tbuckley/cabot-search huggingface dataset:
Population bottlenecks and patterns of human polymorphism
Authors: J. Hey, E. Harris
Journal: Molecular Biology and Evolution (1999)

Fay and Wu (1999) examine a historical model in which a population quickly shrinks, stays small for some time, and then suddenly recovers its original population size, at which it stays until samples are drawn from it.This is a bottleneck model of the kind traditionally used in population genetics (Nei, Maruyama, and Chakraborty 1975); however, it is not the model that is most commonly considered in the context of genetic evidence of human population size change.That model is one of population size expansion, and it pervades the literature on analysis of mitochondrial DNA (e.g., Rogers and Harpending 1992), as well as the more recent literature on microsatellites (e.g., Kimmel et al. 1998), some of which explicitly confounds ''expansion'' with ''bottleneck.'' Fay and Wu (1999) repeatedly cite Hey (1997), who showed that nuclear genes and mtDNA are not both consistent with simple historical models.However, Hey's paper explored only models of constant population size and models of expansion.Both of these models are considerably simpler than a bottleneck model, and they were the models that had received most of the attention in the literature.However, Hey's (1997) paper may have contributed to a confusion over models, for the final sentence did mention ''bottleneck.'' Fay and Wu (1999) bring up a valuable point, that the time over which the pattern of polymorphism responds to a change in population size will be greater for larger populations.This means that the polymorphism patterns of genes with inherently different population sizes (e.g., mtDNA and nuclear genes) may be out of phase with one another if the period of population size fluctuation is sufficiently short and the fluctuation has been recent.Fay and Wu's letter is also timely in light of the increasing amount of nuclear gene data that are emerging.Since Hey's (1997) paper, which focused mostly on a few small data sets, larger data sets from PDHA1 (Harris and Hey 1999), ␤-globin (Harding et al. 1997), dystrophin (Zietkiewicz et al. 1998), and lipoprotein lipase (Clark et al. 1998) have been published, and all reveal an abundance of intermediate frequency polymorphism and positive values for Tajima's D (Tajima 1989b).Also recently, small samples from a series of X-linked loci revealed that five out of six loci had positive values of D (although three were just slightly positive) (Nachman et al. 1998).Thus, the overall im-
Tumoricidal Effect of Strontium-89
Authors: Mana Yoshimura, Kazuhiro Saito, Jinho Park, Soichi Akata, Kiyoshi Koizumi, Koichi Tokuue, Dai Kakizaki
Journal: Clinical Nuclear Medicine (2011)

Bone-targeted radiopharmaceuticals such as rhenium-186 hydroxyethylidine diphosphonate (HEDP), rhenium-188 HEDP, and strontium-89 (89Sr) are used not only for pain reduction, but also for their tumoricidal effect, the efficacy of which is believed to be enhanced by combining them with chemotherapy and/or radiation therapy. The tumoricidal effect of 89Sr is sometimes estimated from prostate-specific antigen response and/or improved survival of patients with prostate cancer. We confirmed this effect of 89Sr using magnetic resonance imaging and Tc-99m methoxyisobutylisonitrile (MIBI).
Impacted Stone in the Ampulla of Vater
Authors: Kim Eagle, P. Gregory Foutch
Journal: New England Journal of Medicine (1993)

Figure 1. Impacted Stone in the Ampulla of Vater. An impacted common-duct stone is visible in the ampulla of Vater in a patient with suppurative cholangitis. White or tan pus can be seen draining around the margin of the calculus.
AB0941 Clinical characteristics of an early psoriatic arthritis cohort compared to an early rheumatoid arthritis cohort:
Authors: M. Khraishi, R. Aslanov
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Early diagnosis and management of inflammatory arthritis could prevent disease progression associated with destructive joint damage, disability, increased cardiovascular risk, and other co-morbidities. Differentiation of inflammatory arthritis at early stages of disease could be difficult due to similar clinical presentation. <h3>Objectives</h3> To analyze differences in clinical presentation at baseline of early Psoriatic (EPsA) and Rheumatoid (ERA) Arthritis, both defined as &lt;2 years since symptom onset. <h3>Methods</h3> PsA (meeting CASPAR criteria) and RA (meeting 1987 ACR criteria for RA) patients were assessed prospectively at a rheumatology clinic specializing in inflammatory arthritis. Clinical assessment included Tender (TJC) and Swollen (SJC) joint count, standard joint radiography, blood tests, Health Assessment Questionnaire (HAQ), and Disease Activity Score (DAS28) which was calculated for ERA out of 28 joints. Descriptive statistics and t-test were conducted with α≤5% level of significance. <h3>Results</h3> A total of 154 patients with EPsA (84; 54.5%) and ERA (70; 45.5%) with mean (SD) disease duration =0.93 (0.66) were included in this analysis. Gender distribution in EPsA cohort significantly differed towards men (47.6% vs. 17.1%; p&lt;0.001) as compared to ERA cohort. Patients in EPsA were significantly younger both generally (48.04 (10.55) vs. 54.21 (14.04); p=0.002) and at the onset of arthritis (47.85 (10.66) vs. 53.30 (13.98); p=0.007). Table shows the baseline parameters for both cohorts. As expected, patients with ERA did not have either Axial or Mixed (Axial &amp; Peripheral joints affected simultaneously) involvements (0.0% vs. 20.2%; p&lt;0.001 &amp; 0% vs. 19.0%; p&lt;0.001, respectively). Distal Interphalangeal Predominant (DIP) involvement was typical for EPsA patients (57.1% vs. 0%; p&lt;0.001) while Proximal Interphalangeal Predominant (PIP) was common in ERA (92.9% vs. 0%; p&lt;0.001). The most common pattern of joint involvement in both cohorts was polyarticular (59.5% in EPsA &amp; 71.4% in ERA). HAQ scores did not differ significantly between cohorts (0.65 (0.56) vs. 0.78 (0.73); p=0.229). DAS28 was significantly higher in patients with the ERA compared to the EPsA (4.31 (1.41) vs. 3.81 (1.19); p=0.018). <h3>Conclusions</h3> Patients with ERA had higher inflammatory activity, measured by SJC, ESR, and DAS although, both groups presented with relatively low number of inflamed joints. The disability as measured by HAQ was not significant between the cohorts. <h3>Disclosure of Interest</h3> M. Khraishi Grant/Research support from: Dr. Khraishi received non-restricted grants from Abbott Canada and Amgen &amp; Pfizer Canada, R. Aslanov: None Declared
A1.18 Mesenchymal stem cells lose their immuno-protective effects upon changes in their local microenvironment
Authors: H Munir, A Benjamin, JW Allwood, WB Dunn, S He, GB Nash, HM McGettrick
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and objectives</h3> Mesenchymal stem cells (MSC) act as endogenous regulators of the inflammatory infiltrate, communicating with blood vascular endothelial cells (EC) to limit leukocyte recruitment. Indeed exploiting these properties therapeutically is the principle underpinning clinical trials into chronic inflammatory diseases, including rheumatoid arthritis (RA). However, chronic inflammation is associated changes in the phenotype or function of MSC and their progeny, including ectopic fat deposits, which might represent damage-induced aberrant MSC differentiation. Here we examine how adipogenic differentiation of MSC influenced EC recruitment of leukocytes. <h3>Methods</h3> Co-cultures of EC with either MSC or MSC-derived adipocytes were formed on either side of porous filters and stimulated with tumour necrosis factor α (TNFα) for 4h. Neutrophil adhesion from flow was assessed by phase contrast microscopy. Microarray analysis was performed on EC and MSC following co-culture and assessed using BIOGRID and REACTOME. Metabolomic analysis was performed using mass spectrometry and analysed using PUTMEDID-LCMS workflows operating in the Taverna workflow environment. <h3>Results</h3> MSC were immunosuppressive, inhibiting neutrophil recruitment to TNFα-treated EC. Conditioned media from MSC-EC co-cultures, but not MSC mono-cultures, was able to recapitulate these effects and IL-6 was identified as the bioactive mediator. In co-culture, EC up-regulated 464 genes linked cytokine (eg, IL-6, IL-1) and chemokine (e.g. CXCL2) signalling pathways and leukocyte-endothelial interactions (eg, E-selectin). Moreover, 49 metabolites were up-regulated in EC following co-culture with MSC, including arachidonic acid metabolism, tryptophan and tyrosine metabolism, branched chain amino acids and sphingolipid metabolism. In contrast, MSC-derived adipocytes were no longer able to suppress PMN adhesion to inflamed EC. Neutralisation of IL-6 reversed the stimulatory effects of MSC-derived adipocytes in co-culture. Here we identified &gt;40 extracellular metabolites differentially expressed between the EC-MSC and EC-MSC-derived adipocyte co-cultures. <h3>Conclusions</h3> Thus in the correct environment MSC act to endogenously dampen EC responses to cytokines, thereby limiting leukocyte recruitment in an IL-6 dependent manner. However, upon differentiation MSC lose this intrinsic immuno-protective capacity, adopting a more stimulatory, pro-inflammatory behaviour. Alterations in the phenotype and function of MSC may contribute to pathogenic inflammatory responses by altering the way in which IL-6 exerts its effects from anti-inflammatory to pro-inflammatory.
Abstract 287: A SILAC proteomics analysis to identify bladder cancer metastasis-associated candidates
Authors: Laura Grau, Jose L. Luque-García, Pilar González-Peramato, Dan Theodorescu, Marta Gil, Joan Palou, Joaquin Bellmunt, Marta Sanchez-Carbayo
Journal: Cancer Research (2011)

Abstract Bladder cancer is most clinically aggressive when metastases develop, associated with the shortest patient survival. To identify molecular pathways associated with the metastatic process in bladder cancer, we carried out a proteomic analysis of an invasive T24 and a metastatic derived T24T bladder cancer cell line using a SILAC (Stable Isotope Labelling by Amino acids in Cell culture) approach. Protein extracts were fractionated, separated by SDS-PAGE and analyzed by nanoflow LC-ESI-LTQ mass spectrometry (MS). Comparative analysis of the invasive and metastatic bladder cancer cells identified 831 proteins with high confidence (&amp;gt;99%). Protein expression data from SILAC were compared with mRNA expression data obtained from oligonucleotide microarrays. Relatively weak correlations were observed, consistent with the poor associations between RNA and protein expression previously reported. The involvement of the proteins identified in biological networks served to propose how selected candidates may participate in molecular pathways associated with bladder cancer metastasis. Verification analyses included Western Blot using independent protein extracts. Immunohistochemistry analyses of proteins differentially expressed, such as Cul3, a protein involved in the ubiquitination and subsequent proteasomal degradation of target proteins, were performed on bladder tumours spotted onto tissue microarrays (n=284). Cul3 was associated with tumor staging, lymph node metastasis and disease-specific survival. Further functional analyses revealed that Cul3 silencing diminished the proliferative, migration and invasive rates of T24T cells, and restored the expression of other metastasis related cytoskeleton proteins identified by SILAC such as ezrin, moesin, filamin A or caveolin. Hence, this approach not only identified proteins and molecular mechanisms involved in bladder metastasis but also revealed a role for Cul3 in bladder cancer progression, metastasis and clinical outcome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 287. doi:10.1158/1538-7445.AM2011-287
Abstract 3427: A core invasiveness gene signature reveals reduced EMT in samples from patients with IBC, potentially regulated by decreased EGFR- and TGFb-signaling
Authors: Melike Marsan, Ridha Limame, Katrien François, François Bertucci, Nato Ueno, Filip Lardon, Patrick Pauwels, Peter Van Dam, Peter B. Vermeulen, Luc Y. Dirix, Steven J. Van Laere
Journal: Cancer Research (2011)

Abstract Introduction. We identified a core invasiveness gene (CIG) signature that predicts the invasive properties of breast cancer cell lines. In the current study, we investigate the translational utility of the current gene signature in human breast cancer, including inflammatory breast cancer (IBC). The latter is a highly invasive and metastatic breast cancer subtype. Materials and methods. Six publicly available gene expression data sets and a data set on 137 IBC and 252 non-IBC samples were analyzed. Each sample was classified according to sets of stromal (N=2), prognostic (N=2), stem cell (N=3), epithelial-to-mesenchymal transition (EMT) (N=3) and pathway (N=20) gene signatures. In addition, the cell-of-origin subtype classifier and our own CIG-signature were applied. Associations between the CIG-signature and clinicopathological or molecular features were searched for using univariate and multivariate analysis. Results. We identified associations of the CIG signature (FDR&amp;lt;0.01) with a mammosphere-derived classifier (median Rs=0.49) and with two EMT-signatures (Core-EMT: median Rs=0.52; EMT/stromal classifier: median Rs=0.59). In addition EGFR, STAT3 and TGFb were found to be hyperactivated in CIG-positive tumors (median Rs=0.45; 0.33 and 0.60 respectively). No relations between CIG-expression and stromal gene expression, molecular subtypes or any of the clinicopathological variables were observed. Compared to non-IBC, decreased CIG-expression, TGFb- and EGFR-activation were observed in IBC (respectively P&amp;lt;0.0001, P&amp;lt;0.0001 and P=0.036). As for other EMT-associated gene signatures, both positive (Claudin-low and LYN-signatures: P=0.004 and P=0.015) and negative (EMT/stromal classifier: P=0.015) associations with IBC have been observed. When testing the core-EMT signature, no difference was found (P=0.166). Discussion. We show that the CIG signature in breast cancer is correlated with EMT, stem cell biology and EGFR-, TGFb- and STAT3-activation. Samples from patients with IBC demonstrate ambiguous EMT-patterns, suggest that tumor cells from patients with IBC are in a specific state of cell plasticity and EMT as such is not the main mode of invasion in IBC. On the contrary, lowered TGFb signaling in IBC suggest a form of collective invasion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3427. doi:10.1158/1538-7445.AM2011-3427
Abstract 3819: Activation of toll-like receptor 5 on breast cancer cells by flagellin suppresses tumor development and growth
Authors: Cai Zhenyu, Zhongcheng Shi, Sanchez Amir, Dekai Zhang, Wallace L McKeehan
Journal: Cancer Research (2010)

Abstract Toll-like receptors (TLRs) play key roles in both the innate and adaptive immune systems, particularly in inflammatory responses against pathogen infection. Recent evidence showed that functional TLRs are also expressed on a wide variety of tumor cells; however, their activation exhibits either antitumor or pro-tumor effects. In order to investigate the function of TLR signaling pathways in breast cancers, we analyzed the expression of TLRs and their functional status in breast cancer cells by RT-PCR and NF-κB reporter gene assays in response to synthetic ligands for these receptors. We found that only TLR5 signaling is highly responsive in breast cancer cells. The phosphorylation levels of IκB, ERK, and JNK after flagellin (an agonist of TLR5) stimulation were increased in tumor cells. Activation of TLR5 signaling in tumor cells by flagellin induces the secretion of various cytokines and chemokines including interleukin-6, interleukin-8, and TNF-α. Moreover, flagellin/TLR5 signaling in MCF-7 cells inhibits an anchorage-independent growth, a hallmark of tumorigenic transformation. In addition, the secretion of soluble factors induced by flagellin contributed to the growth-inhibitive activity in an autocrine fashion. The inhibitive activity was further confirmed in mouse xenografts of human breast cancer model. Administration of flagellin inhibits tumor growth and therefore prolongs the survival of tumor-bearing mice. These findings indicate that TLR5 activation by flagellin mediates innate immunity to elicit potent antitumor activity in breast cancers, which may serve as a novel therapeutic target for human breast cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3819.
Phase I study of the novel, oral angiogenesis inhibitor PTK787/ZK 222584 (PTK/ZK): Evaluating the pharmacokinetic effect of a high-fat meal in patients with hormone-refractory prostate cancer (HRPC)
Authors: D. George, W. Oh, T. Gilligan, E. Masson, C. Souppart, Y. Wang, Y. Ho, D. Lebwohl, D. Laurent, P. Kantoff
Journal: Journal of Clinical Oncology (2004)

4689 Background: PTK/ZK is a novel, oral angiogenesis inhibitor that potently inhibits all known VEGF receptors, important mediators of tumor growth and metastasis. This phase I study in patients (pts) with HRPC assessed the effect of food on the pharmacokinetics (PK) of PTK/ZK and evaluated safety and preliminary efficacy (defined as changes in serum prostate-specific antigen [PSA] levels). Methods: Pts with HRPC received 1,000 mg/day PTK/ZK and were randomized to fed or fasted conditions on days 15, 18, 22, and 25. Blood was collected over 24 hr to assess the PK of PTK/ZK and PSA levels. Results: Of 23 pts treated, 1 pt discontinued due to disease-related adverse event (AE), and 3 due to drug-related AEs. PK data from 19 evaluable pts showed that administration of PTK/ZK with food resulted in a delay in absorption (Tmax increased from 2.0 to 4.0 hr; P < .001), decreased Cmax by 12% (fed:fasted ratio of 0.88; 90% CI = 0.72, 1.08), and increased AUC by 27% (fed:fasted ratio of 1.27; 90% CI = 1.07, 1.52). PK variability was moderate with intrapatient CV% of 21% - 25% and interpatient CV% of 42% for Cmax and AUC; variability was slightly higher under fed conditions. Commonly reported AEs were mostly grades 1/2: nausea (70%), dizziness (52%), headache (52%), hypertension (39%), vomiting (39%), arthralgia (35%), fatigue (30%), constipation (26%), anorexia (17%), back pain (17%), bone pain (13%), and cough (13%). Grade 3 AEs (> 5%) were hypertension (17%) and syncope (9%). The incidence of AEs was similar on fasting and fed days. Overall median time to PSA progression (TTP) was 2 mo. One pt had a 68% reduction from baseline in serum PSA level and TTP of 12 mo; 2 other pts demonstrated > 40% reductions in PSA and TTP of 4 and 5 mo, respectively. Conclusions: The small food effect observed in this study was not associated with higher frequency or severity of AEs on fed vs fasted days, suggesting that the small but statistically significant food effect is not clinically significant, and that PTK/ZK may be taken with or without food. PTK/ZK also exhibited clinical activity in pts with HRPC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals; Schering AG
Effects of Physiologic Pacing versus Ventricular Pacing on the Risk of Stroke and Death Due to Cardiovascular Causes
Authors: Stuart J. Connolly, Charles R. Kerr, Michael Gent, Robin S. Roberts, Salim Yusuf, Anne M. Gillis, Magdi H. Sami, Mario Talajic, Anthony S.L. Tang, George J. Klein, Ching Lau, David M. Newman
Journal: New England Journal of Medicine (2000)

Evidence suggests that physiologic pacing (dual-chamber or atrial) may be superior to single-chamber (ventricular) pacing because it is associated with lower risks of atrial fibrillation, stroke, and death. These benefits have not been evaluated in a large, randomized, controlled trial.At 32 Canadian centers, patients without chronic atrial fibrillation who were scheduled for a first implantation of a pacemaker to treat symptomatic bradycardia were eligible for enrollment. We randomly assigned patients to receive either a ventricular pacemaker or a physiologic pacemaker and followed them for an average of three years. The primary outcome was stroke or death due to cardiovascular causes. Secondary outcomes were death from any cause, atrial fibrillation, and hospitalization for heart failure.A total of 1474 patients were randomly assigned to receive a ventricular pacemaker and 1094 to receive a physiologic pacemaker. The annual rate of stroke or death due to cardiovascular causes was 5.5 percent with ventricular pacing, as compared with 4.9 percent with physiologic pacing (reduction in relative risk, 9.4 percent; 95 percent confidence interval, -10.5 to 25.7 percent [the negative value indicates an increase in risk]; P=0.33). The annual rate of atrial fibrillation was significantly lower among the patients in the physiologic-pacing group (5.3 percent) than among those in the ventricular-pacing group (6.6 percent), for a reduction in relative risk of 18.0 percent (95 percent confidence interval, 0.3 to 32.6 percent; P=0.05). The effect on the rate of atrial fibrillation was not apparent until two years after implantation. The observed annual rates of death from all causes and of hospitalization for heart failure were lower among the patients with a physiologic pacemaker than among those with a ventricular pacemaker, but not significantly so (annual rates of death, 6.6 percent with ventricular pacing and 6.3 percent with physiologic pacing; annual rates of hospitalization for heart failure, 3.5 percent and 3.1 percent, respectively). There were significantly more perioperative complications with physiologic pacing than with ventricular pacing (9.0 percent vs. 3.8 percent, P<0.001).Physiologic pacing provides little benefit over ventricular pacing for the prevention of stroke or death due to cardiovascular causes.
BENEFICIAL EFFECTS OF LEVOSIMENDAN ON SURVIVAL IN PATIENTS UNDERGOING EXTRACORPOREAL MEMBRANE OXYGENATION FOLLOWING CARDIOVASCULAR SURGERY
Authors: Klaus Distelmaier, Christian Roth, Lore Schrutka, Christina Binder, Barbara Steinlechner, Gottfried Heinz, Irene Lang, Gerald Maurer, Herbert Koinig, Alexander Niessner, Martin Hülsmann, Walter Speidl, Georg Goliasch
Journal: Journal of the American College of Cardiology (2016)
Expression of Hexosaminidase Isoenzymes in Childhood Leukemia
Authors: Roland B. Ellis, Nicholas T. Rapson, A. Desmond Patrick, Melvyn F. Greaves
Journal: New England Journal of Medicine (1978)

Because differences in hexosaminidase isoenzyme profiles of granulocytes and lymphoyctes suggested that such profiles might help to distinguish between various types of leukemia, was examined leukocyte extracts from 55 untreated children and 12 controls by automated anion-exchange chromatography. In 23 of 27 cases of the common form of childhood acute lymphoblastic leukemia, the activity of hexosaminidase component I was greatly increased; the activity ratio of hexosaminidase I to hexosaminidase A was greater than 0.5 in 18 of these cases, whereas for other types of leukemia and for all normal cells tested, the ratio was less than 0.2. A raised hexosaminidase I was shown to be associated with leukemic cells by the finding of normal isoenzyme profiles of bone-marrow cells from 17 patients in remission who had such an increase either at diagnosis or in relapse. Hexosaminidase isoenzyme analysis had diagnostic value and may provide a new marker for study of leukocyte differentiation.