tbuckley/cabot-search huggingface dataset:
Burkitt's cells can be triggered by teleocidin to secrete interferon-γ
Authors: David Benjamin, Dan P. Hartmann, Leonard S. Bazar, Robert J. Jacobson
Journal: American Journal of Hematology (1986)

Abstract The secretion of interferon (IFN)‐γ by T lymphocytes is mediated by the synthesis of interleukin 2 (IL‐2) and the availability of IL‐2 receptors. Since some Burkitt's lymphoma lines express Tac antigen and can be triggered to secrete IL‐2 following activation with the new tumor promoter teleocidin, we addressed the question of whether the induction of IL‐2 by B lymphocytes is accompanied by the induction of IFN‐γ. IFN‐γ has not been detected in any of the 25 cell lines studied, and following stimulation with teleocidin, we triggered the synthesis of IFN‐γ in JLP(C), a pre‐Burkitt's cell line. The mechanism of IFN‐γ secretion by B lymphocytes is not clear. Our findings demonstrate that the synthesis of IL‐2 by B cells is not accompanied by IFN‐γ and suggest that the synthesis of IFN‐γ is not mediated by IL‐2 or IL‐1 or B‐cell growth factor. Neutralization studies have shown that IFN‐γ secretion is not accompanied by the induction of IFN‐α or IFN‐β. Our data imply that B cells can be triggered to secrete IFN‐γ under certain circumstances. Whether similar function occurs in vivo is not known.
CREB in the Pathophysiology of Cancer: Implications for Targeting Transcription Factors for Cancer Therapy
Authors: Kathleen M. Sakamoto, David A. Frank
Journal: Clinical Cancer Research (2009)

Transcription factors are key regulators of the pattern of gene expression in a cell and directly control central processes such as proliferation, survival, self-renewal, and invasion. Given this critical role, the function of transcription factors is normally regulated closely, often through transient phosphorylation. Although transcription factors are not often directly modified by mutations in cancer cells, they frequently become activated constitutively through mutations affecting "upstream" pathways. By continually driving the expression of key target genes, these oncogenic transcription factors play a central role in tumor pathogenesis. One such transcription factor is the cAMP-regulatory element-binding protein (CREB), which can be activated through phosphorylation by a number of kinases, including Akt, p90Rsk, protein kinase A, and calcium/calmodulin-dependent kinases and regulates genes whose deregulated expression promotes oncogenesis, including cyclins, Bcl-2 family members, and Egr-1. CREB is overexpressed and constitutively phosphorylated in a number of forms of human cancer, including acute myeloid leukemia (AML) and non-small cell lung cancer, and appears to play a direct role in disease pathogenesis and prognosis. Although transcription factors have not been a central focus of drug development, recent advances suggest that CREB and other such proteins may be worthwhile targets for cancer therapy.
Chymase-like Angiotensin II–Generating Activity in End-Stage Human Autosomal Dominant Polycystic Kidney Disease
Authors: Elizabeth A. McPherson, Zaiming Luo, Rachel A. Brown, Linda S. LeBard, Christopher C. Corless, Robert C. Speth, Susan P. Bagby
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Autosomal dominant polycystic kidney disease (ADPKD) is characterized by exuberant inflammation and fibrosis, a process believed to contribute to progressive loss of normal renal function. Despite early-onset hypertension and intrarenal renin/angiotensin II (AngII) activation, angiotensin-converting enzyme (ACE) inhibition does not consistently confer renal protection in ADPKD. The hypothesis was that mast cells within the inflammatory interstitium release chymase, an enzyme capable of efficient conversion of AngI to AngII, providing an ACE-independent route of AngII generation. End-stage ADPKD renal tissue extracts and cyst fluids were assayed for time-dependent, chymostatin-inhibitable conversion of 125I-AngI to 125I-AngII under conditions of ACE and aminopeptidase inhibition by means of HPLC. Thirteen of 14 ADPKD kidney extracts exhibited chymase-like AngII-generating capacity; calculated initial reaction rates averaged 3.9 ± 2.9 fmol AngII/min/μg protein with a mean maximal conversion of 55% ± 30% of added substrate. AngII-generating activity was both protein and substrate dependent. All five cyst fluid samples were negative. Chymase-like activity was detectable in only three of six non-ADPKD kidney extracts. Immunoreactive chymase protein was present in/around mast cells within the fibrotic renal interstitium in all samples. Findings demonstrate for the first time the presence of mast cells, mast cell–associated immunoreactive chymase protein, and chymase-like AngII generating capacity in ADPKD cystic kidneys. Results support the potential for ACE-independent AngII generation and for mast cell–initiated inflammatory processes in ADPKD, each with therapeutic implications for ADPKD renal progression.
Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning for Advanced Chronic Lymphocytic Leukemia
Authors: Mohamed L. Sorror, Michael B. Maris, Brenda M. Sandmaier, Barry E. Storer, Monic J. Stuart, Ute Hegenbart, Edward Agura, Thomas R. Chauncey, Jose Leis, Michael Pulsipher, Peter McSweeney, Jerald P. Radich, Christopher Bredeson, Benedetto Bruno, Amelia Langston, Michael R. Loken, Haifa Al-Ali, Karl G. Blume, Rainer Storb, David G. Maloney
Journal: Journal of Clinical Oncology (2005)

Patients with chemotherapy-refractory chronic lymphocytic leukemia (CLL) have a short life expectancy. The aim of this study was to analyze the outcome of patients with advanced CLL when treated with nonmyeloablative conditioning and hematopoietic cell transplantation (HCT).Sixty-four patients diagnosed with advanced CLL were treated with nonmyeloablative conditioning (2 Gy total-body irradiation with [n = 53] or without [n = 11] fludarabine) and HCT from related (n = 44) or unrelated (n = 20) donors. An adapted form of the Charlson comorbidity index was used to assess pretransplantation comorbidities.Sixty-one of 64 patients had sustained engraftment, whereas three patients rejected their grafts. The incidences of grades 2, 3, and 4 acute and chronic graft-versus-host disease were 39%, 14%, 2%, and 50%, respectively. Three patients who underwent transplantation in complete remission (CR) remained in CR. The overall response rate among 61 patients with measurable disease was 67% (50% CR), whereas 5% had stable disease. All patients with morphologic CR who were tested by polymerase chain reaction (n = 11) achieved negative molecular results, and one of these patients subsequently experienced disease relapse. The 2-year incidence of relapse/progression was 26%, whereas the 2-year relapse and nonrelapse mortalities were 18% and 22%, respectively. Two-year rates of overall and disease-free survivals were 60% and 52%, respectively. Unrelated HCT resulted in higher CR and lower relapse rates than related HCT, suggesting more effective graft-versus-leukemia activity.CLL is susceptible to graft-versus-leukemia effects, and allogeneic HCT after nonmyeloablative conditioning might prolong median survival for patients with advanced CLL.
Current Perspective on the Role of Apoptosis in Atherothrombotic Disease
Authors: Ziad Mallat, Alain Tedgui
Journal: Circulation Research (2001)

Abstract —Thrombus formation on a disrupted atherosclerotic plaque is a threatening event that leads to vessel occlusion and acute ischemia. In this current perspective, we present evidence for apoptosis as a major determinant of the thrombogenicity of the plaque lipid core and a potential contributor to plaque erosion and associated thrombosis. Moreover, apoptosis may directly affect blood thrombogenicity through the release of apoptotic cells and microparticles into the bloodstream.
Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: Lessons from the HALT-C trial
Authors: Gregory T. Everson, John C. Hoefs, Leonard B. Seeff, Herbert L. Bonkovsky, Deepa Naishadham, Mitchell L. Shiffman, Jeffrey A. Kahn, Anna S. F. Lok, Adrian M. Di Bisceglie, William M. Lee, Jules L. Dienstag, Marc G. Ghany, Chihiro Morishima
Journal: Hepatology (2006)

In patients with chronic hepatitis C, advanced fibrosis and cirrhosis are associated with lower rates of sustained virologic response (SVR) to interferon (IFN)-based therapy. In this study, we assessed virologic response to retreatment with peginterferon alfa-2a and ribavirin (RBV), as a function of the baseline fibrosis score (Ishak staging) and platelet count, in 1,046 patients enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. All patients had failed prior treatment with IFN or peginterferon ± RBV and had Ishak fibrosis scores ≥ 3. Four groups of patients with increasingly severe liver disease were compared: (A) bridging fibrosis (Ishak 3 and 4) with platelet counts >125,000/mm3 (n = 559); (B) bridging fibrosis with platelet counts ≤125,000/mm3 (n = 96); (C) cirrhosis (Ishak 5 and 6) with platelet counts >125,000/mm3 (n = 198); and (D) cirrhosis with platelet counts ≤125,000/mm3 (n = 193). SVR rates were 23%, 17%, 10%, and 9% in groups A, B, C, and D, respectively (P < .0001 for trend). Reduction in SVR as a function of increasingly severe disease was independent of age, percent African American, HCV genotype, HCV level, and type of prior therapy. Dose reduction lowered SVR frequencies, but to a lesser extent than disease severity. By logistic regression, cirrhosis (P < .0001) was the major determinant that impaired virologic response, independent of dose reduction or platelet count. In conclusion, disease severity is a major independent determinant of rate of SVR in patients with advanced chronic hepatitis C. New strategies are needed to optimize antiviral therapy in these "difficult-to-cure" patients. (HEPATOLOGY 2006;44:1675–1684.)
An Antagonist of Monocyte Chemoattractant Protein 1 (MCP-1) Inhibits Arthritis in the MRL-<i>lpr</i> Mouse Model
Authors: Jiang-Hong Gong, Leslie G. Ratkay, J. Douglas Waterfield, Ian Clark-Lewis
Journal: The Journal of Experimental Medicine (1997)

An antagonist of human monocyte chemoattractant protein (MCP)-1, which consists of MCP-1(9-76), had previously been characterized and shown to inhibit MCP-1 activity in vitro. To test the hypothesis that, by inhibiting endogenous MCP-1, the antagonist has antiinflammatory activity in vivo, we examined its effect in the MRL-lpr mouse model of arthritis. This strain spontaneously develops a chronic inflammatory arthritis that is similar to human rheumatoid arthritis. Daily injection of the antagonist, MCP-1(9-76), prevented the onset of arthritis as monitored by measuring joint swelling and by histopathological evaluation of the joints. In contrast, controls treated with native MCP-1 had enhanced arthritis symptoms, indicating that the inhibitory effect is specific to the antagonist. In experiments where the antagonist was given only after the disease had already developed, there was a marked reduction in symptoms and histopathology, although individuals varied in the magnitude of the response. The mechanism of inhibition of disease is not known, although the results suggest that it could be more complex than the competitive inhibition of ligand binding that is observed in vitro. The demonstration of the beneficial effects of an MCP-1 antagonist in arthritis suggests that chemokine receptor antagonists could have therapeutic application in inflammatory diseases.
Survival of patients with multiple primary malignancies: a study of 783 patients with gastrointestinal stromal tumor
Authors: R.K. Pandurengan, A.G. Dumont, D.M. Araujo, J.A. Ludwig, V. Ravi, S. Patel, J. Garber, R.S. Benjamin, S.S. Strom, J.C. Trent
Journal: Annals of Oncology (2010)
Molecular Determinants of Altered Ca <sup>2+</sup> Handling in Human Chronic Atrial Fibrillation
Authors: Ali El-Armouche, Peter Boknik, Thomas Eschenhagen, Lucie Carrier, Michael Knaut, Ursula Ravens, Dobromir Dobrev
Journal: Circulation (2006)

Background— Abnormal Ca 2+ handling may contribute to impaired atrial contractility and arrhythmogenesis in human chronic atrial fibrillation (cAF). Here, we assessed the phosphorylation levels of key proteins involved in altered Ca 2+ handling and contractility in cAF patients. Methods and Results— Total and phosphorylation levels of Ca 2+ -handling and myofilament proteins were analyzed by Western blotting in right atrial appendages of 49 patients in sinus rhythm and 52 cAF patients. We found a higher total activity of type 1 (PP1) and type 2A phosphatases in cAF, which was associated with inhomogeneous changes of protein phosphorylation in the cellular compartments, ie, lower protein kinase A (PKA) phosphorylation of myosin binding protein-C (Ser-282 site) at the thick myofilaments but preserved PKA phosphorylation of troponin I at the thin myofilaments and enhanced PKA (Ser-16 site) and Ca 2+ -calmodulin protein kinase (Thr-17 site) phosphorylation of phospholamban. PP1 activity at sarcoplasmic reticulum is controlled by inhibitor-1 (I-1), which blocks PP1 in its PKA-phosphorylated form only. In cAF, the ratio of Thr-35–phosphorylated to total I-1 was 10-fold higher, which suggests that the enhanced phosphorylation of phospholamban may result from a stronger PP1 inhibition by PKA-hyperphosphorylated (activated) I-1. Conclusions— Altered Ca 2+ handling in cAF is associated with impaired phosphorylation of myosin binding protein-C, which may contribute to the contractile dysfunction after cardioversion. The hyperphosphorylation of phospholamban probably results from enhanced inhibition of sarcoplasmic PP1 by hyperphosphorylated I-1 and may reinforce the leakiness of ryanodine channels in cAF. Restoration of sarcoplasmic reticulum–associated PP1 function may represent a new therapeutic option for treatment of atrial fibrillation.
Increased superoxide anion production by immunologically activated and chemically elicited macrophages
Authors: Jr RB Johnston, CA Godzik, ZA Cohn
Journal: The Journal of Experimental Medicine (1978)

We studied the capacity of cultured mouse peritoneal macrophages to generate superoxide anion (O(2-)), the initial product of conversion of oxygen to microbicidal species, during phagocytosis of opsonized zymosan or upon contact with the membrane-active agent phorbel myristate acetate (PMA). Macrophages from mice infected with Bacille Calmette-Guerin (BCG) or injected intraperitoneally with thioglycollate broth or endotoxin, released up to 12 times more O(2-) than did resident peritoneal macrophages, depending upon the cell type and whether the stimulus was zymosan or PMA. There was little if any O(2-) release from resting (unstimulated) macrophages. The density of cells on culture dishes was an important variable since crowding of the dish markedly reduced the efficiency of O(2-) production. The enhanced O(2-) release of chemically elicited and infection-activated macrophages was noted after stimulation with a wide range of concentrations of PMA and zymosan, at all time points studied (up to 120 min), and with cells maintained for 140 rain to 16 days in culture. The O(2-) response of resident cells improved twofold to zymosan and ninefold to PMA during the first 3 days in culture. The capacity to release O~ appears to be limited to actively phagocytic cell types: murine macrophage-like tumor lines and cultured human monocytes released O(2-) when stimulated by PMA or zymosan, fibroblast and endothelial lines and embryo-derived cells did not. Activity of superoxide dismutase, which removes O(2-), was not detectable in culture supernates of any cell type, and thus, differences in detectable O(2-) could not be attributed to variations in the release of this enzyme. We conclude that the phagocytosis- associated respiratory burst is significantly enhanced in mononuclear phagocytes obtained ai~r chemical inflammation or BCG infection. Increased capacity to generate O(2-) and other oxygen radicals during phagocytosis could contribute to the improved microbicidal and tumoricidal activity of activated macrophages.
Polymyositis associated with ulcerative colitis.
Authors: S Chugh, J B Dilawari, I M Sawhney, N Dang, B D Radotra, Y K Chawla
Journal: Gut (1993)

An elderly woman with chronic ulcerative colitis who developed proximal muscle weakness, increased serum creatine phosphokinase activity, and histological and electromyographic abnormalities characteristic of polymyositis is described. Treatment with corticosteroids and 5-acetylsalicylic acid was followed by a remission in bowel symptoms, improvement in muscle power, and reversal of electromyographic changes. An autoimmune link between the two disorders seems likely.
TRANSFER OF DELAYED HYPERSENSITIVITY TO DIPHTHERIA TOXIN IN MAN
Authors: H. S. Lawrence, A. M. Pappenheimer
Journal: The Journal of Experimental Medicine (1956)

Simultaneous transfer of delayed hypersensitivity to diphtheria toxin and to tuberculin has been accomplished in eight consecutive instances in man using extracts from washed leucocytes taken from the peripheral blood of tuberculin-positive, Schick-negative donors who were highly sensitive (i.e., pseudoreactors) to purified diphtheria toxin and toxoid. The leucocyte extracts used for transfer contained no detectable antitoxin. The recipient subjects were Schick-positive (<0.001 unit antitoxin per ml. serum) and tuberculin-negative at the time of transfer. All the recipients remained Schick-positive for at least 2 weeks following transfer and in every case their serum contained less than 0.001 units antitoxin at the time when they exhibited maximal skin reactivity to toxoid. Evidence is presented which indicates that the transfer factor may be released from leucocyte suspensions under mild conditions in which most of the cells appear to remain morphologically intact. Four adult Schick-positive subjects have been sensitized to diphtheria toxoid by intradermal injection of a few micrograms of purified toxoid in the form of a washed toxoid-antitoxin precipitate. Two of these sensitized individuals showed severe delayed skin reactions specifically directed against diphtheria toxin (or toxoid) at a time when their serum antitoxin level was less than 0.001 units/ml.
Obstructive Nephropathy in the Mouse
Authors: VOLKER VIELHAUER, HANS-JOACHIM ANDERS, MATTHIAS MACK, JOSEF CIHAK, FRANK STRUTZ, MANFRED STANGASSINGER, BRUNO LUCKOW, HERMANN-JOSEF GRO[Combining Diaeresis]NE, DETLEF SCHLO[Combining Diaeresis]NDORFF
Journal: Journal of the American Society of Nephrology (2001)

Abstract. The infiltration of leukocytes plays a major role in mediating tubulointerstitial inflammation and fibrosis in chronic renal disease. CC chemokines participate in leukocyte migration and infiltration into inflamed renal tissue. Because CC chemokine-directed leukocyte migration is mediated by target cell expression of a group of CC chemokine receptors, this study examined the expression of CC chemokines and their receptors during initiation of tubulointerstitial fibrosis after unilateral ureteral obstruction in C57BL/6 mice. Obstructed kidneys developed hydronephrosis, tubular cell damage, interstitial inflammation, and fibrosis. From days 2 to 10, a progressive interstitial influx of F4/80+ macrophages and CD3+ lymphocytes occurred (macrophages, 4-fold; lymphocytes, 20-fold at day 10, compared with contralateral control kidneys). In parallel, the number of activated fibroblast-specific protein 1+ fibroblasts and interstitial collagen IV accumulation increased from days 2 to 10. The mRNA expression of CC chemokines (predominantly monocyte chemoattractant protein-1 [MCP-1]/CCL2, RANTES/CCL5) and their receptors CCR1, CCR2, CCR5 increased progressively from days 2 to 10. By in situ hybridization, a prominent interstitial mRNA expression of MCP-1 and RANTES and their receptors CCR2 and CCR5 localized to interstitial mononuclear cell infiltrates. MCP-1 and RANTES expression was also seen in tubular epithelial cells. Fluorescence-activated cell sorter analysis of single-cell suspensions from obstructed kidneys revealed a prominent expression of CCR2 and CCR5 by infiltrating macrophages, whereas most lymphocytes expressed CCR5 only. These data demonstrate an increased expression of MCP-1/CCL2 and RANTES/CCL5 at sites of tubulointerstitial damage and progressive fibrosis during unilateral ureteral obstruction that correlates with simultaneous accumulation of interstitial macrophages and T lymphocytes expressing the respective surface receptors CCR2 and CCR5. The chemokine receptor—mediated leukocyte influx into the tubulointerstitium could offer a new potential target for therapeutic intervention in progressive renal tubulointerstitial fibrosis.
IgA anti-endomysium antibody. A new immunological marker of dermatitis herpetiformis and coeliac disease
Authors: T.P. CHORZELSKI, E.H. BEUTNER, J. SULEJ, H. TCHORZEWSKA, S. JABLONSKA, V. KUMAR, A. KAPUSCINSKA
Journal: British Journal of Dermatology (1984)

The recently described IgA anti‐endomysial antibodies (IgA‐EmA) are directed against the intermyofibril substance of the smooth muscle, which may correspond either to a reticulin‐like structure or a surface component of smooth muscle fibrils. These antibodies occurred in about 80% of sera of thirty‐eight patients with dermatitis herpetiformis (DH), in about 70% of twenty‐eight patients with coeliac disease and in about 20% of nine patients with other enteropathies. IgG class anti‐gliadin antibodies (AGA) also occur in each of these diseases. Both antibodies were detected on monkey oesophagus by immunofluorescence. The IgA‐EmA could not be detected in 122 control sera from patients with other gut or skin diseases, including fifteen cases with ulcerative colitis and fifteen cases with linear IgA bullous dermatosis (LABD). The presence and the titre of IgA‐EmA and AGA paralleled the severity of the jejunal changes in patients with coeliac disease.
Burn-Wound Infection With Phycomycetes Requiring Amputation of Hand
Authors: F. Daniel Foley
Journal: JAMA (1968)

A phycomycotic burn-wound infection of the fingers occurred in a severely burned patient. Extensive ischemic necrosis developed due to the tendency for this group of fungi to invade vessels, and amputation of the hand was required. An increase in fungal colonization of the burn wound has also been noted coincident with the use of topical chemotherapy.
Is Aberrant Nucleic Acid Methylation Related to Malignant Transformation?1
Authors: R. Raymond Gantt
Journal: JNCI Journal of the National Cancer Institute (1974)

Journal Article Is Aberrant Nucleic Acid Methylation Related to Malignant Transformation? Get access R. Raymond Gantt R. Raymond Gantt 2Tissue Culture Section, Laboratory of Biology, National Cancer Institute, National Institutes of Health, Public Health Service, U.S. Department of Health, Education, and Welfare, Bethesda, Md. 20014. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 53, Issue 5, November 1974, Pages 1505–1508, https://doi.org/10.1093/jnci/53.5.1505 Published: 01 November 1974
Some Things Medical Ethics Is Not
Authors: K. Danner Clouser
Journal: JAMA (1973)

Medical ethics has frequently been identified or coupled with other areas of study: history of medicine, family and community medicine, religion, counseling, and psychiatry. Such identifications are incorrect and are due to certain misconceptions. Aside from guiding those contemplating programs in medical ethics and alerting those already involved, the purpose of this article is to clear the ground for a positive definition and description of medical ethics.