tbuckley/cabot-search huggingface dataset:
Tumor Necrosis Factor <b>Sustains the Generalized Lymphoproliferative Disorder (</b> <i>gld</i> <b>) Phenotype</b>
Authors: Heinrich Körner, Erika Cretney, Patricia Wilhelm, Janice M. Kelly, Martin Röllinghoff, Jonathon D. Sedgwick, Mark J. Smyth
Journal: The Journal of Experimental Medicine (2000)

Tumor necrosis factor (TNF) and Fas ligand (FasL) play major roles in the homeostasis of the peripheral immune system. This becomes dramatically obvious in the absence of a functional FasL. Mice with such a deficiency develop a profound lymphadenopathy, splenomegaly, hypergammaglobulinemia, and strain-dependent systemic autoimmune disease, and succumb to premature death. It is consequently termed generalized lymphoproliferative disorder (gld). By contrast, TNF deficiency alone does not result in a striking phenotype. Thus, we sought to determine what role TNF might play in contributing to the gld phenotype by creating C57BL/6.gld.TNF−/− mice. Contrary to the expected outcome, mice deficient for both FasL and TNF had a substantially milder gld phenotype with regard to mortality, lymphoaccumulation, germinal center formation, and hypergammaglobulinemia. To confirm these data in a strain highly permissive for the phenotype, C3H/HeJ.gld and C3H.HeJ.lpr mice were treated with a TNF-specific monoclonal antibody. This transient neutralization of TNF also resulted in a significantly attenuated lymphoproliferative phenotype. We conclude that TNF is necessary for the full manifestation of the lymphoproliferative disorder, in particular playing a critical role in lymphoaccumulation. Most importantly, absence of TNF protects gld mice against premature death.
Urinary tract infections and lupus erythematosus
Authors: C Hidalgo-Tenorio
Journal: Annals of the Rheumatic Diseases (2004)

Infections are one of the main causes of morbidity and mortality in patients with systemic lupus erythematosus.To analyse urinary tract infection (UTI) risk factors in lupus patients; the influence of these factors on disease activity, organ damage, and disease development; the type and prevalence of UTI; and the micro-organisms involved.86 control subjects and 81 lupus patients were studied prospectively over a 12 month period and examined on five occasions. Epidemiological data and information on urinary symptoms, disease activity (SLEDAI), and organ damage (SLICC/ACR) data were collected. Autoantibodies, complement levels, urine culture, and antibiogram were determined; urological studies were also carried out. SPPS 10.0 and STATA 6.0. were used for statistical analysis.The prevalence of UTI in lupus patients was 36%. Lupus influences the onset of UTI (p = 0.001), regardless of other variables. UTI risk factors in lupus patients were age (p = 0.002), previous cases of UTI (p = 0.0001), antinuclear antibodies (ANA) >1/80 IU/ml (p = 0.022), thrombocytopenia (p = 0.02), and admission to hospital due to UTI (p = 0.002). Leucopenia (p = 0.09) and the weekly administration of methotrexate (p = 0.06) had a bearing on the onset of UTI; disease development (p = 0.99), lupus activity (p = 0.32), and organ damage (p = 0.36) do not. The uropathogen most frequently isolated was E coli (60%).Lupus patients are likely to have UTI, usually manifesting in the lower tract. They are community acquired, basically caused by E coli, and favoured by age, previous UTI, admissions to hospital due to UTI, thrombopenia, ANA, leucopenia, and methotrexate treatments.
Randomized Controlled Clinical Effectiveness Trial of Cognitive Behavior Therapy Compared With Treatment As Usual for Persistent Insomnia in Patients With Cancer
Authors: Colin A. Espie, Leanne Fleming, James Cassidy, Leslie Samuel, Lynne M. Taylor, Craig A. White, Neil J. Douglas, Heather M. Engleman, Heidi-Louise Kelly, James Paul
Journal: Journal of Clinical Oncology (2008)

Purpose Persistent insomnia is a common complaint in cancer survivors, but is seldom satisfactorily addressed. The adaptation to cancer care of a validated, cost-effective intervention may offer a practicable solution. The aim of this study was to investigate the clinical effectiveness of protocol-driven cognitive behavior therapy (CBT) for insomnia, delivered by oncology nurses. Patients and Methods Randomized, controlled, pragmatic, two-center trial of CBT versus treatment as usual (TAU) in 150 patients (103 females; mean age, 61 years.) who had completed active therapy for breast, prostate, colorectal, or gynecological cancer. The study conformed to CONSORT guidelines. Primary outcomes were sleep diary measures at baseline, post-treatment, and 6-month follow-up. Actigraphic sleep, health-related quality of life (QOL), psychopathology, and fatigue were secondary measures. CBT comprised five, small group sessions across consecutive weeks, after a manualized protocol. TAU represented normal clinical practice; the appropriate control for a clinical effectiveness study. Results CBT was associated with mean reductions in wakefulness of 55 minutes per night compared with no change in TAU. These outcomes were sustained 6 months after treatment. Standardized relative effect sizes were large for complaints of difficulty initiating sleep, waking from sleep during the night, and for sleep efficiency (percentage of time in bed spent asleep). CBT was associated with moderate to large effect sizes for five of seven QOL outcomes, including significant reduction in daytime fatigue. There was no significant interaction effect between any of these outcomes and baseline demographic, clinical, or sleep characteristics. Conclusion CBT for insomnia may be both clinically effective and feasible to deliver in real world practice.
Rapid Evolution by Positive Darwinian Selection in the Extracellular Domain of the Abundant Lymphocyte Protein CD45 in Primates
Authors: L. C. Filip
Journal: Molecular Biology and Evolution (2004)

CD45, encoded by PTPRC in humans, is the most abundantly expressed protein on the surface of many lymphocytes. We investigated whether the extracellular region of CD45 was under positive selection in Old World primates, and whether there was differential selection across this region, particularly on exons that were involved in alternative splicing and those that were not alternatively spliced. The results show extraordinarily strong and consistent positive Darwinian selection on the extracellular part of CD45 throughout the evolution of Old World monkeys, apes and humans. Positive selection is concentrated in exons 9 and 14, which code for the previously neglected linker and fibronectin III domains. These exons have a high rate of evolution at nonsynonymous sites that is roughly twice as high as that of the intronic rate in this gene. In contrast, alternatively spliced exons 4-6, which code for the variable domains, are under weaker positive selection and are evolving more slowly than the intronic rate. These data provide a striking example of positive selection in a well-known gene that should provide an impetus for further functional studies to elucidate its species-specific function.
When gout goes to the heart: does gout equal a cardiovascular disease risk factor?
Authors: Jasvinder A Singh
Journal: Annals of the Rheumatic Diseases (2015)

Cardiovascular disease is among the leading causes of mortality in the world1 and its prevalence is rising over time.2 Inflammatory disorders such as rheumatoid arthritis and others are commonly associated with a higher risk and an earlier onset of cardiovascular disease. This increased risk may be mediated at least partially by non-traditional cardiovascular risk factors (inflammation and other disease activity factors), in addition to the traditional cardiovascular risk factors.3 ,4

In a study by Clarson et al, 5 the authors found that gout was a risk factor in women for incident coronary heart disease, any vascular event and peripheral vascular disease, but not cerebrovascular disease. The cardiovascular risk associated with gout was lower in men. The study used the Clinical Practice Research Database (CPRD) that includes 3.5 million people in the UK from general practices, stated by the authors to be representative of the general population with gout. The authors compared 8386 patients with gout with 39 766 non-gout patients. Despite the strengths of this study, including a large sample size, exclusion of patients with previously known heart disease and adjustment for important covariates, the study's findings must be interpreted in the light of two important limitations. First, the diagnoses of gout and most cardiac outcomes were not validated, but obtained from primary care records, which are likely to lead to some misclassification. Second, from an epidemiologic perspective, some people with disease may not seek care despite having access to healthcare due to either low/intermittent disease activity or personal health beliefs; also, there may be surveillance or detection bias because patients with gout may be more likely to visit primary care physicians than those who are healthy or do not have gout. Thus, the study's findings may be generally applicable to the UK population, but one may …
Dimerization and Ubiquitin Mediated Recruitment of A20, a Complex Deubiquitinating Enzyme
Authors: Timothy T. Lu, Michio Onizawa, Gianna E. Hammer, Emre E. Turer, Qian Yin, Ermelinda Damko, Alexander Agelidis, Nataliya Shifrin, Rommel Advincula, Julio Barrera, Barbara A. Malynn, Hao Wu, Averil Ma
Journal: Immunity (2013)
Neutrophils released from the bone marrow by granulocyte colony‐stimulating factor sequester in lung microvessels but are slow to migrate
Authors: S.F. van Eeden, E. Lawrence, Y. Sato, Y. Kitagawa, J.C. Hogg
Journal: European Respiratory Journal (2000)

Inflammatory mediators such as granulocyte colony-stimulating factor (G-CSF) release polymorphonuclear leukocytes (PMNL) from the bone marrow. This growth factor is used to promote the host response to infection but its effect on the behaviour of leukocytes at the inflammatory site is unclear. This study examined the sequestration and migration of PMNL released from the bone marrow by G-CSF in a model of streptococcal pneumonia. Eight hours following the administration of either human G-CSF (n=6) or saline (n=3) in rabbits, a focal Streptococcus pneumoniae pneumonia was induced and the animals were followed for 2 h. The thymidine analogue 5'-bromo-2'-deoxyuridine (BrdU) was used to label PMNL (PMNL(BrdU)) in the marrow and as a marker of PMNL newly released by the bone marrow. The PMNL(BrdU) in the lung and blood were identified using immunohistochemistry. G-CSF pretreatment elevated the circulating PMNL (3.6+/-0.4 (mean+/-SEM) to 8.3+/-1X10(9) x L(-1), p<0.05) and PMNL(BrdU) (5.4+/-2.1 to 12.5+/-3.1%, p<0.05) counts at 8 h with little further increase caused by the subsequent 2 h pneumonia. These counts did not change in the control group. Morphometric studies of the lung showed that the total number of PMNL sequestered in lung capillaries were increased in the G-CSF group and the percentage of the these PMNL that were BrdU-labelled, was higher than in circulating blood (p<0.05). In the G-CSF group, only 11.2+/-2.6% of the PMNL that migrated into the airspaces were PMNL(BrdU) compared to 50.8+/-8% PMNL(BrdU) in the pulmonary capillaries. In vitro studies showed PMNL(BrdU) released from the bone marrow by G-CSF are less deformable than unlabelled circulating PMNL (p<0.01). It is concluded that granulocyte colony-stimulating factor treatment causes the marrow to release polymorphonuclear leukocytes that preferentially sequester in lung microvessels but are slow to migrate out of the vascular space into the airspace at the pneumonic site.
Is FDG PET a Better Imaging Tool Than Somatostatin Receptor Scintigraphy in Patients With Relapsing Multiple Myeloma?
Authors: Esther G.M. de Waal, Riemer H.J.A. Slart, Edo Vellenga
Journal: Clinical Nuclear Medicine (2012)

Osseous involvement defined by lytic bone lesions is shown by skeletal survey in multiple myeloma (MM). This technique has limitations because it detects only lesions with more than 30% trabecular bone loss. In addition, lesions persist after chemotherapy, thereby limiting its usefulness at relapsing disease. Alternative techniques to detect new bone lesions are somatostatin receptor scintigraphy (SRS) and 18F-fluordeoxyglucose (FDG) PET so far predominantly studied in patients with newly diagnosed MM. Malignant plasma cells can have a high expression of somatostatin receptors and an elevated metabolic activity. Therefore, these techniques might be useful in patients with relapsing MM because they are not hampered by preexisting skeletal defects. The purpose of this study was to demonstrate which technique is most optimal to detect skeletal lesions in patients with relapsing MM.In patients with relapsing MM (n = 21), 3 separate methods were used (skeletal survey, SRS, and FDG PET) for detecting new skeletal lesions.Of all patients, 55% had new lesions on the skeletal survey [mean (SD), 1.45 (1.76); range, 0-5], 52% had new SRS lesions [mean (SD), 1.43 (0.38); range, 0-5], and 71% demonstrated new lesions on the FDG PET-scan [mean (SD), 4.05 (0.9); range, 0-12]. The lesions on skeletal survey and SRS corresponded with FDG PET. The number of lesions was higher with the FDG PET versus that with SRS (P = 0.01) and with FDG PET versus that with skeletal survey (P = 0.01).The results demonstrate that FDG PET is more valuable than skeletal survey and SRS to detect disease activity in relapsing MM.
Hypoxia Enhances the Phosphorylation and Cytotoxicity of Ganciclovir and Zidovudine in Kaposi's Sarcoma-Associated Herpesvirus–Infected Cells
Authors: David A. Davis, Kathleen E. Singer, Irene P. Reynolds, Muzammel Haque, Robert Yarchoan
Journal: Cancer Research (2007)

Abstract Primary effusion lymphoma (PEL) is a rare B-cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV). PEL is poorly responsive to standard cytotoxic chemotherapy and portends a poor survival. Consequently, new effective treatment options are urgently needed. It is known that KSHV encodes two lytic genes, ORF36 (phosphotransferase) and KSHV ORF21 (thymidine kinase), which can phosphorylate ganciclovir and azidothymidine, respectively. Here, we have explored whether these genes can be used as therapeutic targets for PEL. PEL arises in pleural spaces and other effusions that provide a hypoxic environment. Based on Northern blot analysis, exposure of PEL cells to hypoxia up-regulated the expression of both ORF36 and ORF21. Using a newly developed nonradioactive reverse-phase high-performance liquid chromatography/mass spectrometry method to separate and quantify the phosphorylated forms of ganciclovir and azidothymidine, we found that PEL cells exposed to hypoxia produced increased amounts of the toxic triphosphates of these drugs. Moreover, we found that hypoxia increased the cell toxicity of ganciclovir and azidothymidine in PEL cells but had no significant effect on the herpesvirus-negative cell line CA46. These findings may have clinical applicability in the development of effective therapies for PEL or other KSHV-related malignancies. [Cancer Res 2007;67(14):7003–10]
Effects of diuretic treatment and of dietary sodium on renal binding of 3H-metolazone.
Authors: Z F Chen, D A Vaughn, K Beaumont, D D Fanestil
Journal: Journal of the American Society of Nephrology (1990)

We report a series of experiments designed to determine if agents and conditions that have been reported to alter sodium reabsorption, Na-K-ATPase activity or cellular structure in the rat distal nephron might also regulate the density or affinity of binding of 3H-metolazone to the putative thiazide receptor in the distal nephron. Experimental conditions selected for study were acute (60-min) and chronic hydrochlorothiazide (HCTZ), acute acetazolamide, acute and chronic furosemide, and 14 days of varied intake of dietary sodium. The density of the binding of 3H-metolazone was increased 47% by acute HCTZ (P less than 0.001) and 39% (P less than 0.001) by acute furosemide. In contrast, acute acetazolamide produced no change in binding despite eliciting a dramatic diuresis. Chronic HCTZ (5 days) and chronic furosemide (7 days) increased binding of 3H-metolazone by 46% (P less than 0.001) and by 101% (P less than 0.001), respectively. Variation of dietary sodium intake over a range that allowed normal growth of the animal and that produced urinary excretion of Na varying from 0.28 to 2.62 mEq/100 g/day failed to alter the density of binding of 3H-metolazone. These studies are the first indication that the density of the thiazide receptor is regulated by a variety of both acute and chronic conditions that have previously been associated with changes in transport, ultrastructure or Na-K-ATPase activity in the distal nephron.(ABSTRACT TRUNCATED AT 250 WORDS)
Phase III Study of Gemcitabine and Cisplatin With or Without Aprinocarsen, a Protein Kinase C-Alpha Antisense Oligonucleotide, in Patients With Advanced-Stage Non–Small-Cell Lung Cancer
Authors: Luis Paz-Ares, Jean-Yves Douillard, Piotr Koralewski, Christian Manegold, Egbert F. Smit, José Miguel Reyes, Gee-Chen Chang, William J. John, Patrick M. Peterson, Coleman K. Obasaju, Michael Lahn, David R. Gandara
Journal: Journal of Clinical Oncology (2006)

Purpose To determine whether aprinocarsen, an antisense oligonucleotide directed against protein kinase C-alpha, when added to the chemotherapy regimen of gemcitabine and cisplatin improved survival in patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with previously untreated stage IIIB/IV NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly assigned to either a control arm of gemcitabine 1,250 mg/m 2 on days 1 and 8 and cisplatin 80 mg/m 2 on day 1, or experimental arms consisting of the identical chemotherapy plus aprinocarsen 2 mg/kg/d as continuous infusion for 14 days, starting on either day 1 or 3 days before chemotherapy. Cycles were repeated every 21 days. Results A total of 670 patients were randomly assigned between the control (n = 328) and experimental arms (n = 342). Due to the results from another phase III study of aprinocarsen in NSCLC, further enrollment was stopped, and the study was terminated early. The median number of cycles was four on the control arm and three on the combined experimental arms. Median overall survival was not different between the two groups (control, 10.4 months [95% CI, 8.6 to 12.2]; experimental, 10.0 months [95% CI, 8.4 to 10.8]; P = .613; hazard ratio = 1.05 [95% CI, 0.88 to 1.25]). Response rates (control arm, 35.0%; experimental arms, 28.9%; P = .124) and other time-to-event measures were not significantly different. Grade 3 and 4 toxicities were significantly increased for thrombocytopenia (P &lt; .0001), epistaxis, and thrombosis/embolism in the experimental arms. Conclusion Adding aprinocarsen to gemcitabine and cisplatin regimen did not enhance survival and other efficacy measures in patients with advanced NSCLC.
Suppression of bile acid synthesis, but not of hepatic cholesterol 7α-hydroxylase expression, by obstructive cholestasis in humans
Authors: Marco Bertolotti, Lucia Carulli, Mauro Concari, Pietro Martella, Paola Loria, Enrico Tagliafico, Sergio Ferrari, Marina Del Puppo, Barbara Amati, Emma De Fabiani, Maurizio Crestani, Claudio Amorotti, Antonio Manenti, Francesca Carubbi, Adriano Pinetti, Nicola Carulli
Journal: Hepatology (2001)

Regulation of bile acid synthesis, a key determinant of cholesterol homeostasis, is still incompletely understood. To elucidate the feedback control exerted on bile acid biosynthesis in humans with obstructive cholestasis, 16 patients with bile duct obstruction were studied. In vivo 7α–hydroxylation, reflecting bile acid synthesis, was assayed in 13 of them by tritium release analysis. Serum 27–hydroxycholesterol was determined by gas chromatography–mass spectrometry. In a subgroup, hepatic cholesterol 7α–hydroxylase mRNA was assayed by real–time polymerase chain reaction (PCR), enzyme activity was determined by isotope incorporation, and microsomal cholesterol content was assayed by gas chromatography-mass spectrometry. Age–matched control subjects were studied in parallel. Hydroxylation rates were lower in cholestatic patients (108 ± 33 mg of cholesterol per day, mean ± SEM; controls: 297 ± 40 mg/d; P &lt; .01). The reduction was proportional to the severity of cholestasis, and synthetic rates were normalized in 4 subjects restudied after resolution of biliary obstruction. Consistent findings were obtained by analysis of serum 7α–hydroxycholesterol levels. On the other hand, hepatic cholesterol 7α–hydroxylase mRNA, microsomal enzyme activity, and cholesterol content tended to be increased in cholestasis. Finally, serum 27–hydroxycholesterol levels were slightly reduced in cholestatic subjects and were not related with the severity of the disease. Suppression of in vivo bile acid synthesis with no corresponding reduction in tissue 7α–hydroxylase expression and activity is consistent with nontranscriptional, posttranslational levels of regulation; these may play a role in the feedback control of bile acid synthesis in particular conditions. Alteration of the alternate biosynthetic pathway seems unlikely according to the present data.
Some Observations on Biological Effects of Deuterium, with Special Reference to Effects on Neoplastic Processes&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Joseph J. Katz, Henry L. Crespi, Robert J. Hasterlik, John F. Thomson, Asher J. Finkel
Journal: JNCI Journal of the National Cancer Institute (1957)

Journal Article Some Observations on Biological Effects of Deuterium, with Special Reference to Effects on Neoplastic Processes Get access Joseph J. Katz, Joseph J. Katz Argonne National Laboratory, Lemont, Illinois, and Argonne Cancer Research Hospital, Chicago, Illinois Search for other works by this author on: Oxford Academic PubMed Google Scholar Henry L. Crespi, Henry L. Crespi Argonne National Laboratory, Lemont, Illinois, and Argonne Cancer Research Hospital, Chicago, Illinois Search for other works by this author on: Oxford Academic PubMed Google Scholar Robert J. Hasterlik, Robert J. Hasterlik Argonne National Laboratory, Lemont, Illinois, and Argonne Cancer Research Hospital, Chicago, Illinois Search for other works by this author on: Oxford Academic PubMed Google Scholar John F. Thomson, John F. Thomson Argonne National Laboratory, Lemont, Illinois, and Argonne Cancer Research Hospital, Chicago, Illinois Search for other works by this author on: Oxford Academic PubMed Google Scholar Asher J. Finkel Asher J. Finkel Argonne National Laboratory, Lemont, Illinois, and Argonne Cancer Research Hospital, Chicago, Illinois Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 18, Issue 5, May 1957, Pages 641–659, https://doi.org/10.1093/jnci/18.5.641 Published: 01 May 1957 Article history Received: 14 January 1957 Published: 01 May 1957
CELLULAR IMMUNITY IN VACCINIA INFECTION OF MICE
Authors: Martin S. Hirsch, André J. Nahmias, Frederick A. Murphy, Joel H. Kramer
Journal: The Journal of Experimental Medicine (1968)

Rabbit anti-mouse thymocyte serum suppressed host cell-mediated responsiveness to intravenously administered vaccinia virus, thereby augmenting the morbidity and mortality of this infection. It did not affect either humoral antibody or interferon production in response to vaccinia virus. No effects were noted on primary or secondary immunity to intracerebral virus inoculation.