tbuckley/cabot-search huggingface dataset:
Interleukin 2-induced proliferation of murine natural killer cells in vivo.
Authors: C A Biron, H A Young, M T Kasaian
Journal: The Journal of Experimental Medicine (1990)

The growth factor, IL-2, was administered to mice to evaluate the in vivo responsiveness of NK cells to this factor. The immediate effects of this factor on NK cells were determined by examining cytotoxic activity at 18-24 h after a single treatment with rIL-2. Although moderate doses of rIL-2 (3 x 10(4) U) could be shown to activate existing cytotoxic cells on a per cell basis, higher doses (10(6) U) were required to elicit blast size killer cells. The elicited killer cells were characterized as NK cells by the following criteria: (a) they were readily induced in athymic mice; (b) they mediated killing of NK-sensitive YAC-1 target cells but not NK-resistant P815 target cells; and (c) they expressed the NK cell determinants asialo ganglio-n-tetraosylceramide and NK1.1, but not the T cell determinants CD3, L3T4, or Lyt-2. High-dose IL-2 treatment induced not only the appearance of blast size NK cells, but also the expansion of this population. After treatments, the number of large granular lymphocytes and the number of NK1.1+ cells were increased at least twofold. Analysis of DNA content within the NK1.1+ cell subset demonstrated that IL-2 preferentially drove NK1.1+ cells into S and G2/M phases of the cell cycle. The in vivo elicited blast lymphocytes were examined by Northern blot analysis and in situ hybridization for expression of the IL-2-R p55 alpha chain gene. As previous work from this laboratory has demonstrated that NK cells proliferate in response to IFNs and IFN inducers in vivo, blast lymphocytes were also prepared after IFN treatments. The NK cells were not induced to express detectable levels of the alpha chain gene under any of the conditions examined. Blast T lymphocytes, isolated at times during viral infections when IL-2 production can be demonstrated in vitro, were induced to transcribe the alpha chain gene. Treatments of euthymic mice with high-dose IL-2 also induced transcription of the alpha chain gene in 41% of the non-B blast lymphocytes, but only background percentages of the NK1.1+ cells expressed the alpha chain gene. Transcription of the alpha chain gene was not induced in the NK cell-abundant athymic mice after IL-2 treatment. All of the in vivo elicited blast lymphocytes were induced to express IFN-gamma. Taken together, these data definitively demonstrate that IL-2 can induce NK cell proliferation and expansion in vivo. They also show that exposure to IL-2 in vivo, either by administration or endogenous production of the factor, induces transcription of the IL-2-R alpha chain gene in populations of cells containing T cell subsets. The results suggest, however, that murine NK cells are not induced to express high levels of the alpha chain gene in response to IL-2 in vivo.
Long noncoding RNA in liver diseases
Authors: Kenji Takahashi, Irene Yan, Hiroaki Haga, Tushar Patel
Journal: Hepatology (2014)

The identification of the presence of large RNA transcripts that do not code for proteins but that may have biological functions has provided an important new perspective in gene regulation. These long noncoding RNAs (lncRNAs) are being increasingly recognized to contribute to many biological processes through diverse mechanisms. The roles of these emerging genes are being recognized across kingdoms. These findings are profoundly altering our understanding of disease pathobiology and leading to the emergence of new biological concepts underlying human diseases. Strategies for the discovery and characterization of lncRNAs are highlighted. Several lncRNAs have been described in liver disease, and in liver cancers in particular. Their molecular mechanisms of action, function, and contributions to disease pathophysiology are reviewed. LncRNA genes associated with liver diseases have potential roles as biomarkers of disease diagnosis, prognosis, or therapeutic response as well as direct targets for therapeutic intervention. Conclusion : The emerging knowledge in this rapidly advancing field offers promise for new fundamental knowledge and clinical applications that will be relevant for human liver diseases. (Hepatology 2014;60:744–753)
VLA‐4 antagonists: Potent inhibitors of lymphocyte migration
Authors: Ginger X. Yang, William K. Hagmann
Journal: Medicinal Research Reviews (2003)

Abstract Circulating lymphocytes normally migrate through extravascular spaces in relatively low numbers as important members of the immunosurveillance process. That is until signals are received by endothelial cells that there is an underlying infection or inflammatory condition. These vascular surface cells in turn overexpress and present ligands to circulating lymphocyte adhesion molecules. Upon encountering this higher density of ligands, lymphocytes, which had been leisurely rolling along the vascular surface, now become more firmly attached, change shape, and migrate through tight junctions to the sites of infection or inflammation. If the initiating events are not resolved and the condition becomes chronic, there can be a sustained extravasation of lymphocytes that can exacerbate the inflammatory condition, which in turn will continue to recruit more inflammatory cells resulting in unwanted tissue destruction. It is for the attenuation of this cycle of sustained inflammatory cell recruitment that very late activating antigen‐4 (VLA‐4) antagonists are being developed. Most lymphocytes, except neutrophils, express VLA‐4 on their surface and they interact with endothelial vascular cell adhesion molecule‐1 (VCAM‐1). It is this interaction that VLA‐4 antagonists are intended to disrupt, thus, putting an end to the cycle of chronic inflammation, which is the hallmark of many diseases. This review will provide an update of VLA‐4 antagonists that have appeared since early 2001 and will discuss some of the issues, both positive and negative, that may be encountered in their development. © 2003 Wiley Periodicals, Inc. Med Res Rev, 23, No. 3, 369‐392, 2003
ANTIGEN-SPECIFIC CELLS IN MOUSE BONE MARROW
Authors: Harold C. Miller, Gustavo Cudkowicz
Journal: The Journal of Experimental Medicine (1971)

Quantitative and qualitative changes of mouse bone marrow cells were studied by limiting dilution assays 2-3.5 months after immunization of donors with sheep erythrocytes or unrelated antigens (Salmonella typhimurium, horse and chicken erythrocytes). Irradiated (C3H x C57BL/10)F(1) mice were reconstituted with an excess of nonprimed thymocytes and small graded numbers of primed bone marrow cells. Direct and indirect plaque-forming cells (PFC) were induced by secondary stimulation with SRBC and enumerated on the 9th day after cell transplantation. Marrow precursors of PFC (P-PFC) cooperated with thymocytes in the production of direct and indirect PFC after SRBC priming. The limiting dilution plots, which were not compatible with predictions of the Poisson model before immunization, changed and conformed to this model afterwards, as if the population of P-PFC had become functionally more homogeneous. The concentration of marrow P-PFC increased up to the 3rd month after priming, and decreased during the 4th, varying over two logarithms of nucleated marrow cells. The fluctuation was simultaneous and of the same order of magnitude for precursors of direct and indirect PFC, which were class restricted. A third effect of immunization was detected at 3.5 months: individual precursor units generated 3-4 times more direct and indirect PFC than at earlier intervals. Qualitative and quantitative changes of marrow P-PFC participating in anti-sheep responses were specific, since antigens unrelated to SRBC failed to induce them. The data suggested that marrow-derived cells were the major carriers of immunologic memory, but that they functioned in cooperation with thymus-derived inducer cells during secondary anti-sheep responses.
Integrative Genomic Analysis of Temozolomide Resistance in Diffuse Large B-Cell Lymphoma
Authors: Violetta V. Leshchenko, Pei-Yu Kuo, Zewei Jiang, Venu K. Thirukonda, Samir Parekh
Journal: Clinical Cancer Research (2013)

Despite advances, there is an urgent need for effective therapeutics for relapsed diffuse large B-cell lymphoma, particularly in elderly patients and primary central nervous system (CNS) lymphoma. Temozolomide (TMZ), an oral DNA-alkylating agent routinely used in the therapy of glioblastoma multiforme, is active in patients with primary CNS lymphoma but the response rates are low. The mechanisms contributing to TMZ resistance are unknown.We undertook an unbiased and genome-wide approach to understand the genomic methylation and gene expression profiling differences associated with TMZ resistance in diffuse large B-cell lymphoma cell lines and identify mechanisms to overcome TMZ resistance.TMZ was cytotoxic in a subset of diffuse large B-cell lymphoma cell lines, independent of MGMT promoter methylation or protein expression. Using Connectivity Map (CMAP), we identified several compounds capable of reversing the gene expression signature associated with TMZ resistance. The demethylating agent decitabine (DAC) is identified by CMAP as capable of reprogramming gene expression to overcome TMZ resistance. Treatment with DAC led to increased expression of SMAD1, a transcription factor involved in TGF-β/bone morphogenetic protein (BMP) signaling, previously shown to be epigenetically silenced in resistant diffuse large B-cell lymphoma. In vitro and in vivo treatment with a combination of DAC and TMZ had greater antilymphoma activity than either drug alone, with complete responses in TMZ-resistant diffuse large B-cell lymphoma murine xenograft models.Integrative genome-wide methylation and gene expression analysis identified novel genes associated with TMZ resistance and demonstrate potent synergy between DAC and TMZ. The evidence from cell line and murine experiments supports prospective investigation of TMZ in combination with demethylating agents in diffuse large B-cell lymphoma.
Immunosuppression and other risk factors for early and late non-Hodgkin lymphoma after kidney transplantation
Authors: Marina T. van Leeuwen, Andrew E. Grulich, Angela C. Webster, Margaret R.E. McCredie, John H. Stewart, Stephen P. McDonald, Janaki Amin, John M. Kaldor, Jeremy R. Chapman, Claire M. Vajdic
Journal: Blood (2009)
The Angiotensin II–Dependent Association of Jak2 and c-Src Requires the N-Terminus of Jak2 and the SH2 Domain of c-Src
Authors: Peter P. Sayeski, M. Showkat Ali, Kim Hawks, Stuart J. Frank, Kenneth E. Bernstein
Journal: Circulation Research (1999)

Abstract —The binding of angiotensin II (Ang II) to AT 1 is known to increase the kinase activity of several nonreceptor tyrosine kinases including Jak2 and c-Src. In the present study, we demonstrate that treatment of vascular smooth muscle cells with Ang II results in a rapid and transient association of Jak2 and c-Src. This association is dependent on a catalytically active Jak2 kinase, because it is blocked both by pharmacological means and by the inability of a catalytically inactive Jak2 to associate with c-Src. c-Src bound tyrosine phosphorylated Jak2 but was unable to bind an equal amount of unphosphorylated Jak2 protein, indicating that the SH2 domain of c-Src mediates this association. In vivo studies indicated that c-Src binds the N-terminus of Jak2 as expression of a Jak2 molecule lacking the initial 240 amino acids, including 16 tyrosines, and was unable to bind c-Src. Lastly, using transiently transfected COS-7 cells, we found that Ang II treatment induced an association between c-Src and wild-type Jak2 but not between c-Src and the Jak2 molecule that lacks the initial 240 amino acids. Thus, our data suggest that in addition to increasing the kinase activities Jak2 and c-Src, treatment of cells with Ang II results in the physical association of Jak2 and c-Src; an association that is mediated by the SH2 domain of c-Src and the N-terminus of Jak2.
AN EXPLANATION FOR AND EXPERIMENTAL CORRECTION OF THE ABNORMAL WATER DIURESIS IN CIRRHOSIS *
Authors: Harold P. Schedl, Frederic C. Bartter
Journal: Journal of Clinical Investigation (1960)

It is well established that certain patients with hepatic cirrhosis show impaired water diuresis fol- lowing water loads (1).With this limitation in free water excretion, hyponatremia may develop on average water intakes.It has been asserted and denied that antidiuretic hormone (ADH), secreted in excess or inadequately inactivated, is responsi- ble for the water retention (2, 3).In this study the role of antidiuretic hormone in cirrhosis is re- examined.The results do not support the concept that it plays the primary role in the retention of water.Since free water is presumably produced by the reabsorption of sodium (4, 5), these patients pre- sent a paradox in that they show almost quantita- tive reabsorption of filtered sodium.The paradox could be resolved by postulating that proximal tubular sodium reabsorption in these subjects is so great as to allow little sodium to pass to the distal site where free water is generated.It fol- lows a) that the defect should be corrected by de- livery of proximal tubular fluid into the distal tubules and b) that normal subjects should show a similar "defect" correctable by the same process when depleted of sodium.In the present study these propositions are examined. SUBJECTS AND METHODSEight normal subjects and 8 patients with cirrhosis were maintained in an air-conditioned environment in a metabolic ward.They were fasted, and fluids were with- held after 6:00 p.m. the day prior to the tests.On the day of the study they were weighed at 7:30 a.m. and water loads (20 ml per kg) were drunk in approximately 1 hour, or infused intravenously in 1 to 1.5 hours.Over- night urine specimens were collected from 10:30 p.m. on the previous day to 7:30 a.m. on the day of the study to provide an estimate of the state of hydration of the sub-
Clustering of Cardiovascular Risk Factors Associated With the Insulin Resistance Syndrome
Authors: M. Elisabetta Zanolin, Flavia Tosi, Giacomo Zoppini, Roberto Castello, Giovanna Spiazzi, Romolo Dorizzi, Michele Muggeo, Paolo Moghetti
Journal: Diabetes Care (2006)

OBJECTIVE—Hyperinsulinemia is often associated with several metabolic abnormalities and increased blood pressure, which are risk factors for cardiovascular disease. It has been hypothesized that insulin resistance may underlie all these features. However, recent data suggest that some links between insulin resistance and these alterations may be indirect. The aim of our study was to further investigate this issue in a sample of young hyperandrogenic women, who often show insulin resistance and other metabolic abnormalities typical of the insulin resistance syndrome. RESEARCH DESIGN AND METHODS—We tested the hypothesis of a single factor underlying these features by principal component analysis, which should recognize one component if a single mechanism explains this association. The analysis was carried out in a sample of 255 young nondiabetic hyperandrogenic women. Variables selected for this analysis included the basic features of the insulin resistance syndrome and some endocrine parameters related to hyperandrogenism. RESULTS—Principal component analysis identified four separate factors, explaining 64.5% of the total variance in the data: the first included fasting and postchallenge insulin levels, BMI, triglycerides, HDL cholesterol, and uric acid; the second, BMI, blood pressure, and serum free testosterone; the third, fasting plasma glucose, postchallenge glucose and insulin levels, serum triglycerides, and free testosterone; and the fourth, postchallenge plasma insulin, serum free testosterone, and gonadotropin-releasing hormone agonist–stimulated 17-hydroxyprogesterone. CONCLUSIONS—These results support the hypothesis of multiple determinants in the clustering of abnormalities in the so-called insulin resistance syndrome.
Survival of Irradiated Hybrid Female Mice Inoculated With Maternal Bone Marrow: A Preliminary Report
Authors: Delta E. Uphoff
Journal: JNCI Journal of the National Cancer Institute (1973)

In 2 genetically different, lethally irradiated, hybrid recipients of bone marrow transplants, the inoculation of maternal marrow resulted in a significantly better overall survival of female mice than was obtained with normal parental-strain marrow from donors not previously exposed to paternal alloantigens. Although the mortality from the graft-versus-host reaction was reduced by the use of maternal marrow, the genetic disparity between the maternal and paternal strains of the hybrid cross still controlled the severity of the reaction.
Quantitative computed tomography: emphysema and airway wall thickness by sex, age and smoking
Authors: T. B. Grydeland, A. Dirksen, H. O. Coxson, S. G. Pillai, S. Sharma, G. E. Eide, A. Gulsvik, P. S. Bakke
Journal: European Respiratory Journal (2009)

We investigated how quantitative high-resolution computed tomography (HRCT) measures of emphysema and airway wall thickness (AWT) vary with sex, age and smoking history. We included 463 chronic obstructive pulmonary disease (COPD) cases and 431 controls. All included subjects were current or ex-smokers aged > or = 40 yrs, and all underwent spirometry and HRCT examination. The HRCT images were quantitatively assessed, providing indices on lung density and airway dimensions. The median (25-75th percentile) %LAA950 (% low-attenuation area < -950 HU) was 8.9 (3-19) and 4.7 (1-16) in male and female COPD cases, respectively, and 0.71 (0.3-1.6) and 0.32 (0.1-0.8) in male and female controls, respectively. %LAA950 was higher in ex-smokers and increased with increasing age and with increasing number of pack-years. The mean+/-SD standardised AWT was 0.504+/-0.030 and 0.474+/-0.031 in male and female COPD cases, respectively, and 0.488+/-0.028 and 0.463+/-0.025 in male and female controls, respectively. AWT decreased with increasing age in cases, and increased with the degree of current smoking in all subjects. We found significant differences in quantitative HRCT measures of emphysema and AWT between varying sex, age and smoking groups of both control and COPD subjects.
Lung bullae, bronchiectasis, and Hashimoto's disease associated with ulcerative colitis treated by colectomy.
Authors: J M Shneerson
Journal: Thorax (1981)

Naftidrofuryl enhances oxidative phosphorylation and might therefore be expected to improve exercise tolerance and breathlessness in advanced chronic bronchitis. This hypothesis was tested in a four-week placebo-controlled trial in 11 bronchitic patients. Seven patients completed the study. There was no evidence of any benefit from naftidrofuryl either subjectively or after a 12-minute walking test.
Thrombocytopenia in Experimental Trypanosomiasis
Authors: Charles E. Davis, Robert S. Robbins, Richard D. Weller, Abraham I. Braude
Journal: Journal of Clinical Investigation (1974)

The effect of experimental trypanosomiasis on coagulation was studied because a patient in this hospital with Rhodesian trypanosomiasis developed thrombocytopenia with disseminated intravascular coagulation. Rats injected intraperitoneally with this strain of Trypanosoma rhodesiense consistently developed trypanosomiasis and severe thrombocytopenia without changes in hematocrit or concentration of fibrinogen or fibrin split products. At the time of 50% mortality (4-5 days) mean platelet counts per cubic millimeter of infected rats were 18,000+/-9,000 (+/-2 SEM) compared to 1,091,000+/-128,000 in uninfected controls. In vitro, concentrated trypanosomes and trypanosomefree supernates of disrupted organisms added to normal rat, rabbit, or human blood produced platelet aggregation within 30 min. This platelet aggregation was not blocked by inhibitors of ADP, kinins, or early or late components of complement. In vivo thrombocytopenia also occurred in infected rabbits congenitally deficient in C6 and in infected, splenectomized rats. Although the aggregating substance obtained from disrupted trypanosomes is heat-labile, it is active in the presence of complement inhibitors, suggesting that this trypanosomal product may be a protein enzyme or toxin. Since the phenomenon is independent of immune complexes, complement, ADP, and kinins, it appears to represent a new mechanism of microbial injury of platelets and the induction of thrombocytopenia.
American Society of Clinical Oncology/American Society of Hematology Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin in Adult Patients With Cancer
Authors: J. Douglas Rizzo, Melissa Brouwers, Patricia Hurley, Jerome Seidenfeld, Murat O. Arcasoy, Jerry L. Spivak, Charles L. Bennett, Julia Bohlius, Darren Evanchuk, Matthew J. Goode, Ann A. Jakubowski, David H. Regan, Mark R. Somerfield
Journal: Journal of Clinical Oncology (2010)

To update American Society of Clinical Oncology/American Society of Hematology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer.An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched.The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews.For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels ≥ 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.
Role of Mast Cells in Progressive Renal Diseases
Authors: Stephen R. Holdsworth, Shaun A. Summers
Journal: Journal of the American Society of Nephrology (2008)

Advances in understanding mast cell biology reveal their diverse functional capacity well beyond already established roles in host defense against parasites and allergic disease. Mast cells can initiate, amplify, and direct innate and adaptive immune responses. They also modulate inflammation and regulate immunity. Mast cells potentially induce tissue repair and direct fibrosis; however, they also play other roles in tissue remodeling and repair. Various activation and differentiating signals result in a diverse range of functional phenotypes called "mast cell heterogeneity." Mast cells are significant participants in chronic progressive kidney disease, and their presence is associated with function loss and fibrosis. This suggests a potential role in the fibrotic process, which may involve mast cell activation of local renin-angiotensin systems. Experimental animal studies suggest, however, they do not directly cause renal fibrosis but rather spark inflammation. Evidence for both pro- and anti-inflammatory roles in nephritis is emerging.