tbuckley/cabot-search huggingface dataset:
Epigenetic Enhancement of Antigen Processing and Presentation Promotes Immune Recognition of Tumors
Authors: A. Francesca Setiadi, Kyla Omilusik, Muriel D. David, Robyn P. Seipp, Jennifer Hartikainen, Rayshad Gopaul, Kyung Bok Choi, Wilfred A. Jefferies
Journal: Cancer Research (2008)

Abstract Histone deacetylase inhibitors (HDACi) have been hailed as a powerful new class of anticancer drugs. The HDACi, trichostatin A (TSA), is thought to interfere with epigenetic control of cell cycle progression in G1 and G2-M phase, resulting in growth arrest, differentiation, or apoptosis. Here, we describe a novel mechanism of action of HDACis in promoting immune responses against tumors. We report that treatment of carcinoma cells with TSA increases the expression of many components of the antigen processing machinery, including TAP-1, TAP-2, LMP-2, and Tapasin. Consistent with this result, we found that treatment of metastatic carcinoma cells with TSA also results in an increase in MHC class I expression on the cell surface that functionally translates into an enhanced susceptibility to killing by antigen-specific CTLs. Finally, we observed that TSA treatment suppresses tumor growth and increases tap-1 promoter activity in TAP-deficient tumor cells in vivo. Intriguingly, this in vivo anti-tumoral effect of TSA is entirely mediated by an increase in immunogenicity of the tumor cells, as it does not occur in immunodeficient mice. These novel insights into the molecular mechanisms controlling tumor immune escape may help revise immunotherapeutic modalities for eradicating cancers. [Cancer Res 2008;68(23):9601–7]
<i>Pten</i> Inactivation Accelerates Oncogenic <i>K-ras</i>–Initiated Tumorigenesis in a Mouse Model of Lung Cancer
Authors: Kentaro Iwanaga, Yanan Yang, Maria Gabriela Raso, Lijiang Ma, Amy E. Hanna, Nishan Thilaganathan, Seyed Moghaddam, Christopher M. Evans, Huaiguang Li, Wei-Wen Cai, Mitsuo Sato, John D. Minna, Hong Wu, Chad J. Creighton, Francesco J. Demayo, Ignacio I. Wistuba, Jonathan M. Kurie
Journal: Cancer Research (2008)

Abstract Phosphatase and tensin homologue deleted from chromosome 10 (Pten) is expressed aberrantly in non–small cell lung cancer cells, but the role of Pten in lung neoplasia has not been fully elucidated. In this study, we used a genetic approach to inactivate Pten in the bronchial epithelium of mice. Although, by itself, Pten inactivation had no discernible effect on bronchial epithelial histology, it accelerated lung tumorigenesis initiated by oncogenic K-ras, causing more rapid lethality than that induced by oncogenic K-ras alone (8 weeks versus 24 weeks of median duration of survival, respectively). Lung tumors arose in K-ras mutant, Pten-deficient mice that rapidly obstructed bronchial lumina and replaced alveolar spaces. Relative to K-ras mutant tumors, the K-ras mutant, Pten-deficient tumors exhibited more advanced histologic severity and more prominent inflammation and vascularity. Thus, Pten inactivation cooperated with oncogenic K-ras in promoting lung tumorigenesis. [Cancer Res 2008;68(4):1119–27]
Randomized Trial of Tamoxifen Versus Combined Tamoxifen and Octreotide LAR Therapy in the Adjuvant Treatment of Early-Stage Breast Cancer in Postmenopausal Women: NCIC CTG MA.14
Authors: Kathleen I. Pritchard, Lois E. Shepherd, Judith-Anne W. Chapman, Brian D. Norris, Jacques Cantin, Paul E. Goss, Susan F. Dent, David Walde, Ted A. Vandenberg, Brian Findlay, Susan E. O'Reilly, Carolyn F. Wilson, Lei Han, Ettie Piura, Timothy J. Whelan, Michael N. Pollak
Journal: Journal of Clinical Oncology (2011)

Somatostatin analogs act directly on breast cancer cells and indirectly on insulin and insulin-like growth factor 1 (IGF-1) levels. This trial was undertaken to assess whether octreotide would lower insulin and IGF-1 levels and reduce risk of breast cancer recurrence.The NCIC CTG MA.14 (NCIC Clinical Trials Group MA.14) trial randomly assigned postmenopausal women to 5 years of tamoxifen 20 mg daily (TAM) or TAM plus 2 years of octreotide 90 mg depot intramuscular injections monthly (TAM-OCT) as adjuvant therapy. The primary end point was event-free survival (EFS). Secondary end points were relapse-free survival (RFS), overall survival (OS), toxicity, and effects of treatment on IGF physiology.Among 667 women with a median follow-up of 7.9 years, 220 events occurred-108 with TAM-OCT and 112 with TAM. Adjusted hazard ratios (HRs; TAM-OCT to TAM) were 0.93 for EFS (95% CI, 0.71 to 1.22; P = .62), 0.84 for RFS (95% CI, 0.59 to 1.18; P = .31), and 0.97 for OS (95% CI, 0.69 to 1.37; P = .86). Among patients with normal baseline gallbladder imaging, cholecystectomy was required in 23.0% of those receiving TAM-OCT but in only 1.4% of those receiving TAM (P < .001). At 4 months, TAM-OCT had significantly (P < .001) lowered IGF-1, IGF binding protein 3, and C-peptide levels. Older age (P = .02), tumor size (P = .001), nodal status (P = .01), high C-peptide levels (P < .001), and higher body mass index (BMI) in models excluding C-peptide (P < .001) were associated with poorer EFS in multivariate analysis.Octreotide-related changes in circulating IGF-1 and C-peptide levels were statistically significant. Octreotide did not add significant clinical benefit. High C-peptide levels (surrogate for insulin secretion rate) and high BMI were associated with poor outcome.
Significance of Necrosis in Grading of Oligodendroglial Neoplasms: A Clinicopathologic and Genetic Study of Newly Diagnosed High-Grade Gliomas
Authors: C. Ryan Miller, Christopher P. Dunham, Bernd W. Scheithauer, Arie Perry
Journal: Journal of Clinical Oncology (2006)

Purpose High-grade gliomas (HGGs; WHO grades 3-4) are highly diverse, with survival times ranging from months to years. WHO 2000 grading criteria for high-grade oligodendroglial neoplasms [anaplastic oligoastrocytoma (AOA) and anaplastic oligodendroglioma (AO)] remain subjective, and the existence of grade 4 variants is controversial. Patients and Methods Overall survival (OS) of 1,093 adult patients with a cerebral HGG newly diagnosed between 1990 and 2005 was analyzed by univariate and multivariate models for significance of the following factors: patient age, surgery type, year of diagnosis, endothelial proliferation, necrosis, oligodendroglial histology, treatment center, and chromosome 1p, 19q, 7p (EGFR), and 10q (PTEN) abnormalities by fluorescence in situ hybridization (FISH). Results Necrosis was a statistically significant predictor of poor OS on univariate and multivariate analyses in AOA but not in AO. Median OS for patients with necrotic AOA (22.8 months) was significantly worse than for patients with non-necrotic AOA (86.9 months; P &lt; .0001) but was better than conventional glioblastomas (9.8 months; P &lt; .0001). In addition to patient age, the following were significant independent prognostic factors (P ≤ .001): grade and surgery type for the entire HGG cohort; modified grade for AOA (3 v 4); and modified grade, 1p/19q codeletion status, and oligodendroglial histology for the 586 HGGs analyzed by FISH. Conclusion Stratification of AOA, but not of pure AO, into grades 3 and 4 on the basis of necrosis is prognostically justified and is more powerful than the current approach. Both routine histology and genetic testing provide independent, prognostically useful information.
Alterations in Central Blood Volume and Cardiac Output Induced by Positive Pressure Breathing and Counteracted by Metaraminol (Aramine)
Authors: E. BRAUNWALD, J. T. BINION, W. L. MORGAN, S. J. SARNOFF, W. Anderson.
Journal: Circulation Research (1957)

High levels of positive pressure breathing in the dog resulted in substantial depression of central blood volume as well as cardiac output and arterial pressure. The administration of metaraminol elevated these lowered values while positive pressure breathing was maintained. The beneficial effects observed are thought to be attributable to this drug's influence on venous and arteriolar tone and myocardial contractility. The mechanism of the circulatory depression produced by positive pressure breathing is discussed.
RETRACTED: Verification of cell viability in bioengineered tissues and organs before clinical transplantation
Authors: Philipp Jungebluth, Johannes C Haag, Mei L Lim, Greg Lemon, Sebastian Sjöqvist, Ylva Gustafsson, Fatemeh Ajalloueian, Irina Gilevich, Oscar E Simonson, Karl H Grinnemo, Matthias Corbascio, Silvia Baiguera, Costantino Del Gaudio, Staffan Strömblad, Paolo Macchiarini
Journal: Biomaterials (2013)
Evolution of the mammalian mitochondrial control region--comparisons of control region sequences between monotreme and therian mammals
Authors: N. J. Gemmell, P. S. Western, J. M. Watson, J. A. Graves
Journal: Molecular Biology and Evolution (1996)

The platypus mitochondrial control region has been cloned and sequenced. Comparative analysis of this sequence with the published control region sequences of several other mammalian species has identified regions of sequence consensus that are conserved throughout the Mammalia. Regions predicted to form thermodynamically stable secondary structures in the platypus are also homologous to such putative structures in other species. In addition to these conserved structures, the platypus mitochondrial control region also contains a number of unusual features, including two regions of repetitive sequence, one of which gives rise to pronounced length variation between animals. Possible functions for the conserved structures and a mechanism for the generation of the control region length variation are proposed with respect to our current understanding of mitochondrial replication and transcription.
Role of Functional Imaging in the Management of Lymphoma
Authors: Bruce D. Cheson
Journal: Journal of Clinical Oncology (2011)

18-F-fluorodeoxyglucose (FDG) -positron emission tomography (PET), and more recently PET/computed tomography (CT), is the most sensitive and specific imaging technique currently available for patients with lymphoma. Nevertheless, despite being increasingly used in pretreatment assessment, midtreatment evaluation of response, post-treatment restaging, and surveillance during follow-up of patients with lymphoma, its impact on clinical outcome in most clinical situations remains to be confirmed. PET/CT provides its greatest clinical benefit in the post-treatment evaluation of Hodgkin's lymphoma and diffuse large B-cell lymphoma; however, the role of metabolic imaging in other indications and in other histologies remains to be demonstrated. Ongoing risk-adapted studies will hopefully provide evidence for clinical improvement on the basis of altering treatment as a result of interim PET results. Efforts are ongoing to better standardize the conduct and interpretation of FDG-PET scans. FDG-PET has the potential to improve lymphoma patient management; however, its usefulness will likely vary by histology, stage, therapy, and clinical setting.
Cat litter is a possible trigger for sarcoidosis
Authors: M. Drent, P. A. Wijnen, A. W. Boots, A. Bast
Journal: European Respiratory Journal (2011)

To the Editors:

Sarcoidosis is characterised by cellular immune activity with noncaseating granuloma formation in various organ systems with a multifactorial cause. Many causative agents are considered to be involved in the pathogenesis [1–5]. Gene–environment interactions offer the potential for strengthening the evidence of causation between exposures and sarcoidosis. It is important to identify every potential exposure to triggers in order to avoid irreversible damage. Inorganic agents, including silica, have been reported to initiate inflammation and granulomatous reactions [6, 7]. It is well known that cats can cause allergic reactions, but less is known about the association of inflammation and cat litter. We propose that silica, the major component of cat litter, might be such an agent. We report a case of biopsy-proven sarcoidosis with birefringent material, mainly silica, within the lung biopsy specimen. The patient had no relevant occupational history, but had cats and was extensively exposed to silica-containing cat litter. Initially, the patient improved after starting immunosuppressive drugs and terminating contact with litter. However, she deteriorated twice after autoprovocation (re-exposure) to cat litter. After changing the silica-containing cat litter for litter without silica, her clinical condition improved substantially. Obviously, she appeared to be “hypersensitive” not to the cats but to the cat litter.

A 44-yr-old female was admitted to the former ILD Care Team (a tertiary referral centre) of the Dept of …
Noncleavable poly(ADP-ribose) polymerase-1 regulates the inflammation response in mice
Authors: Virginie Pétrilli, Zdenko Herceg, Paul O. Hassa, Nimesh S.A. Patel, Rosanna Di Paola, Ulrich Cortes, Laura Dugo, Helder-Mota Filipe, Christoph Thiemermann, Michael O. Hottiger, Salvatore Cuzzocrea, Zhao-Qi Wang
Journal: Journal of Clinical Investigation (2004)

Poly(ADP-ribosyl)ation is rapidly formed in cells following DNA damage and is regulated by poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is known to be involved in various cellular processes, such as DNA repair, genomic stability, transcription, and cell death. During apoptosis, PARP-1 is cleaved by caspases to generate 89-kDa and 24-kDa fragments, a hallmark of apoptosis. This cleavage is thought to be a regulatory event for cellular death. In order to understand the biological significance of PARP-1 cleavage, we generated a PARP-1 knockin (PARP-1KI/KI) mouse model, in which the caspase cleavage site of PARP-1, DEVD214, was mutated to render the protein resistant to caspases during apoptosis. While PARP-1KI/KI mice developed normally, they were highly resistant to endotoxic shock and to intestinal and renal ischemia-reperfusions, which were associated with reduced inflammatory responses in the target tissues and cells due to the compromised production of specific inflammatory mediators. Despite normal binding of NF-κB to DNA, NF-κB–mediated transcription activity was impaired in the presence of caspase-resistant PARP-1. This study provides a novel insight into the function of PARP-1 in inflammation and ischemia-related pathophysiologies.
Which patients with which needs are leading the patient-led NHS?
Authors: Diana M Jelley
Journal: BMJ (2006)

I t was the summer of 1992 when we first met. She was a retired nurse, aged 76, recovering from a heart attack. I was new to the practice, and we talked at some length. She told me about her work in the hospital, her children and grandchildren. And we talked about my experiences on the same wards and my growing family. She was checking out the new doctor, while I was putting into practice the “bio-psychosocial” approach drummed into us as we prepared for our college membership exams.

A few months later I was called to see her at home. She was short of breath and showing the first signs of heart failure. We talked about medication, investigations, or outpatient referral. She wanted as little “interference” as possible—preferably never to go near hospital again. We worked our way through various treatments and her symptoms improved a little. But gone were the daily walks to the baker or the newsagent—a few steps down …
Medical Management of Influenza Infection
Authors: Anne Moscona
Journal: Annual Review of Medicine (2007)

Antiviral drugs are important in the management of seasonal influenza and critical to pandemic planning. Although several other classes of anti-influenza compounds exist, the neuraminidase (NA) inhibitors are currently the only option in most clinical settings. These drugs, zanamivir and oseltamivir, prevent the release of newly replicated influenza virions from infected cells. They are highly effective when used for treatment of seasonal influenza early in the course of infection, or for prevention when given soon after exposure. Treatment strategies for avian influenza infections in humans are still provisional owing to inadequate clinical data. As predicted by molecular studies, resistance to the NA inhibitors is now emerging, although at a level less significant than adamantane resistance. NA inhibitor resistance is a cause for concern if indeed some mutant strains of avian influenza are transmissible and pathogenic. In the near term, appropriate use of the available NA inhibitors will be of major benefit in lessening morbidity and mortality due to influenza infection. Priorities include developing appropriate formulations and guidelines for use of these drugs in children and people infected with avian influenza, study of the mechanisms and clinical significance of drug resistance, and identification of new antiviral therapies that target different points in the viral life cycle in order to limit the effect of emerging drug resistance.
Leptin Enhances the Calcification of Vascular Cells
Authors: Farhad Parhami, Yin Tintut, Alex Ballard, Alan M. Fogelman, Linda L. Demer
Journal: Circulation Research (2001)

Abstract —Leptin, the product of the ob gene, regulates food intake, energy expenditure, and other physiological functions of the peripheral tissues. Leptin receptors have been identified in the hypothalamus and in extrahypothalamic tissues. Increased circulating leptin levels have been correlated with cardiovascular disease, obesity, aging, infection with bacterial lipopolysaccharide, and high-fat diets. All these conditions have also been correlated with increased vascular calcification, a hallmark of atherosclerotic and age-related vascular disease. In addition, the differentiation of marrow osteoprogenitor cells is regulated by leptin. Thus, we hypothesized that leptin may regulate the calcification of vascular cells. In this report, we tested the effects of leptin on a previously characterized subpopulation of vascular cells that undergo osteoblastic differentiation and calcification in vitro. When treated with leptin, these calcifying vascular cells had a significant 5- to 10-fold increase in alkaline phosphatase activity, a marker of osteogenic differentiation of osteoblastic cells. Prolonged treatment with leptin enhanced the calcification of these cells, further supporting the pro-osteogenic differentiation effects of leptin. Furthermore, the presence of the leptin receptor on calcifying vascular cells was demonstrated using reverse transcriptase polymerase chain reaction, immunocytochemistry, and Western blot analysis. We also identified the presence of leptin receptor in the mouse artery wall, localized to subpopulations of medial and adventitial cells, and the expression of leptin by artery wall cells and atherosclerotic lesions in mice. Taken together, these results suggest that leptin regulates the osteoblastic differentiation and calcification of vascular cells and that the artery wall may be an important peripheral tissue target of leptin action.
Age-Accelerated Atherosclerosis Correlates With Failure to Upregulate Antioxidant Genes
Authors: Alan R. Collins, Christopher J. Lyon, Xuefeng Xia, Joey Z. Liu, Rajendra K. Tangirala, Fen Yin, Rima Boyadjian, Alfiya Bikineyeva, Domenico Praticò, David G. Harrison, Willa A. Hsueh
Journal: Circulation Research (2009)

Excess food intake leads to obesity and diabetes, both of which are well-known independent risk factors for atherosclerosis, and both of which are growing epidemics in an aging population. We hypothesized that aging enhances the metabolic and vascular effects of high fat diet (HFD) and therefore examined the effect of age on atherosclerosis and insulin resistance in lipoprotein receptor knockout (LDLR −/− ) mice. We found that 12-month-old (middle-aged) LDLR −/− mice developed substantially worse metabolic syndrome, diabetes, and atherosclerosis than 3-month-old (young) LDLR −/− mice when both were fed HFD for 3 months, despite similar elevations in total cholesterol levels. Microarray analyses were performed to analyze the mechanism responsible for the marked acceleration of atherosclerosis in middle-aged mice. Chow-fed middle-aged mice had greater aortic expression of multiple antioxidant genes than chow-fed young mice, including glutathione peroxidase-1 and -4, catalase, superoxide dismutase-2, and uncoupling protein-2. Aortic expression of these enzymes markedly increased in young mice fed HFD but decreased or only modestly increased in middle-aged mice fed HFD, despite the fact that systemic oxidative stress and vascular reactive oxygen species generation, measured by plasma F2α isoprostane concentration (systemic) and dihydroethidium conversion and p47phox expression (vascular), were greater in middle-aged mice fed HFD. Thus, the mechanism for the accelerated vascular injury in older LDLR −/− mice was likely the profound inability to mount an antioxidant response. This effect was related to a decrease in vascular expression of 2 key transcriptional pathways regulating the antioxidant response, DJ-1 and forkhead box, subgroup O family (FOXOs). Treatment of middle-aged mice fed HFD with the antioxidant apocynin attenuated atherosclerosis, whereas treatment with the insulin sensitizer rosiglitazone attenuated both metabolic syndrome and atherosclerosis. Both treatments decreased oxidative stress. A novel effect of rosiglitazone was to increase expression of Nrf2 (nuclear factor [erythroid-derived 2]-like 2), a downstream target of DJ-1 contributing to enhanced expression of vascular antioxidant enzymes. This investigation underscores the role of oxidative stress when multiple atherosclerotic risk factors, particularly aging, converge on the vessel wall and emphasizes the need to develop effective strategies to inhibit oxidative stress to protect aging vasculature.
Human immunodeficiency virus 1 envelope proteins induce interleukin 1, tumor necrosis factor alpha, and nitric oxide in glial cultures derived from fetal, neonatal, and adult human brain.
Authors: P Koka, K He, J A Zack, S Kitchen, W Peacock, I Fried, T Tran, S S Yashar, J E Merrill
Journal: The Journal of Experimental Medicine (1995)

Although microglia are the only cells found to be productively infected in the central nervous system of acquired immunodeficiency disease syndrome (AIDS) patients, there is extensive white and gray matter disease nonetheless. This neuropathogenesis is believed to be due to indirect mechanisms other than infection with human immunodeficiency virus 1 (HIV-1). Cytokines and toxic small molecules have been implicated in the clinical and histopathological findings in CNS AIDS. Previously, we have demonstrated in rodent glial cultures the presence of biologically active epitopes of gp120 and gp41 that are capable of inducing interleukin 1 and tumor necrosis factor alpha. In this study, we map the HIV-1 envelope epitopes that induce nitric oxide, inducible nitric oxide synthase, interleukin 1, and tumor necrosis factor alpha in human glial cultures. Epitopes in the carboxy terminus of gp120 and the amino terminus of gp41 induce these proinflammatory entities. In addition, we compare HIV-1 infection and pathology in glial cells derived from human brain taken at different states of maturation (fetal, neonatal, and adult brain) in an effort to address some of the clinical and histological differences seen in vivo. This study demonstrates that, in the absence of virus infection and even in the absence of distinct viral tropism, human glia respond like rodent glia to non-CD4-binding epitopes of gp120/gp41 with cytokine and nitric oxide production. Differences among fetal, neonatal, and adult glial cells' infectivity and cytokine production indicate that, in addition to functional differences of glia at different stages of development, cofactors in vitro and in vivo may also be critical in facilitating the biological responses of these cells to HIV-1.