tbuckley/cabot-search huggingface dataset:
β-Catenin Downregulation Is Required for Adaptive Cardiac Remodeling
Authors: Anthony Baurand, Laura Zelarayan, Russell Betney, Christina Gehrke, Sandra Dunger, Claudia Noack, Andreas Busjahn, Joerg Huelsken, Makoto Mark Taketo, Walter Birchmeier, Rainer Dietz, Martin W. Bergmann
Journal: Circulation Research (2007)

The armadillo-related protein β-catenin has multiple functions in cardiac tissue homeostasis: stabilization of β-catenin has been implicated in adult cardiac hypertrophy, and downregulation initiates heart formation in embryogenesis. The protein is also part of the cadherin/catenin complex at the cell membrane, where depletion might result in disturbed cell–cell interaction similar to N-cadherin knockout models. Here, we analyzed the in vivo role of β-catenin in adult cardiac hypertrophy initiated by angiotensin II (Ang II). The cardiac-specific mifepristone-inducible αMHC-CrePR1 transgene was used to induce β-catenin depletion (loxP-flanked exons 3 to 6, β-cat Δex3–6 mice) or stabilization (loxP-flanked exon 3, β-cat Δex3 mice). Levels of β-catenin were altered both in membrane and nuclear extracts. Analysis of the β-catenin target genes Axin2 and Tcf-4 confirmed increased β-catenin–dependent transcription in β-catenin stabilized mice. In both models, transgenic mice were viable and healthy at age 6 months. β-Catenin appeared dispensable for cell membrane function. Ang II infusion induced cardiac hypertrophy both in wild-type mice and in mice with β-catenin depletion. In contrast, mice with stabilized β-catenin had decreased cross-sectional area at baseline and an abrogated hypertrophic response to Ang II infusion. Stabilizing β-catenin led to impaired fractional shortening compared with control littermates after Ang II stimulation. This functional deterioration was associated with altered expression of the T-box proteins Tbx5 and Tbx20 at baseline and after Ang II stimulation. In addition, atrophy-related protein IGFBP5 was upregulated in β-catenin–stabilized mice. These data suggest that β-catenin downregulation is required for adaptive cardiac hypertrophy.
Evaluating Clinical Management Decisions by Recent Graduates in the Era of High-Value, Cost-Conscious Care
Authors: Ayokunle T. Abegunde, Benjamin Mba
Journal: JAMA Internal Medicine (2015)

To the Editor Sirovich and colleagues present an interesting article on the association of the intensity of the internal medicine (IM) training environment and clinical management decisions made by graduates of US IM residency programs.1 However, their results have several limitations.
HHV8-positive Kaposi sarcoma in a long-term human immunodeficiency virus-exposed but uninfected patient carrying the CCR5-promoter mutation A59029G
Authors: M. Mempel, W. Groer, C. Schnopp, S. Burggraf, M. Mohrenschlager, R. Engst, J. Ring, H. Hofmann
Journal: British Journal of Dermatology (2005)
Genetics of the low density lipoprotein receptor. Diminished receptor activity in lymphocytes from heterozygotes with familial hypercholesterolemia.
Authors: D W Bilheimer, Y K Ho, M S Brown, R G Anderson, J L Goldstein
Journal: Journal of Clinical Investigation (1978)

Using circulating mononuclear cells as a readily available tissue and using the rate of high affinity degradation of 125-I-labeled low density lipoprotein (LDL) as an index of cell surface LDL receptor activity, we have measured receptor activity in cells from 53 individuals. This group includes 32 healthy subjects, 15 subjects with the heterozygous form of familial hypercholesterolemia, and 6 subjects with hyperlipidemic disorders other than familial hypercholesterolemia. 7 of the healthy subjects and 10 of the heterozygotes were members of a single large kindred with five-generation transmission of the mutant familial hypercholesterolemia gene. LDL receptor activity was assayed in blood mononuclear cells under two sets of conditions. First, 125I-LDL degradation was measured in purified lymphocytes that had been incubated for 3 days in the absence of lipoproteins so as to induce a high level of LDL receptor activity. Phase-contrast autoradiograms of cells incubated with 125I-LDL and electron micrographs of cells incubated with ferritin-labeled LDL confirmed the existence of LDL receptors on lymphocytes. Second, 125I-LDL degradation was measured in mixed mononuclear cells (85-90% lymphocytes and 5-15% monocytes) immediately after their isolation from the bloodstream. This assay represented an attempt to assess the number of receptors actually expressed on the cells when they were in the circulation. Under both sets of conditions, cells from the familial hypercholesterolemia heterozygotes expressed an average of about one-half the normal number of LDL receptors. The current findings are consistent with the conclusion that heterozygotes with familial hypercholesterolemia possess only one functional allele at the LDL receptor locus and that the consequent deficiency of LDL receptors produces the clinical syndrome of heterozygous familial hypercholesterolemia.
Mucosa-Associated Lymphoid Tissue Lymphoma: Novel Translocations Including Rearrangements of <i>ODZ2, JMJD2C</i>, and <i>CNN3</i>
Authors: Ursula Vinatzer, Michaela Gollinger, Leonhard Müllauer, Markus Raderer, Andreas Chott, Berthold Streubel
Journal: Clinical Cancer Research (2008)

The well-known translocations identified in MALT lymphomas include t(11;18)/API2-MALT1, t(1;14)/IGH-BCL10, and t(14;18)/IGH-MALT1. Molecular investigations have suggested that these three disparate translocations affect a common pathway, resulting in the constitutive activation of nuclear factor-kappaB. However, the vast majority of MALT lymphomas are negative for any of the above-mentioned translocations and the underlying pathogenesis is unclear.Fresh tissue of 29 gastric and extragastric MALT lymphomas was studied for genetic aberrations by conventional karyotyping, long-distance inverse PCR (LDI-PCR), fluorescence in situ hybridization (FISH), reverse transcription-PCR (RT-PCR), and real-time quantitative RT-PCR (QRT-PCR).Conventional cytogenetics, FISH, and RT-PCR identified aberrations in 26 of 29 MALT lymphoma. Balanced translocations were found in 21 cases. IGH was rearranged in the majority of cases with balanced translocations (n = 17/21); 3 cases had t(11;18)/API2-MALT1 and 1 case had novel t(6;7)(q25;q11), respectively. IGH partner genes involved MALT1, FOXP1, BCL6, and four new chromosomal regions on chromosome arms 1p, 1q, 5q, and 9p. LDI-PCR identified three novel partner genes on 1p (CNN3), 5q (ODZ2), and 9p (JMJD2C). FISH assays were established and confirmed LDI-PCR results. QRT-PCR showed deregulation of the novel genes in the translocation-positive cases.Our study expands the knowledge on the genetic heterogeneity of MALT lymphomas.
MutS homologue hMSH4: interaction with eIF3f and a role in NHEJ-mediated DSB repair
Authors: Yen-Lin Chu, Xiling Wu, Yang Xu, Chengtao Her
Journal: Molecular Cancer (2013)

Abstract Background DNA mismatch repair proteins participate in diverse cellular functions including DNA damage response and repair. As a member of this protein family, the molecular mechanisms of hMSH4 in mitotic cells are poorly defined. It is known that hMSH4 is promiscuous, and among various interactions the hMSH4-hMSH5 interaction is involved in recognizing DNA intermediate structures arising from homologous recombination (HR). Results We identified a new hMSH4 interacting protein eIF3f – a protein that functions not only in translation but also in the regulation of apoptosis and tumorigenesis in humans. Our studies have demonstrated that hMSH4-eIF3f interaction is mediated through the N-terminal regions of both proteins. The interaction with eIF3f fosters hMSH4 protein stabilization, which in turn sustains γ-H2AX foci and compromises cell survival in response to ionizing radiation (IR)-induced DNA damage. These effects can be, at least partially, attributed to the down-regulation of NHEJ activity by hMSH4. Furthermore, the interplay between hMSH4 and eIF3f inhibits IR-induced AKT activation, and hMSH4 promotes eIF3f-mediated bypass of S phase arrest, and ultimately enhancing an early G2/M arrest in response to IR treatment. Conclusion Our current study has revealed a role for hMSH4 in the maintenance of genomic stability by suppressing NHEJ-mediated DSB repair.
ICUD-EAU International Consultation on Bladder Cancer 2012: Non–Muscle-Invasive Urothelial Carcinoma of the Bladder
Authors: Maximilian Burger, Willem Oosterlinck, Badrinath Konety, Sam Chang, Sigurdur Gudjonsson, Raj Pruthi, Mark Soloway, Eduardo Solsona, Paul Sved, Marko Babjuk, Maurizio A. Brausi, Christopher Cheng, Eva Comperat, Colin Dinney, Wolfgang Otto, Jay Shah, Joachim Thürof, J. Alfred Witjes
Journal: European Urology (2012)
A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3)
Authors: Victor Enciso-Mora, Peter Broderick, Yussanne Ma, Ruth F Jarrett, Henrik Hjalgrim, Kari Hemminki, Anke van den Berg, Bianca Olver, Amy Lloyd, Sara E Dobbins, Tracy Lightfoot, Flora E van Leeuwen, Asta Försti, Arjan Diepstra, Annegien Broeks, Jayaram Vijayakrishnan, Lesley Shield, Annette Lake, Dorothy Montgomery, Eve Roman, Andreas Engert, Elke Pogge von Strandmann, Katrin S Reiners, Ilja M Nolte, Karin E Smedby, Hans-Olov Adami, Nicola S Russell, Bengt Glimelius, Stephen Hamilton-Dutoit, Marieke de Bruin, Lars P Ryder, Daniel Molin, Karina Meden Sorensen, Ellen T Chang, Malcolm Taylor, Rosie Cooke, Robert Hofstra, Helga Westers, Tom van Wezel, Ronald van Eijk, Alan Ashworth, Klaus Rostgaard, Mads Melbye, Anthony J Swerdlow, Richard S Houlston
Journal: Nature Genetics (2010)
Lysophosphatidic Acid Receptors Determine Tumorigenicity and Aggressiveness of Ovarian Cancer Cells
Authors: Shuangxing Yu, Mandi M. Murph, Yiling Lu, Shuying Liu, Hassan S. Hall, Jinsong Liu, Clifton Stephens, Xianjun Fang, Gordon B. Mills
Journal: JNCI Journal of the National Cancer Institute (2008)

BackgroundLysophosphatidic acid (LPA) acts through the cell surface G protein–coupled receptors, LPA1, LPA2, or LPA3, to elicit a wide range of cellular responses. It is present at high levels in intraperitoneal effusions of human ovarian cancer increasing cell survival, proliferation, and motility as well as stimulating production of neovascularizing factors. LPA2 and LPA3 and enzymes regulating the production and degradation of LPA are aberrantly expressed by ovarian cancer cells, but the consequences of these expression changes in ovarian cancer cells were unknown.
5-azacytidine(5- AC), all-trans retinoic acid (ATRA), and valproic acid (VPA) in patients with acute myelogenous leukemia (AML): Molecular and clinical implications
Authors: Andres Soriano, Hui Yang, Srdan Verstovsek, William Wierda, Charles Koller, Zeev Estrov, Souzanne Ouzounian, Hagop Kantarjian, Jean Pierre Issa, Guillermo Garcia-Manero
Journal: Clinical Cancer Research (2006)

B48   Background: The combination of a hypomethylating agent with a histone deacetylase inhibitor (HDACI) has synergistic activity. The combination of ATRA with either a hypomethylating agent or a HDACI restores ATRA sensitivity in resistant cells. The combination of VPA and ATRA has activity in patients with AML. Based on this, we developed a phase I/II study of the combination of 5-AC, VPA and ATRA for patients with AML.Methods: The dose of 5-AC was fixed: 75 mg/m 2  sq daily x 7. ATRA dose was: 45 mg/m 2  orally daily x 5 starting on day 3. Three dose levels of VPA were studied: 50, 62.5 and 75 mg/kg orally daily x 7. The phase I portion of the study followed a 3+3 design. Phase II was single arm with stopping rules. Patients with relapsed/refractory AML and patients older than 60 years with untreated disease and adequate renal, hepatic functions and performance status were eligible.Results: Thirty one patients were registered and 27 were evaluable. Median age was 60 years (5-78). Median number of prior therapies was 2 (0-5). Twenty three patients (85%) had abnormal cytogenetics. At a VPA dose of 50 mg/kg, 1 of 6 patients developed grade 3 non-hematological toxicity; at 62.5 mg/kg, 2 of 7, and at 75 mg/kg, 3 of 6. The dose limiting toxicity was neurotoxicity including confusion and somnolence. Six patient had a CR (ANC 10  9 /L, plat 100 x 10  9 /L, and a bone marrow with 5% or less blasts), 2 patients had a CRP (same criteria as of CR but without complete platelet recovery), and 1 a complete marrow response (marrow blasts
Antitumor Efficacy of Intermittent Treatment Schedules with the Rapamycin Derivative RAD001 Correlates with Prolonged Inactivation of Ribosomal Protein S6 Kinase 1 in Peripheral Blood Mononuclear Cells
Authors: Anne Boulay, Sabine Zumstein-Mecker, Christine Stephan, Iwan Beuvink, Frederic Zilbermann, Roland Haller, Sonja Tobler, Christoph Heusser, Terence O’Reilly, Barbara Stolz, Andreas Marti, George Thomas, Heidi A. Lane
Journal: Cancer Research (2004)

Abstract The orally bioavailable rapamycin derivative RAD001 (everolimus) targets the mammalian target of rapamycin pathway and possesses potent immunosuppressive and anticancer activities. Here, the antitumor activity of RAD001 was evaluated in the CA20948 syngeneic rat pancreatic tumor model. RAD001 demonstrated dose-dependent antitumor activity with daily and weekly administration schedules; statistically significant antitumor effects were observed with 2.5 and 0.5 mg/kg RAD001 administered daily [treated tumor versus control tumor size (T/C), 23% and 23–30%, respectively], with 3–5 mg/kg RAD001 administered once weekly (T/C, 14–36%), or with 5 mg/kg RAD001 administered twice weekly (T/C, 36%). These schedules were well tolerated and exhibited antitumor potency similar to that of the cytotoxic agent 5-fluorouracil (T/C, 23%). Moreover, the efficacy of intermittent treatment schedules suggests a therapeutic window allowing differentiation of antitumor activity from the immunosuppressive properties of this agent. Detailed biochemical profiling of mammalian target of rapamycin signaling in tumors, skin, and peripheral blood mononuclear cells (PBMCs), after a single administration of 5 mg/kg RAD001, indicated that RAD001 treatment blocked phosphorylation of the translational repressor eukaryotic initiation factor 4E-binding protein 1 and inactivated the translational activator ribosomal protein S6 kinase 1 (S6K1). The efficacy of intermittent treatment schedules was associated with prolonged inactivation of S6K1 in tumors and surrogate tissues (≥72 h). Furthermore, detailed analysis of the dose dependency of weekly treatment schedules demonstrated a correlation between antitumor efficacy and prolonged effects (≥7 days) on PBMC-derived S6K1 activity. Analysis of human PBMCs revealed that S6K1 also underwent a concentration-dependent inactivation after RAD001 treatment ex vivo (&amp;gt;95% inactivation with 20 nm RAD001). In contrast, human PBMC-derived eukaryotic initiation factor 4E-binding protein 1 was present predominantly in the hypophosphorylated form and was unaffected by RAD001 treatment. Taken together, these results demonstrate a correlation between the antitumor efficacy of intermittent RAD001 treatment schedules and prolonged S6K1 inactivation in PBMCs and suggest that long-term monitoring of PBMC-derived S6K1 activity levels could be used for assessing RAD001 treatment schedules in cancer patients.
Epidermal Growth Factor Receptor Mutations in Non–Small Cell Lung Cancer: Predicting Clinical Response to Kinase Inhibitors
Authors: Lecia V. Sequist, Daniel A. Haber, Thomas J. Lynch
Journal: Clinical Cancer Research (2005)

In this issue of Clinical Cancer Research , Taron et al., describe their experience with 68 gefitinib-treated, chemorefractory patients with advanced non–small cell lung cancer (NSCLC) from Asia, Europe, and North America ([1][1]). By sequencing exons 18, 19, and 21 of the epidermal growth factor
The effects of sublingually administered nitroglycerin on forearm vascular resistance in patients with heart failure and in normal subjects.
Authors: T Imaizumi, A Takeshita, T Ashihara, M Nakamura
Journal: Circulation (1985)

This study examined the effects of sublingually administered nitroglycerin on forearm resistance vessels in normal subjects (n = 9) and in patients with congestive heart failure (n = 8). Forearm blood flow was measured with a strain-gauge plethysmograph and forearm vascular resistance was calculated. To assess the magnitude of reflex forearm vasoconstriction triggered by decreased central venous pressure after sublingual nitroglycerin, lower body negative pressure (LBNP) was applied to produce a comparable decrease in central venous pressure to that after nitroglycerin. The change in forearm vascular resistance during LBNP was compared with that after nitroglycerin. In normal subjects, LBNP increased but nitroglycerin did not change forearm vascular resistance. In patients with congestive heart failure neither nitroglycerin nor LBNP changed forearm vascular resistance. The direct vasodilator effect of nitroglycerin on forearm resistance vessels assessed by the difference between the change in forearm vascular resistance produced by nitroglycerin and that during LBNP tended to be less in patients with congestive heart failure than in normal subjects, which might have resulted from decreased vasodilator capacity of resistance vessels in patients with congestive heart failure. Changes in forearm vascular resistance with a cold pressor test were not different between normal subjects and patients with congestive heart failure. These data suggest that in normal subjects, nitroglycerin does not alter forearm vascular resistance because its dilator effect is offset by reflex vasoconstriction. In patients with congestive heart failure, reflex vasoconstriction is impaired but the direct vasodilator effect of nitroglycerin also tends to be reduced, so that as a net effect forearm vascular resistance is not altered.
Prkdc participates in mitochondrial genome maintenance and prevents Adriamycin-induced nephropathy in mice
Authors: Natalia Papeta, Zongyu Zheng, Eric A. Schon, Sonja Brosel, Mehmet M. Altintas, Samih H. Nasr, Jochen Reiser, Vivette D. D’Agati, Ali G. Gharavi
Journal: Journal of Clinical Investigation (2010)

Adriamycin (ADR) is a commonly used chemotherapeutic agent that also produces significant tissue damage. Mutations to mitochondrial DNA (mtDNA) and reductions in mtDNA copy number have been identified as contributors to ADR-induced injury. ADR nephropathy only occurs among specific mouse inbred strains, and this selective susceptibility to kidney injury maps as a recessive trait to chromosome 16A1-B1. Here, we found that sensitivity to ADR nephropathy in mice was produced by a mutation in the Prkdc gene, which encodes a critical nuclear DNA double-stranded break repair protein. This finding was confirmed in mice with independent Prkdc mutations. Overexpression of Prkdc in cultured mouse podocytes significantly improved cell survival after ADR treatment. While Prkdc protein was not detected in mitochondria, mice with Prkdc mutations showed marked mtDNA depletion in renal tissue upon ADR treatment. To determine whether Prkdc participates in mtDNA regulation, we tested its genetic interaction with Mpv17, which encodes a mitochondrial protein mutated in human mtDNA depletion syndromes (MDDSs). While single mutant mice were asymptomatic, Prkdc/Mpv17 double-mutant mice developed mtDNA depletion and recapitulated many MDDS and ADR injury phenotypes. These findings implicate mtDNA damage in the development of ADR toxicity and identify Prkdc as a MDDS modifier gene and a component of the mitochondrial genome maintenance pathway.
Suramin-Induced Decrease in Prostate-Specific Antigen Expression With No Effect on Tumor Growth in the LNCaP Model of Human Prostate Cancer
Authors: G. N. Thalmann, R. A. Sikes, S.-M. Chang, D. A. Johnston, A. C. von Eschenbach, L. W. K. Chung
Journal: JNCI Journal of the National Cancer Institute (1996)

Background:Suramin, a polysulfonated naphthylurea and a recognized antitrypanosomal agent, has shown some promise in phase II clinical trials in the management of hormone-refractory human prostate cancer. Reduction of serum prostate-specific antigen (PSA) levels has been proposed as an end point for evaluating the antitumor efficacy of treatments for hormone-refractory prostate cancer.
Miss, Mister, Doctor: Doctor or Mister?
Authors: S. Moore
Journal: Journal of the Royal Society of Medicine (2006)

How we are titled is of little consequence I found the editorial (April 2006 JRSM 1 ) on how we are titled most interesting.This is a continuation of the debate that the dental profession has been having for many years, fuelled by both an influx of overseas graduates styling themselves as 'Doctor', and by the development of the role of dentists from 'toothwrights' to practitioners with a more holistic approach encompassing the oral health and wellbeing of those in their care.However all of us, physicians, surgeons, general practitioners and dentists have one thing in commonpatients.But that may be about to change.The same week as the editorial appeared, the chief executive of the Sussex Partnership NHS Trust ordered staff not to refer to people receiving medical care as patients but as clients.This not only demonstrates a misunderstanding of our roles but also devalues both practitioners and those that we care for.Patients are not simply clients or users of health services.Patients are those receiving care, who are given time, are listened to and treated with sympathy, understanding and expertise.There is something special about the term patient, and although to give a precise dictionary definition is difficult, it is well understood by those who deliver the care.How we are titled may well, as the editorial states, be of little consequence; far more important is how we refer to, and perceive, those in our care.
Lack of immunodominance in the T cell response to herpes simplex virus glycoprotein D after administration of infectious virus.
Authors: K Yamashita, E Heber-Katz
Journal: The Journal of Experimental Medicine (1989)

Glycoprotein D (gD) of HSV has been shown to be a potent immunogen. To analyze the T cell antigenic determinants on gD, a series of 28 overlapping 20-mer peptides that span the extracellular portion of gD-1 were examined for their ability to stimulate T cells from rgD-1 or infectious HSV-1-primed H-2d mice in vitro. rgD-1-primed cells responded exclusively to peptide 241-260, the immunodominant determinant of gD in H-2d mice. In contrast, infectious HSV-primed T cells were shown to respond to 17 (and up to 22) of 28 synthetic gD peptides. These results indicate an extensive diversity in the T cell repertoire to gD in H-2d mice with T cells directed to a broad array of peptide determinants being recruited during the acute phase of an HSV infection.