tbuckley/cabot-search huggingface dataset:
Cytoplasmic Accumulation of Sequestosome 1 (p62) Is a Predictor of Biochemical Recurrence, Rapid Tumor Cell Proliferation, and Genomic Instability in Prostate Cancer
Authors: Christoph Burdelski, Viktor Reiswich, Claudia Hube-Magg, Martina Kluth, Sarah Minner, Christina Koop, Markus Graefen, Hans Heinzer, Maria Christina Tsourlakis, Corinna Wittmer, Hartwig Huland, Ronald Simon, Thorsten Schlomm, Guido Sauter, Stefan Steurer
Journal: Clinical Cancer Research (2015)

Sequestosome 1 (p62) is a multifunctional adapter protein accumulating in autophagy-defective cells.To evaluate the clinical impact and relationship with key genomic alterations in prostate cancer, p62 protein levels were analyzed by immunohistochemistry on a tissue microarray containing 12,427 prostate cancers. Data on ERG status and deletions of PTEN, 3p13, 5q21, and 6q15 were available from earlier studies.p62 immunostaining was absent in benign prostatic glands but present in 73% of 7,822 interpretable prostate cancers. Strong cytoplasmic p62 staining was tightly linked to high Gleason grade, advanced pathologic tumor (pT) stage, positive nodal status, positive resection margin, and early PSA recurrence (P < 0.0001 each). Increased levels of p62 were significantly linked to TMPRSS2-ERG fusions, both by FISH and immunohistochemical analysis (P < 0.0001 each). For example, moderate or strong p62 immunostaining was seen in 28.5% of cancers with TMPRSS2-ERG fusion detected by FISH and in 23.1% of cancers without such rearrangements (P < 0.0001). Strong p62 staining was significantly linked to the presence of all tested deletions, including PTEN (P < 0.0001), 6q15 (P < 0.0001), 5q21 (P = 0.0002), 3p13 (P = 0.0088), and 6q15 (P < 0.0001), suggesting a link between p62 accumulation and loss of genomic stability. The prognostic role of p62 protein accumulation was striking and independent of Gleason grade, pT stage, pN stage, surgical margin status, and preoperative PSA, regardless of whether preoperative or postoperative parameters were used for modeling.Our study identifies cytoplasmic accumulation of p62 as a strong predictor of an adverse prognostic behavior of prostate cancer independently from established clinicopathologic findings.
Targeted Gene Disruption Demonstrates That P-Selectin Glycoprotein Ligand 1 (Psgl-1) Is Required for P-Selectin–Mediated but Not E-Selectin–Mediated Neutrophil Rolling and Migration
Authors: Jing Yang, Takako Hirata, Kevin Croce, Glenn Merrill-Skoloff, Boris Tchernychev, Eric Williams, Robert Flaumenhaft, Barbara C. Furie, Bruce Furie
Journal: The Journal of Experimental Medicine (1999)

P-selectin glycoprotein ligand 1 (PSGL-1) is a mucin-like selectin counterreceptor that binds to P-selectin, E-selectin, and L-selectin. To determine its physiological role in cell adhesion as a mediator of leukocyte rolling and migration during inflammation, we prepared mice genetically deficient in PSGL-1 by targeted disruption of the PSGL-1 gene. The homozygous PSGL-1-deficient mouse was viable and fertile. The blood neutrophil count was modestly elevated. There was no evidence of spontaneous development of skin ulcerations or infections. Leukocyte infiltration in the chemical peritonitis model was significantly delayed. Leukocyte rolling in vivo, studied by intravital microscopy in postcapillary venules of the cremaster muscle, was markedly decreased 30 min after trauma in the PSGL-1-deficient mouse. In contrast, leukocyte rolling 2 h after tumor necrosis factor alpha stimulation was only modestly reduced, but blocking antibodies to E-selectin infused into the PSGL-1-deficient mouse almost completely eliminated leukocyte rolling. These results indicate that PSGL-1 is required for the early inflammatory responses but not for E-selectin-mediated responses. These kinetics are consistent with a model in which PSGL-1 is the predominant neutrophil P-selectin ligand but is not a required counterreceptor for E-selectin under in vivo physiological conditions.
Constitutively Active K-cyclin/cdk6 Kinase in Kaposi Sarcoma–Associated Herpesvirus–Infected Cells
Authors: Rukiyah Van Dross, Shan Yao, Shaheena Asad, Grant Westlake, Deborah J. Mays, Laura Barquero, Stephanie Duell, Jennifer A. Pietenpol, Philip J. Browning
Journal: JNCI Journal of the National Cancer Institute (2005)

Kaposi sarcoma-associated human herpesvirus (KSHV) encodes K-cyclin, a homologue of D-type cellular cyclins, which binds cyclin-dependent kinases to phosphorylate various substrates. K-cyclin/cdk phosphorylates a subset of substrates normally targeted by cyclins D, E, and A. We used cells naturally infected with KSHV to further characterize the biochemical features of K-cyclin.We used immunoprecipitation with K-cyclin antibodies to examine the association of K-cyclin with cdk2, cdk6, p21Cip1, and p27Kip1 proteins in BC3 cells. We separated populations of BC3 cells enriched in cells in G1, S, or G2/M phases by elutriation and measured K-cyclin protein and the kinase activity of K-cyclin/cdk6 complexes. The half-life of K-cyclin and cyclin D2 proteins was determined by blocking protein synthesis with cycloheximide and measuring proteins in cell lysates by western blot analysis. We fused the entire K-cyclin sequence to the carboxyl-terminal sequence of cellular cyclin D that contains the PEST degradation sequence to produce K-cyclin/D2 and transfected K-cyclin/D2 into K-cyclin-negative cells to investigate the effect of the PEST sequence on K-cyclin's stability.Viral K-cyclin interacted with cyclin-dependent kinases cdk2, cdk4, and cdk6 and with the cyclin/cdk inhibitory proteins p21Cip1 and p27Kip1 in BC3 cell lysates. Unlike D-type cyclins, whose expression is cell cycle dependent, the level of K-cyclin was stable throughout the cell cycle, and the kinase associated with the K-cyclin/cdk6 complex was constitutively active. The half-life of K-cyclin (6.9 hours) was much longer than that of cellular cyclin D2 (0.6 hour) and that of K-cyclin/D2 (0.5 hour), probably because K-cyclin lacks the PEST degradation sequence present in D-type cyclins.The constitutive activation of K-cyclin/cdk complexes in KSHV-infected cells appears to result from the extended half-life of K-cyclin and may explain its role in Kaposi sarcoma.
438. Development of a Myeloid Cell-Binding Adenovirus for the Potential Gene Therapy of Alpha-1 Anti-Trypsin Deficiency
Journal: Molecular Therapy (2013)

Alpha-1 anti-trypsin (A1AT) deficiency lung disease represents an ideal candidate for definitive gene therapy treatment. As the liver is the major locale for A1AT synthesis, the majority of gene therapy approaches have been directed towards induction of functional wild type A1AT within hepatocytes. Despite the diverse range of gene therapy strategies applied, the levels of serum A1AT achieved have not been sufficient to correct the elastase/anti-elastase balance within the lung. To this end, we hypothesized that in vivo gene delivery to pulmonary endothelium could provide A1AT augmentation of Epithelial Lining Fluid (ELF) more effectively than liver-based transduction methods.

To re-target the expression of transgene in the lung, the knob domain of Ad5 has been successfully modified genetically in our lab. We have identified a novel peptide sequence called myeloid binding peptide (MBP) which increases the lung targeting. Based on this we created a recombinant adenovirus expressing A1AT with MBP in the fiber protein (AdMBPA1AT). When we injected this Ad systemically in mice we saw a high expression of the transgene in the serum in comparison to the control Ad expressing A1AT without MBP in the fiber protein. In order to confirm that the AdMBPA1AT localizes to the lung, we analyzed viral copy number using total DNA extracted from the organs of mice by qPCR and the expression of the protein in serum and ELF. Our strategy will test the hypothesis that A1AT deriving from the pulmonary endothelium can augment more effectively ELF A1AT to provide a corrective anti-elastase screen.
The Complex Role of Estrogens in Inflammation
Authors: Rainer H. Straub
Journal: Endocrine Reviews (2007)

There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal models of chronic inflammatory diseases. On the other hand, we realize the immunosupportive role of estrogens in trauma/sepsis and the proinflammatory effects in some chronic autoimmune diseases in humans. This review examines possible causes for this paradox. This review delineates how the effects of estrogens are dependent on criteria such as: 1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses (e.g., T cell inhibited by estrogens vs. activation of B cell); 2) the cell types involved during different phases of the disease; 3) the target organ with its specific microenvironment; 4) timing of 17β-estradiol administration in relation to the disease course (and the reproductive status of a woman); 5) the concentration of estrogens; 6) the variability in expression of estrogen receptor α and β depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens. This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned criteria. It also explains that a uniform concept as to the action of estrogens cannot be found for all inflammatory diseases due to the enormous variable responses of immune and repair systems.
Inhaled Corticosteroids in Patients With Chronic Obstructive Pulmonary Disease
Authors: James Wall
Journal: JAMA (2009)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Characteristics of a Serially Transplanted Mouse Mammary Tumor and Its Tissue-Culture-Adapted Derivative
Authors: Sara C. Rockwell, Robert F. Kallman, Luis Felipe Fajardo
Journal: JNCI Journal of the National Cancer Institute (1972)

The KHJJ tumor line, derived from a primary mammary tumor arising in a BALB/c mouse after implantation of a hyperplastic alveolar nodule, has been maintained for over 100 transplant generations. The 25th generation of this tumor was grown and selected in cell culture, producing a new tumor cell line, EMT6. This new line can be grown and studied either as an animal tumor or a cell culture and allows the in vitro assay of cell survival after the treatment of animal tumors in situ. Retrospective examination of tumor specimens throughout the history of the tumor lines suggests that these tumor lines were derived from 2 morphologically distinct subpopulations of a mixed primary tumor. The morphology, latent period, and transplantation characteristics (assayed by TD50) of the 2 lines throughout their histories of serial transplantation are described. The antigenicity, growth patterns, and cell population kinetics (analyzed by the percent-labeled mitosis technique and model-based computer analysis) are described for both tumors. Characteristics of EMT6 cells in culture are compared with those of cells in the tumor.
Surgical repair of complete proximal hamstring tendon ruptures in water skiers and bull riders: a report of four cases and review of the literature
Authors: J Chakravarthy, N Ramisetty, A Pimpalnerkar, N Mohtadi
Journal: British Journal of Sports Medicine (2005)

Objective: Hamstring strains are one of the most common muscle strains in athletes; however, complete rupture of the proximal hamstring origin is rare and results from significant trauma. The objective of this paper is to present our experience of management of complete ruptures where surgical repair resulted in good results in both acute and delayed cases. Methods: Two water skiers and two bull riders sustained complete rupture of the proximal origin of the hamstring muscles. All underwent repair of the hamstring origin and sciatic nerve neurolysis. A post operative hamstring rehabilitation programme was instituted. Regular follow up was performed at 2, 3, 6, 9, and 12 months. Results: At a minimum final follow up of 12 months all patients had regained functional knee flexion strength with no pain and a near normal range of knee flexion. All four individuals were able to return to their previous line of work and three were able to return to their pre-injury level of sport. Conclusion: Complete rupture of the hamstring origin is a potentially devastating sports injury that has implications affecting the individual’s activities of daily living as well as potential as a sportsperson. Surgical repair restores the distorted anatomy, allows early functional rehabilitation, and avoids the potential debilitating neurological problem of gluteal sciatica.
Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leukemia cells
Authors: Joya Chandra, Jennifer Hackbarth, Son Le, David Loegering, Nancy Bone, Laura M. Bruzek, Ven L. Narayanan, Alex A. Adjei, Neil E. Kay, Ayalew Tefferi, Judith E. Karp, Edward A. Sausville, Scott H. Kaufmann
Journal: Blood (2003)
Chitinase 3–Like 1 Suppresses Injury and Promotes Fibroproliferative Responses in Mammalian Lung Fibrosis
Authors: Yang Zhou, Hong Peng, Huanxing Sun, Xueyan Peng, Chuyan Tang, Ye Gan, Xiaosong Chen, Aditi Mathur, Buqu Hu, Martin D. Slade, Ruth R. Montgomery, Albert C. Shaw, Robert J. Homer, Eric S. White, Chang-Min Lee, Meagan W. Moore, Mridu Gulati, Chun Geun Lee, Jack A. Elias, Erica L. Herzog
Journal: Science Translational Medicine (2014)

Chitinase 3–like 1 protects against lung injury but has a profibrotic role during the repair phase.
Effect of Inspiratory Flow Rate on Respiratory Rate in Intubated Ventilated Patients
Authors: STEPHEN CORNE, DANIEL GILLESPIE, DANIEL ROBERTS, MAGDY YOUNES
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

It has previously been demonstrated that in normal subjects using a volume-cycled ventilator, increasing inspiratory flow rate increases respiratory rate. We undertook the current study to determine (1) whether this effect is also present in patients with respiratory disease and (2) whether the effect is independent of upper airway receptors. Eight ventilator-dependent patients in the intensive care unit were studied. Patients were ventilated in the assist-control mode with the back-up rate set at 0.5 breaths/min to ensure that all breaths were patient-triggered. While tidal volume was held constant, flow was changed from a baseline flow of 60 L/min. Trials involved changing flow to either 30 or 90 L/min. There was a significant decrease in respiratory rate (–3.4 ± 0.6 min− 1, p < 0.001) when flow was decreased from 60 to 30 L/min. There was a significant increase in respiratory rate (2.3 ± 0.8 min− 1, p < 0.05) when flow was increased from 60 to 90 L/min. As a result of the change in respiratory rate, Te (expiratory time) showed a variable response to changes in flow rate, with some patients actually demonstrating a reduced Te with higher flow rates. No patients experienced the increase in Te that would have been predicted without a change in respiratory rate. We conclude that in intubated ventilated patients, spontaneous respiratory rate is sensitive to inspiratory flow rate. This effect appears to be independent of upper airway receptors, since it was observed with a bypassed upper airway. The increase in respiratory rate seen at higher flow rates undermines attempts to increase Te by increasing flow rates. It may also cause a tendency toward respiratory alkalosis.
AIP1 Prevents Graft Arteriosclerosis by Inhibiting Interferon-γ–Dependent Smooth Muscle Cell Proliferation and Intimal Expansion
Authors: Luyang Yu, Lingfeng Qin, Haifeng Zhang, Yun He, Hong Chen, Jordan S. Pober, George Tellides, Wang Min
Journal: Circulation Research (2011)

ASK1-interacting protein-1 (AIP1), a Ras GTPase-activating protein family member, is highly expressed in endothelial cells and vascular smooth musccells (VSMCs). The role of AIP1 in VSMCs and VSMC proliferative disease is not known. We used mouse graft arteriosclerosis models characterized by VSMC accumulation and intimal expansion to determine the function of AIP1. In a single minor histocompatibility antigen (male to female)-dependent aorta transplantation model, AIP1 deletion in the graft augmented neointima formation, an effect reversed in AIP1/interferon-γ receptor (IFN-γR) doubly-deficient aorta donors. In a syngeneic aortic transplantation model in which wild-type or AIP1-knockout mouse aortas were transplanted into IFN-γR-deficient recipients and in which neointima formation was induced by intravenous administration of an adenovirus that encoded a mouse IFN-γ transgene, donor grafts from AIP1-knockout mice enhanced IFN-γ-induced VSMC proliferation and neointima formation. Mechanistically, knockout or knockdown of AIP1 in VSMCs significantly enhanced IFN-γ-induced JAK-STAT signaling and IFN-γ-dependent VSMC migration and proliferation, 2 critical steps in neointima formation. Furthermore, AIP1 specifically bound to JAK2 and inhibited its activity. AIP1 functions as a negative regulator in IFN-γ-induced intimal formation, in part by downregulating IFN-γ-JAK2-STAT1/3-dependent migratory and proliferative signaling in VSMCs.
Heberden oration 1978. Recent studies on the control of joint damage: the contribution of the Strangeways Research Laboratory.
Authors: J T Dingle
Journal: Annals of the Rheumatic Diseases (1979)

Cambridge University, decided that knowledge of chronic arthritis was still so sparse as to need a new research impetus.With the aid of a small group of colleagues he raised the funds and supervised the building of the Cambridge Research Hospital, which after his death in 1926 became known as
Is the pathway of energy metabolism modified in advanced cirrhosis?
Authors: Shanmugasundaram Ganapathy-Kanniappan, Swathi Karthikeyan, Jean-Francois Geschwind, Esteban Mezey
Journal: Journal of Hepatology (2014)

The role of metabolic alterations and adaptations is becoming increasingly evident in the pathogenesis of cirrhosis and hepatocellular carcinoma (HCC) [1–4]. Using a rat model of cirrhosis, Nishikawa et al. [5] demonstrate that early stage cirrhotic hepatocytes switch to glycolysis to meet their energy requirements as a result of a decline in oxidative phosphorylation, but that this mechanism fails in late cirrhosis. Since HCC typically arises in the background of liver cirrhosis [6] and also encompasses a glycolytic phenotype [7], it would be important to determine how this is related to the altered metabolism of cirrhotic hepatocytes.
Myeloid Suppressor Cells Regulate the Lung Environment—Response
Authors: Hannah H. Yan, Michael Pickup, Yanli Pang, Agnieszka E. Gorska, Zhaoyang Li, Anna Chytil, Yipeng Geng, Jerome W. Gray, Harold L. Moses, Li Yang
Journal: Cancer Research (2011)

We appreciate the letter by Bosiljcic and colleagues raising questions about our studies published in Cancer Research, in which we showed that Gr-1+CD11b+ cells alter the premetastatic lung in an inflammatory and proliferative environment, diminish immune protection, and induce aberrant vasculature formation (1).The authors have raised concerns about our use of 4T1 mammary carcinoma cells expressing green fluorescent protein (GFP) in syngeneic Balb/c mice. They showed that mice implanted with 4T1-GFP tumor cells develop circulating anti-GFP antibodies in their plasma, indicating that Balb/c mice mount an immune response against 4T1-GFP cells and tumor phenotype.We understand and appreciate the concerns raised by the authors. We are aware that 4T1-GFP cells cause immune response as a result of the expression of the foreign protein GFP. However, the majority of the data were collected using 4T1 cells. The GFP-expressing 4T1 cells were used only in 2 experiments, in which the differentiation of tumor cells from other cells of the hosting organs was fundamentally important. This will be discussed in detail in the following text. We are sorry that we did not specify in our article wherein 4T1-GFP cells were used, and we apologize for the confusion caused by this. We would like to clarify here: No potential conflicts of interest were disclosed.See the original Letter to the Editor, p. 5050
Antivenom for Critically Ill Children with Neurotoxicity from Scorpion Stings
Authors: Leslie V. Boyer, Andreas A. Theodorou, Robert A. Berg, Joanne Mallie, Ariana Chávez-Méndez, Walter García-Ubbelohde, Stephen Hardiman, Alejandro Alagón
Journal: New England Journal of Medicine (2009)

Clinically significant scorpion envenomation by Centruroides sculpturatus produces a dramatic neuromotor syndrome and respiratory insufficiency that often necessitate intensive supportive care. We hypothesized that a scorpion-specific F(ab')(2) antivenom would promptly resolve clinical symptoms in children with this syndrome.In a randomized, double-blind study, the efficacy of scorpion-specific F(ab')(2) antivenom, as compared with placebo, was assessed in 15 children 6 months to 18 years of age who were admitted to a pediatric intensive care unit with clinically significant signs of scorpion envenomation. The primary end point was the resolution of the clinical syndrome within 4 hours after administration of the study drug. Secondary end points included the total dose of concomitant midazolam for sedation and quantitative plasma venom levels, before and after treatment.The clinical syndrome resolved more rapidly among recipients of the antivenom than among recipients of placebo, with a resolution of symptoms in all eight antivenom recipients versus one of seven placebo recipients within 4 hours after treatment (P=0.001). More midazolam was administered in the placebo recipients than in the antivenom recipients (mean cumulative dose, 4.61 vs. 0.07 mg per kilogram of body weight; P=0.01). Plasma venom concentrations were undetectable in all eight antivenom recipients but in only one placebo recipient 1 hour after treatment (P=0.001).Among critically ill children with neurotoxic effects of scorpion envenomation, intravenous administration of scorpion-specific F(ab')(2) antivenom resolved the clinical syndrome within 4 hours, reduced the need for concomitant sedation with midazolam, and reduced the levels of circulating unbound venom. (ClinicalTrials.gov number, NCT00685230.)