tbuckley/cabot-search huggingface dataset:
Targeting XIAP Bypasses Bcl-2–Mediated Resistance to TRAIL and Cooperates with TRAIL to Suppress Pancreatic Cancer Growth <i>In vitro</i> and <i>In vivo</i>
Authors: Meike Vogler, Henning Walczak, Dominic Stadel, Tobias L. Haas, Felicitas Genze, Marjana Jovanovic, Jürgen E. Gschwend, Thomas Simmet, Klaus-Michael Debatin, Simone Fulda
Journal: Cancer Research (2008)

Resistance to apoptosis is a hallmark of pancreatic cancer, a leading cause of cancer deaths. Therefore, novel strategies are required to target apoptosis resistance. Here, we report that the combination of X-linked inhibitor of apoptosis (XIAP) inhibition and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an effective approach to trigger apoptosis despite Bcl-2 overexpression and to suppress pancreatic cancer growth in vitro and in vivo. Knockdown of XIAP by RNA interference cooperates with TRAIL to induce caspase activation, loss of mitochondrial membrane potential, cytochrome c release, and apoptosis in pancreatic carcinoma cells. Loss of mitochondrial membrane potential and cytochrome c release are extensively inhibited by a broad range or caspase-3 selective caspase inhibitor and by RNAi-mediated silencing of caspase-3, indicating that XIAP inhibition enhances TRAIL-induced mitochondrial damage in a caspase-3-dependent manner. XIAP inhibition combined with TRAIL even breaks Bcl-2-imposed resistance by converting type II cells that depend on the mitochondrial contribution to the death receptor pathway to type I cells in which TRAIL-induced activation of caspase-3 and caspase-9 and apoptosis proceeds irrespective of high Bcl-2 levels. Most importantly, XIAP inhibition potentiates TRAIL-induced antitumor activity in two preclinical models of pancreatic cancer in vivo. In the chicken chorioallantoic membrane model, XIAP inhibition significantly enhances TRAIL-mediated apoptosis and suppression of tumor growth. In a tumor regression model in xenograft-bearing mice, XIAP inhibition acts in concert with TRAIL to cause even regression of established pancreatic carcinoma. Thus, this combination of XIAP inhibition plus TRAIL is a promising strategy to overcome apoptosis resistance of pancreatic cancer that warrants further investigation.
Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials
Authors: Jonathan Emberson, Kennedy R Lees, Patrick Lyden, Lisa Blackwell, Gregory Albers, Erich Bluhmki, Thomas Brott, Geoff Cohen, Stephen Davis, Geoffrey Donnan, James Grotta, George Howard, Markku Kaste, Masatoshi Koga, Ruediger von Kummer, Maarten Lansberg, Richard I Lindley, Gordon Murray, Jean Marc Olivot, Mark Parsons, Barbara Tilley, Danilo Toni, Kazunori Toyoda, Nils Wahlgren, Joanna Wardlaw, William Whiteley, Gregory J del Zoppo, Colin Baigent, Peter Sandercock, Werner Hacke
Journal: The Lancet (2014)
Mechanisms Underlying the Evolution and Maintenance of Functionally Heterogeneous 18S rRNA Genes in Apicomplexans
Authors: A. P. Rooney
Journal: Molecular Biology and Evolution (2004)

In many species of the protist phylum Apicomplexa, ribosomal RNA (rRNA) gene copies are structurally and functionally heterogeneous, owing to distinct requirements for rRNA-expression patterns at different developmental stages. The genomic mechanisms underlying the maintenance of this system over long-term evolutionary history are unclear. Therefore, the aim of this study was to investigate what processes underlie the long-term evolution of apicomplexan 18S genes in representative species. The results show that these genes evolve according to a birth-and-death model under strong purifying selection, thereby explaining how divergent 18S genes are generated over time while continuing to maintain their ability to produce fully functional rRNAs. In addition, it was found that Cryptosporidium parvum undergoes a rapid form of birth-and-death evolution that may facilitate host-specific adaptation, including that of type I and II strains found in humans. This represents the first case in which an rRNA gene family has been found to evolve under the birth-and-death model.
London Drinking Water
Authors: J. A. Wanklyn
Journal: BMJ (1872)

widely astray.There are still a good number of conditions which stand out in large outlines to clinical experience, which are vague and dim to the morbid anatomist.Need I do more than mention acute articular rheumatism, typhus, tetanus, and epilepsy?We may be sure that the phrase " granular kidneys," as it occurs in post mortem records, means something else besides thegranulardegeneration of Bright's disease, as practically and clinically understood.And, in fact, the kidneys do often show granular surfaces in cases which have no real claims to be classed with genuine Bright's disease.I can only speak with exactness of some of these cases.In my work on Urinary Diseases (second edition, p. 350), 1 have pointed out the confusion into which morbid anatomists have fallen in not distinguishing the granular appearance of the kidneys consequent on long sustained passive congestion of the kidneys, from the granulation due to Bright's disease.The anatomical identity of these two conditions, although generally assumed, has been denied on high authority, and clinically, they are certainly distinct.* A real combination of regurgitant heart-dis- ease, or cirrhosis ofthe liver, with chronic Bright's disease, is comparatively rare ; and when it exists, the renal affection never fails to vindicate its existence by its appropriate symptoms.But, as a rule, the passive renal congestion which accompanies impediments to the circulation is quite a subordinate condition, and has none of the clinical features of chronic Bright's disease.The urine is of high specific gravity and scanty, and it either contains no albumen at all, or only small quantities.The renal disorder has no progressive tendency of its own ; it does not pro- duce the special secondary effects of Bright's disease, and it oscillates in its intensity strictly with the activity of the primary disease.There are also morbid conditions of the kidney of a temporary cha- racter, which probably leave behind them certain alterations in the cortex of the organs much resembling granulations.When we reflect how many middle-aged persons have suffered in earlier years from scarlatinal and other forms of acute renal disease-from syphilitic tubercles of the kidney, from renal gravel-how many women have suffered from renal congestion during repeated pregnancies, and yet how recovered with practically sound kidneys from all these ailments- it is scarcely a matter for wonder that the organs should, years after- wards, bear upon their surfaces irregularities, depressions, and even more or less granulation with thickening and adherency of the capsules -not as indicating any existing disease, but, like a scar on the skin, as footprints of a bygone disorder.
CMV endothelitis as a factor in the pathogenesis of atherosclerosis
Authors: M Levi
Journal: Cardiovascular Research (2001)

See article by Guetta et al. [8] (pages 538–546) in this issue. 

Although many factors that contribute to the development of atherosclerosis are known, major parts of its etiology need still to be elucidated. Since the 1970's a link between infectious disease and atherosclerotic disease has been hypothesized [1–3]. Infectious agents that are implicated in the pathogenesis of atherosclerosis include bacterial pathogens, such as Helicobacter pylori or Chlamydia pneumoniae, but also viruses are thought to play an important role [4]. Cytomegalovirus (CMV) is one of the most intense studied viruses as related to its potential role as a causative infectious agent that may contribute to the development of atherosclerosis [5]. There are several lines of evidence that CMV may be involved in atherogenesis. Firstly, more than 20 epidemiological studies show a relationship between the presence of CMV antibodies in serum and atherosclerotic disease. The odds ratio for atherosclerosis in CMV antibody positive patients in most of these studies is around 2. Although many of these studies had a relatively small sample size, may have …
New Strategies in the Treatment of Mantle Cell Lymphoma
Authors: Changchun Deng, Sangmin Lee, Owen A. O'Connor
Journal: Clinical Cancer Research (2012)

Mantle cell lymphoma (MCL) is a rare type of non-Hodgkin lymphoma that traditionally has been thought to possess the poor-risk features of both indolent lymphoma, with its incurability, and aggressive lymphoma, with its ability to proliferate rapidly. Although there is considerable debate as to whether MCL can be cured, a number of retrospective studies are beginning to suggest an improvement in overall survival over the past decade, likely coinciding with the introduction of rituximab, more intensive chemotherapy, and the increasing use of autologous stem cell transplant (ASCT) in first remission. At present, intensive induction chemotherapy regimens consistently produce a response rate of >90%, sometimes even 100% in the first-line setting, and consolidation with ASCT in first remission can improve the complete response rate to 90%. The emergence of a more sophisticated understanding of the underlying pathogenesis, coupled with a host of new agents and targets, has again created new opportunities to improve the care of our patients with MCL. Here, we discuss many of these developments and how they may potentially affect the natural history of this disease.
Omega-3 Polyunsaturated Fatty Acid Intake and Islet Autoimmunity in Children at Increased Risk for Type 1 Diabetes
Authors: Jill M Norris, Xiang Yin, Molly M Lamb, Katherine Barriga, Jennifer Seifert, Michelle Hoffman, Heather D Orton, Anna E Barón, Michael Clare-Salzler, H Peter Chase, Nancy J Szabo, Henry Erlich, George S Eisenbarth, Marian Rewers
Journal: JAMA (2007)

Cod liver oil supplements in infancy have been associated with a decreased risk of type 1 diabetes mellitus in a retrospective study.To examine whether intakes of omega-3 and omega-6 fatty acids are associated with the development of islet autoimmunity (IA) in children.A longitudinal, observational study, the Diabetes Autoimmunity Study in the Young (DAISY), conducted in Denver, Colorado, between January 1994 and November 2006, of 1770 children at increased risk for type 1 diabetes, defined as either possession of a high diabetes risk HLA genotype or having a sibling or parent with type 1 diabetes. The mean age at follow-up was 6.2 years. Islet autoimmunity was assessed in association with reported dietary intake of polyunsaturated fatty acids starting at age 1 year. A case-cohort study (N = 244) was also conducted in which risk of IA by polyunsaturated fatty acid content of erythrocyte membranes (as a percentage of total lipids) was examined.Risk of IA, defined as being positive for insulin, glutamic acid decarboxylase, or insulinoma-associated antigen-2 autoantibodies on 2 consecutive visits and still autoantibody positive or having diabetes at last follow-up visit.Fifty-eight children developed IA. Adjusting for HLA genotype, family history of type 1 diabetes, caloric intake, and omega-6 fatty acid intake, omega-3 fatty acid intake was inversely associated with risk of IA (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.21-0.96; P = .04). The association was strengthened when the definition of the outcome was limited to those positive for 2 or more autoantibodies (HR, 0.23; 95% CI, 0.09-0.58; P = .002). In the case-cohort study, omega-3 fatty acid content of erythrocyte membranes was also inversely associated with IA risk (HR, 0.63; 95% CI, 0.41-0.96; P = .03).Dietary intake of omega-3 fatty acids is associated with reduced risk of IA in children at increased genetic risk for type 1 diabetes.
Prednisolone treatment in asthma. Reduction in the numbers of eosinophils, T cells, tryptase-only positive mast cells, and modulation of IL-4, IL-5, and interferon-gamma cytokine gene expression within the bronchial mucosa.
Authors: A M Bentley, Q Hamid, D S Robinson, E Schotman, Q Meng, B Assoufi, A B Kay, S R Durham
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

We have tested the hypothesis that the beneficial effects of corticosteroids in asthma may result from reduction in the number of inflammatory cells infiltrating the bronchial mucosa with inhibition of cytokine gene expression. A randomized parallel group study was performed in 18 moderately severe asthmatic patients in whom an elective trial of corticosteroid treatment was indicated. Fiberoptic bronchoscopy was performed and bronchial biopsies taken from segmental carinae before and after 2 wk treatment with prednisolone (0.6 mg/kg/d) or matched placebo tablets. Immunohistology was performed on 6-microns cryostat sections using monoclonal antibodies. The number of cells expressing cytokine messenger RNA (mRNA) was assessed by in situ hybridization using S35-labeled riboprobes. When prednisolone- and placebo-treated groups were compared there was a decrease in airway methacholine responsiveness (p < 0.01) and an increase in FEV1 (p < 0.05) after prednisolone. This was accompanied by a reduction in CD3+ T lymphocytes (p < 0.05), "activated" EG2+ eosinophils (p < 0.02), and tryptase-only (mucosal-type) MCT cells (p < 0.02) but not MCTC (tryptase+chymase positive) cells in prednisolone-treated patients. In prednisolone-treated patients there was also a reduction in the number of cells expressing mRNA for interleukin-4 (IL-4, p < 0.01), and interleukin-5 (IL-5, p < 0.03) and an increase in cells expressing mRNA for interferon-gamma (IFN-gamma) (p < 0.01). These results support the view that corticosteroid treatment in asthma may act by modulation of cytokine expression with consequent inhibition of the local bronchial inflammatory infiltrate and tissue eosinophilia.
The Relationship Between Diabetes Distress and Clinical Depression With Glycemic Control Among Patients With Type 2 Diabetes
Authors: Lawrence Fisher, Russell E. Glasgow, Lisa A. Strycker
Journal: Diabetes Care (2010)

OBJECTIVE To clarify previous findings that diabetes distress is related to glycemic control and self-management whereas measures of depression are not, using both binary and continuous measures of depression. RESEARCH DESIGN AND METHODS Four hundred and sixty-three type 2 patients completed measures of diabetes distress (Diabetes Distress Scale [DDS]) and clinical depression (Patient Health Questionnaire 8 [PHQ8]). PHQ8 was employed as either a binary (≥10) or continuous variable. Dependent variables were A1C, diet, physical activity (PA), and medication adherence (MA). RESULTS The inclusion of a binary or continuous PHQ8 score yielded no differences in any equation. DDS was significantly associated with A1C and PA, whereas PHQ8 was not; both DDS and PHQ8 were significantly and independently associated with diet and MA. CONCLUSIONS The lack of association between depression and glycemic control is not due to the use of a binary measure of depression. Findings further clarify the significant association between distress and A1C.
301 COMPARATIVE INVESTIGATION OF DIFFERENTIATION POTENTIALS OF HEPATIC STELLATE CELLS AND MONONUCLEAR HEMATOPOIETIC CORD BLOOD STEM CELLS TRANSPLANTED INTO RATS AFTER PARTIAL HEPATECTOMY
Authors: A. Gumerova, A. Shafigullina, D. Andreeva, M. Kaligin, A. Trondin, M. Titova, I. Gazizov, G. Burganova, A. Kiassov
Journal: Journal of Hepatology (2013)
Undesired Effects of Clioquinol Therapy
Authors: P. M. Le Quesne
Journal: BMJ (1971)

In a recent study of 1,263 children with acute leukaemia at the Children's Cancer Research Foundation in Boston we observed two patients with undifferentiated leukaemia and multiple neurofibromatosis.5This fre- quency is not significantly higher than the estimated incidence of neurofibromatosis in the general population (one case per 2,500- 3,300 births).2The association of neuro- fibromatosis with leukaemia has occurred in two other children in the same clinic (not in our series) and has been described in three case reports from France.3-5In one instance the combination of diseases affected siblings.4The eight reported cases of neurofibroma- tosis and childhood leukaemia are of great interest, but the evidence is not sufficient as yet to indicate that the high cancer risk in neurofibromatosis extends to leukaemia.-Iam, etc.,
Transgenic Expression of Fatty Acid Transport Protein 1 in the Heart Causes Lipotoxic Cardiomyopathy
Authors: Hsiu-Chiang Chiu, Attila Kovacs, Robert M. Blanton, Xianlin Han, Michael Courtois, Carla J. Weinheimer, Kathryn A. Yamada, Sylvain Brunet, Haodong Xu, Jeanne M. Nerbonne, Michael J. Welch, Nicole M. Fettig, Terry L. Sharp, Nandakumar Sambandam, Krista M. Olson, Daniel S. Ory, Jean E. Schaffer
Journal: Circulation Research (2004)

Evidence is emerging that systemic metabolic disturbances contribute to cardiac myocyte dysfunction and clinically apparent heart failure, independent of associated coronary artery disease. To test the hypothesis that perturbation of lipid homeostasis in cardiomyocytes contributes to cardiac dysfunction, we engineered transgenic mice with cardiac-specific overexpression of fatty acid transport protein 1 (FATP1) using the α-myosin heavy chain gene promoter. Two independent transgenic lines demonstrate 4-fold increased myocardial free fatty acid (FFA) uptake that is consistent with the known function of FATP1. Increased FFA uptake in this model likely contributes to early cardiomyocyte FFA accumulation (2-fold increased) and subsequent increased cardiac FFA metabolism (2-fold). By 3 months of age, transgenic mice have echocardiographic evidence of impaired left ventricular filling and biatrial enlargement, but preserved systolic function. Doppler tissue imaging and hemodynamic studies confirm that these mice have predominantly diastolic dysfunction. Furthermore, ambulatory ECG monitoring reveals prolonged QT c intervals, reflecting reductions in the densities of repolarizing, voltage-gated K + currents in ventricular myocytes. Our results show that in the absence of systemic metabolic disturbances, such as diabetes or hyperlipidemia, perturbation of cardiomyocyte lipid homeostasis leads to cardiac dysfunction with pathophysiological findings similar to those in diabetic cardiomyopathy. Moreover, the MHC-FATP model supports a role for FATPs in FFA import into the heart in vivo.
Comparative Effectiveness of Laparoscopy vs Open Colectomy Among Nonmetastatic Colon Cancer Patients: An Analysis Using the National Cancer Data Base
Authors: Z. Zheng, A. Jemal, C. C. Lin, C.-Y. Hu, G. J. Chang
Journal: JNCI Journal of the National Cancer Institute (2015)

Randomized clinical trials showed that laparoscopic colectomy (LC) is superior to open colectomy (OC) in short-term surgical outcomes; however, the generalizability among real-world patients is not clear. The National Cancer Data Base was used to identify stage I-III colon cancer patients age 18 to 84 years in 2010 and 2011. A propensity score analysis with 1:1 matching (PS) was used to avoid the effect of treatment selection bias. Patients were clustered at the hospital level for multilevel regression analyses. The main outcomes measured were 30-day mortality, unplanned readmissions, length of stay (LOS), and initiation of adjuvant chemotherapy among stage III patients. All statistical tests were two-sided. A total of 45 876 patients were analyzed, 18 717 (41%) LC and 27 159 (59%) OC. After PS matching, there were 18 230 patients in both groups and they were well balanced on their covariables. Compared with OC, LC showed consistent benefits in 30-day mortality (1.3% vs 2.3 %, odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.69, P < .001) and LOS (median 5 vs 6 days, incident rate ratio = 0.83, 95% CI = 0.8 to 0.84, P < .001). LC was also associated with a higher rate of adjuvant chemotherapy use in stage III patients (72.3% vs 67.0%, P < .001). LC was more likely to be performed by high-volume surgeons in high-volume hospitals, but there was no significant effect of the hospital/surgeon volume on short-term outcomes. In routine clinical practice, laparoscopic colectomy is associated with lower 30-day mortality, shorter length of stay, and greater likelihood of adjuvant chemotherapy initiation among stage III colon cancer patients when compared with open colectomy.
Potassium-39 nuclear magnetic resonance observation of intracellular potassium without chemical shift reagents during metabolic inhibition in the isolated perfused rat heart.
Authors: S Kuki, E Suzuki, H Watari, H Takami, H Matsuda, Y Kawashima
Journal: Circulation Research (1990)

The intracellular potassium content of perfused rat heart was measured by potassium-39 nuclear magnetic resonance (NMR) spectroscopy at 33 degrees C with an inversion recovery technique based on the fact that the spin-lattice relaxation time (T1) of the intracellular potassium (8.3 msec at 8.45 T) is much faster than that of the extracellular potassium (68 msec). Intracellular potassium decreased to 60.2 +/- 4.3% of the control level (mean +/- SEM, n = 6) at 40 minutes from the start of metabolic inhibition (2 mM cyanide, 0 mM glucose). Removal of cyanide restored intracellular potassium to 94.2 +/- 3.9% at 30 minutes from the restart of oxidative metabolism. The cumulative potassium loss was determined from the flow rate and potassium concentration of the coronary effluent, which reached 139 +/- 12 mumol/g dry wt during 40 minutes of metabolic inhibition. This value was calculated as 41.8% of intracellular potassium in the control heart and agreed with the decrement of intracellular potassium measured by NMR. During the metabolic inhibition and recovery period, a linear correlation was observed between the changes in 39K NMR-observed intracellular potassium and the cumulative potassium loss. The present results evaluate the inversion recovery technique as a method to successfully monitor the myocardial intracellular potassium.
Inflammation is Related to Coronary Flow Reserve Detected by Positron Emission Tomography in Asymptomatic Male Twins
Authors: Viola Vaccarino, Durreshahwar Khan, John Votaw, Tracy Faber, Emir Veledar, Dean P. Jones, Jack Goldberg, Paolo Raggi, Arshed A. Quyyumi, J. Douglas Bremner
Journal: Journal of the American College of Cardiology (2011)