meta-analysis was performed on the studies reporting on achieving DMARD-free sustained remission (the reverse of disease persistency). <h3>Results</h3> Out of 836 screened articles, 18 fulfilled the selection criteria and were not duplicates. Ten were scored as high quality. Remission (various definitions) and radiographic progression were frequently studied outcomes. There was strong evidence for an association between symptom duration and radiographic progression. A meta-analysis on datasets evaluating DMARD-free sustained remission showed that symptom duration was independently associated with such remission; HR 0.989 (95% CI 0.983 to 0.995) per week increase in symptom duration. A moderate level of evidence was observed for other remission outcomes. <h3>Conclusions</h3> Even when heterogeneity of patients is taken into account, prolonged symptom duration is associated with radiographic progression and a lower chance on DMARD-free sustained remission. These data may support the presence of a 'window of opportunity'.
THE EFFECT OF PILOCARPINE ON THE OUTPUT OF LYMPHOCYTES THROUGH THE THORACIC DUCT
Authors: F. Peyton Rous
Journal: The Journal of Experimental Medicine (1908)

The intravenous injection of pilocarpine nitrate causes in the dog a rapid and considerable increase in the output of lymphocytes through the thoracic duct. The corresponding lymphocytosis induced by the drug in the blood of this animal is not profound, and increased cell-output with the lymph will explain a large part if not all of it. Quickened lymph-flow and dyspnoeic breathing are accessory in the production of the large cell-output with the lymph, but it is mainly dependent on some undetermined element. The evidence points to the mechanical nature of this element. It is probably to be sought in direct pressure from contraction of smooth muscle, as suggested by Harvey, but his observation that atropine prevents the appearance of a lymphocytosis after pilocarpine cannot be quoted in proof because atropine much slows the lymph-flow, and thus decreases cell-output. These findings are in accord with the theory that makes mechanical factors responsible for rapidly appearing lymphocytosis. They show that there are more such factors than has been supposed. Especially do they indicate that the contribution of cells through the thoracic duct may be important in the production of lymphocytosis, and is not, as is often asserted, subsidiary to direct migration into the blood of cells from spleen, bone-marrow and the lymph-glands.
Mcl-1: A Gateway to TRAIL Sensitization
Authors: Seok-Hyun Kim, M. Stacey Ricci, Wafik S. El-Deiry
Journal: Cancer Research (2008)

Abstract The proapoptotic cytokine tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is being evaluated presently as a selective anticancer agent, but its limited effects against cancer cell lines has raised some concerns about its ultimate clinical utility. Here, we review recent findings that cancer cell sensitivity to TRAIL is greatly increased when the Bcl-2 family protein Mcl-1 is down-regulated by the Raf/vascular endothelial growth factor kinase inhibitor sorafenib, a Food and Drug Administration–approved cancer drug. Using the TRAIL-sorafenib combination as a tactic to more effectively kill cancer cells may provide an effective tool to attack a variety of human cancers that are largely presently untreatable. [Cancer Res 2008;68(7):2062–4]
Mitogenic effects of growth hormone in cultured human fibroblasts. Evidence for action via local insulin-like growth factor I production.
Authors: J J Cook, K M Haynes, G A Werther
Journal: Journal of Clinical Investigation (1988)

We examined human growth hormone's (hGH) effect on mitogenesis in cultured human fibroblasts, and the role of local insulin-like growth factor I (IGF-I). With 0.5% human hypopituitary serum (HPS), hGH increased thymidine incorporation (TI) over serum-free medium dose responsively, with half-maximal effect at 10 ng/ml (0.5 nM) (hGH 127 +/- 8.8%; IGF-I 107 +/- 1.7% [SEM]) (n = 10). Similarly, with 0.5% HPS, hGH and IGF-I increased cell replication by 172 +/- 8.2% and 169 +/- 25%, respectively (n = 4). Specific IGF-I monoclonal antibody (Sm1.2) dose dependently blunted TI stimulated by 10 ng/ml hGH or IGF-I (at 1:1000, 38 +/- 6.5% and 30 +/- 14% reduction, respectively). Sm1.2 also reduced cell replication by both 10 ng/ml hGH and IGF-I, respectively, to 32% and 42% of stimulated values. Dexamethasone (0.1 microM) synergistically enhanced TI by both IGF-I and hGH. A 28-h time course for TI showed that hGH stimulated a similar peak to IGF-I, lagging in its effect by 4-10 h. We have provided further evidence that hGH stimulates growth of cultured human fibroblasts via local IGF-I production, consistent with IGF-I's paracrine-autocrine role.
Identification of genes modulated in multiple myeloma using genetically identical twin samples
Authors: Nikhil C. Munshi, Teru Hideshima, Daniel Carrasco, Masood Shammas, Daniel Auclair, Faith Davies, Nicholas Mitsiades, Constantine Mitsiades, Ryung Suk Kim, Cheng Li, S. Vincent Rajkumar, Rafael Fonseca, Lief Bergsagel, Dharminder Chauhan, Kenneth C. Anderson
Journal: Blood (2003)
Heart rate variability and cardiac troponin I are incremental and independent predictors of one-year all-cause mortality after major noncardiac surgery in patients at risk of coronary artery disease
Authors: Miodrag Filipovic, Raban Jeger, Cecilia Probst, Thierry Girard, Matthias Pfisterer, Lorenz Gürke, Karl Skarvan, Manfred D. Seeberger
Journal: Journal of the American College of Cardiology (2003)
Use of Propranolol (Inderal) in Treatment of Hypertension
Authors: B. N. C. Prichard, P. M. C. Gillam
Journal: BMJ (1964)

BWDIHLJOURNAL 725obtained in the final 14 days of each 21-day period.The patients' own general assessment of each treatment is based upon the whole 21-day periods and scored on a five-point scale in the following way: -1 worsening of the angina; + 1, + 2, and +3 indicating slight, moderate, and marked improvement respectively; and 0 showing that the condition had remained unchanged when compared with that before the start of the trial.The results are summarized in Tables I andII.TABLE II.-Summarized Results and Statistical Analysis of Trial Criterion Propranolol Placebo Difference t-Value Days pain free .mean4-40 3055 0-85 ± 1-08 0-8 NS Daya ain ree range 0-14 0-14 -11-+10 No. of attacks fmean 35-5 43?3 -7-8±44
Plasmonic Nanobubbles Rapidly Detect and Destroy Drug-Resistant Tumors
Authors: Ekaterina Y. Lukianova-Hleb, Xiaoyang Ren, Debra Townley, Xiangwei Wu, Michael E. Kupferman, Dmitri O. Lapotko
Journal: Theranostics (2012)

The resistance of residual cancer cells after oncological resection to adjuvant chemoradiotherapies results in both high recurrence rates and high non-specific tissue toxicity, thus preventing the successful treatment of such cancers as head and neck squamous cell carcinoma (HNSCC). The patients' survival rate and quality of life therefore depend upon the efficacy, selectivity and low non-specific toxicity of the adjuvant treatment. We report a novel, theranostic in vivo technology that unites both the acoustic diagnostics and guided intracellular delivery of anti-tumor drug (liposome-encapsulated doxorubicin, Doxil) in one rapid process, namely a pulsed laser-activated plasmonic nanobubble (PNB). HNSCC-bearing mice were treated with gold nanoparticle conjugates, Doxil, and single near-infrared laser pulses of low energy. Tumor-specific clusters of gold nanoparticles (solid gold spheres) converted the optical pulses into localized PNBs. The acoustic signals of the PNB detected the tumor with high specificity and sensitivity. The mechanical impact of the PNB, co-localized with Doxil liposomes, selectively ejected the drug into the cytoplasm of cancer cells. Cancer cell-specific generation of PNBs and their intracellular co-localization with Doxil improved the in vivo therapeutic efficacy from 5-7% for administration of only Doxil or PNBs alone to 90% thus demonstrating the synergistic therapeutic effect of the PNB-based intracellular drug release. This mechanism also reduced the non-specific toxicity of Doxil below a detectable level and the treatment time to less than one minute. Thus PNBs combine highly sensitive diagnosis, overcome drug resistance and minimize non-specific toxicity in a single rapid theranostic procedure for intra-operative treatment.
Painful Schmorl's Node: Another Cause of Vertebral Photopenia on Indium-111-Labeled Leukocyte Scintigraphy
Authors: IAN D. KIRKWOOD, DOUGLAS I. QUINT, ANDREW HAIG, RICHARD L. WAHL
Journal: Clinical Nuclear Medicine (1999)

The authors describe an In-111-labeled leukocyte study in a 28-year-old man with lower back pain. SPECT images showed photopenia of the L2 vertebra. Plain radiographs showed disc space narrowing at the L2-3 level but no other abnormality. MRI showed a large, apparently intraosseous disc herniation (Schmorl's node) through the inferior endplate of L2 with associated extensive contrast-enhancing marrow edema and reactive changes. A repeated CT showed findings consistent with an intraosseous disc herniation. There was no evidence of infection or tumor. Thus a painful Schmorl's node may cause vertebral photopenia on labeled leukocyte scintigraphy, presumably because of associated marrow edema.
Systematic Underestimation of Tree Branch Lengths by Lake's Operator Metrics: An Effect of Position-dependent Substitution Rates
Authors: Gary Olsen
Journal: Molecular Biology and Evolution (1991)

Lake has proposed a method, which he calls "operator metrics," for estimating branch lengths (as transversion differences) on an unrooted phylogenetic tree of nucleotide sequences.Examination of published applications of operator metrics reveals that it often assigns branch lengths that sum to less than the observed sequence differences, indicating a substantial systematic bias.The problem occurs in all sets of sequence data examined.It is shown analytically that operator metrics does not yield the claimed estimate of transversion sequence differences when sequence positions differ in their nucleotide substitution rate, in which case the method underestimates tree branch lengths.The site-to-site variations in substitution rate that have been characterized by previous authors are of sufficient magnitude to explain the problems observed in the operator-metrics branch length estimates.Transversion substitutions estimated using Kimura's two-parameter (transition / transversion) model are less subject to this problem and are more consistent with directly observed differences.1.
A Melanoma Cell State Distinction Influences Sensitivity to MAPK Pathway Inhibitors
Authors: David J. Konieczkowski, Cory M. Johannessen, Omar Abudayyeh, Jong Wook Kim, Zachary A. Cooper, Adriano Piris, Dennie T. Frederick, Michal Barzily-Rokni, Ravid Straussman, Rizwan Haq, David E. Fisher, Jill P. Mesirov, William C. Hahn, Keith T. Flaherty, Jennifer A. Wargo, Pablo Tamayo, Levi A. Garraway
Journal: Cancer Discovery (2014)

Most melanomas harbor oncogenic BRAF(V600) mutations, which constitutively activate the MAPK pathway. Although MAPK pathway inhibitors show clinical benefit in BRAF(V600)-mutant melanoma, it remains incompletely understood why 10% to 20% of patients fail to respond. Here, we show that RAF inhibitor-sensitive and inhibitor-resistant BRAF(V600)-mutant melanomas display distinct transcriptional profiles. Whereas most drug-sensitive cell lines and patient biopsies showed high expression and activity of the melanocytic lineage transcription factor MITF, intrinsically resistant cell lines and biopsies displayed low MITF expression but higher levels of NF-κB signaling and the receptor tyrosine kinase AXL. In vitro, these MITF-low/NF-κB-high melanomas were resistant to inhibition of RAF and MEK, singly or in combination, and ERK. Moreover, in cell lines, NF-κB activation antagonized MITF expression and induced both resistance marker genes and drug resistance. Thus, distinct cell states characterized by MITF or NF-κB activity may influence intrinsic resistance to MAPK pathway inhibitors in BRAF(V600)-mutant melanoma.Although most BRAF(V600)-mutant melanomas are sensitive to RAF and/or MEK inhibitors, a subset fails to respond to such treatment. This study characterizes a transcriptional cell state distinction linked to MITF and NF-κB that may modulate intrinsic sensitivity of melanomas to MAPK pathway inhibitors.
Computer-integrated revision total hip replacement surgery: concept and preliminary results
Authors: Russell H. Taylor, Leo Joskowicz, Bill Williamson, André Guéziec, Alan Kalvin, Peter Kazanzides, Robert Van Vorhis, Jianhua Yao, Rajesh Kumar, Andrew Bzostek, Alind Sahay, Martin Börner, Armin Lahmer
Journal: Medical Image Analysis (1999)

This paper describes an ongoing project to develop a computer-integrated system to assist surgeons in revision total hip replacement (RTHR) surgery. In RTHR surgery, a failing orthopedic hip implant, typically cemented, is replaced with a new one by removing the old implant, removing the cement and fitting a new implant into an enlarged canal broached in the femur. RTHR surgery is a difficult procedure fraught with technical challenges and a high incidence of complications. The goals of the computer-based system are the significant reduction of cement removal labor and time, the elimination of cortical wall penetration and femur fracture, the improved positioning and fit of the new implant resulting from precise, high-quality canal milling and the reduction of bone sacrificed to fit the new implant. Our starting points are the ROBODOC(R) system for primary hip replacement surgery and the manual RTHR surgical protocol. We first discuss the main difficulties of computer-integrated RTHR surgery and identify key issues and possible solutions. We then describe possible system architectures and protocols for preoperative planning and intraoperative execution. We present a summary of methods and preliminary results in CT image metal artifact removal, interactive cement cut-volume definition and cement machining, anatomy-based registration using fluoroscopic X-ray images and clinical trials using an extended RTHR version of ROBODOC. We conclude with a summary of lessons learned and a discussion of current and future work.
Articulating “Archiannelids”: Phylogenomics and Annelid Relationships, with Emphasis on Meiofaunal Taxa
Authors: Sónia C.S. Andrade, Marta Novo, Gisele Y. Kawauchi, Katrine Worsaae, Fredrik Pleijel, Gonzalo Giribet, Greg W. Rouse
Journal: Molecular Biology and Evolution (2015)

Annelid disparity has resulted in morphological-based classifications that disagree with phylogenies based on Sanger sequencing and phylogenomic analyses. However, the data used for the latter studies came from various sources and technologies, involved poorly occupied matrices and lacked key lineages. Here, we generated a new Illumina-based data set to address annelid relationships from a fresh perspective, independent from previously generated data and with nearly fully occupied matrices. Our sampling reflects the span of annelid diversity, including two symbiotic annelid groups (Myzostomida and Spinther) and five meiofaunal groups once referred to as part of Archiannelida (three from Protodrilida, plus Dinophilus and Polygordius). As well as the placement of these unusual annelids, we sought to address the overall phylogeny of Annelida, and provide a new perspective for naming of major clades. Our results largely corroborate the phylogenomic results of Weigert et al. (2014; Illuminating the base of the annelid tree using transcriptomics. Mol Biol Evol. 31:1391-1401), with "Magelona + Owenia" and Chaetopteridae forming a grade with respect to all other annelids. Echiura and Sipuncula are supported as being annelid groups, with Sipuncula closest to amphinomids as sister group to Sedentaria and Errantia. We recovered the three Protodrilida terminals as sister clade to Phyllodocida and Eunicida (=clade Aciculata). We therefore place Protodrilida as part of Errantia. Polygordius was found to be sister group to the scaleworm terminal and the possibility that it is a simplified scaleworm clade, as has been shown for the former family Pisionidae, is discussed. Our results were equivocal with respect to Dinophilus, Myzostomida, and Spinther possibly owing to confounding long-branch effects.
Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models
Authors: Melissa A Penny, Robert Verity, Caitlin A Bever, Christophe Sauboin, Katya Galactionova, Stefan Flasche, Michael T White, Edward A Wenger, Nicolas Van de Velde, Peter Pemberton-Ross, Jamie T Griffin, Thomas A Smith, Philip A Eckhoff, Farzana Muhib, Mark Jit, Azra C Ghani
Journal: The Lancet (2015)

The phase 3 trial of the RTS,S/AS01 malaria vaccine candidate showed modest efficacy of the vaccine against Plasmodium falciparum malaria, but was not powered to assess mortality endpoints. Impact projections and cost-effectiveness estimates for longer timeframes than the trial follow-up and across a range of settings are needed to inform policy recommendations. We aimed to assess the public health impact and cost-effectiveness of routine use of the RTS,S/AS01 vaccine in African settings.We compared four malaria transmission models and their predictions to assess vaccine cost-effectiveness and impact. We used trial data for follow-up of 32 months or longer to parameterise vaccine protection in the group aged 5-17 months. Estimates of cases, deaths, and disability-adjusted life-years (DALYs) averted were calculated over a 15 year time horizon for a range of levels of Plasmodium falciparum parasite prevalence in 2-10 year olds (PfPR2-10; range 3-65%). We considered two vaccine schedules: three doses at ages 6, 7·5, and 9 months (three-dose schedule, 90% coverage) and including a fourth dose at age 27 months (four-dose schedule, 72% coverage). We estimated cost-effectiveness in the presence of existing malaria interventions for vaccine prices of US$2-10 per dose.In regions with a PfPR2-10 of 10-65%, RTS,S/AS01 is predicted to avert a median of 93,940 (range 20,490-126,540) clinical cases and 394 (127-708) deaths for the three-dose schedule, or 116,480 (31,450-160,410) clinical cases and 484 (189-859) deaths for the four-dose schedule, per 100,000 fully vaccinated children. A positive impact is also predicted at a PfPR2-10 of 5-10%, but there is little impact at a prevalence of lower than 3%. At $5 per dose and a PfPR2-10 of 10-65%, we estimated a median incremental cost-effectiveness ratio compared with current interventions of $30 (range 18-211) per clinical case averted and $80 (44-279) per DALY averted for the three-dose schedule, and of $25 (16-222) and $87 (48-244), respectively, for the four-dose schedule. Higher ICERs were estimated at low PfPR2-10 levels.We predict a significant public health impact and high cost-effectiveness of the RTS,S/AS01 vaccine across a wide range of settings. Decisions about implementation will need to consider levels of malaria burden, the cost-effectiveness and coverage of other malaria interventions, health priorities, financing, and the capacity of the health system to deliver the vaccine.PATH Malaria Vaccine Initiative; Bill & Melinda Gates Foundation; Global Good Fund; Medical Research Council; UK Department for International Development; GAVI, the Vaccine Alliance; WHO.
C-reactive protein in atherosclerosis: A causal factor?
Authors: E PAFFEN, M DEMAAT
Journal: Cardiovascular Research (2006)

Atherosclerosis is considered a to be multifactorial disease driven by inflammatory reactions. The process of inflammation also contributes to the pathogenesis of acute atherothrombotic events. C-reactive protein (CRP) is an acute phase protein and its concentration in serum reflects the inflammatory condition of the patient. Levels of CRP are consistently associated with cardiovascular disease (CVD) and predict myocardial infarctions and stroke. Since CRP is present in the atherosclerotic lesion, it may actively contribute to the progression and/or instability of the atherosclerotic plaque. The role of CRP in inflammation and its causality in atherosclerosis are the subject of many investigations but are not yet fully elucidated. This review focuses on recently identified mechanisms by which CRP may modulate and evolve the process of atherosclerosis. We discuss the function of CRP and review the most recent evidence for an independent role of CRP in the development of atherosclerosis. Many studies suggest such a role, but a number of the described effects may be the result of contamination of the CRP preparations.