tbuckley/cabot-search huggingface dataset:
microRNA and mRNA expression signatures of Myc and E2F1 oncogenic pathways
Authors: Jongwook Kim, Anil Potti, Joseph R. Nevins
Journal: Clinical Cancer Research (2006)

A80   While the use of gene expression profiles to differentiate various tumor subtypes according to their physiology has become a common practice in cancer biology, efforts to utilize the ensuing data to better understand the biology of cancer have been limited. To this end, we recently generated a series of messenger RNA signatures reflecting deregulated oncogenic pathways. These signatures are capable of predicting pathway status of a given tumor, and potentially to serve as a platform for guided therapeutics in a clinical setting. A critical component of the gene regulatory complexity derives from the microRNAs, small regulatory RNA molecules that have been shown to play important roles in key cellular processes, aberration of which lead to numerous pathologies, including cancer. Given their regulatory capacities, obtaining unique expression profiles of microRNAs in the context of various oncogenic pathways will enrich us of information regarding gene regulation that will not only complement aforementioned mRNA expression oncogenic pathway predictor, but will also set the stage for further investigation on the role of these miRNAs in oncogenesis. Indeed, our studies demonstrate that unique miRNA signatures can be generated that can predict the deregulation of the Myc and E2F1 pathways. We further show that microRNA data can be combined with mRNA microarray expression data, using classification tree models, to generate a signature of Myc pathway activation that integrates the two datasets. Among the miRNAs that contributed to the confirmed signature was miR-20a, one that has been previously reported to be a direct transcriptional target of Myc, further supporting the validity of this approach. Taken together, these results suggest that microRNAs are inherent component of major oncogenic pathways, whose information may further contribute to our understanding of malignant processes.
Uric Acid and Diet — Insights into the Epidemic of Cardiovascular Disease
Authors: Richard J. Johnson, Bruce A. Rideout
Journal: New England Journal of Medicine (2004)

Gout is the only enemy that I do not wish to have at my feet.— Reverend Sydney Smith, 1841Gout, a disease that has been known since antiquity, is an acute, often recurrent arthritis mediated by the crystallization of uric acid within the joints and typically associated with hyperuricemia. Described by Hippocrates during the Golden Age of Greece, gout was originally a disease of the affluent, primarily observed in middle-aged men of the wealthy upper class (“the Patrician malady”). A “disease of kings and king of diseases,” gout has often kept good company, afflicting kings (including Alexander the Great, . . .
Phase II Trial of the Antiangiogenic Agent Thalidomide in Patients With Recurrent High-Grade Gliomas
Authors: Howard A. Fine, William D. Figg, Kurt Jaeckle, Patrick Y. Wen, Athanassios P. Kyritsis, Jay S. Loeffler, Victor A. Levin, Peter M. Black, Richard Kaplan, James M. Pluda, W.K. Alfred Yung
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Little progress has been made in the treatment of adult high-grade gliomas over the last two decades, thus necessitating a search for novel therapeutic strategies. Malignant gliomas are vascular or angiogenic tumors, which leads to the supposition that angiogenesis inhibition may represent a potentially promising strategy in the treatment of these tumors. We present the results of a phase II trial of thalidomide, a putative inhibitor of angiogenesis, in the treatment of adults with previously irradiated, recurrent high-grade gliomas. PATIENTS AND METHODS: Patients with a histologic diagnosis of anaplastic mixed glioma, anaplastic astrocytoma, or glioblastoma multiforme who had radiographic demonstration of tumor progression after standard external-beam radiotherapy with or without chemotherapy were eligible. Patients were initially treated with thalidomide 800 mg/d with increases in dose by 200 mg/d every 2 weeks until a final daily dose of 1,200 mg was achieved. Patients were evaluated every 8 weeks for response by both clinical and radiographic criteria. RESULTS: A total of 39 patients were accrued, with 36 patients being assessable for both toxicity and response. Thalidomide was well tolerated, with constipation and sedation being the major toxicities. One patient developed a grade 2 peripheral neuropathy after treatment with thalidomide for nearly a year. There were two objective radiographic partial responses (6%), two minor responses (6%), and 12 patients with stable disease (33%). Eight patients were alive more than 1 year after starting thalidomide, although almost all with tumor progression. Changes in serum levels of basic fibroblastic growth factor (bFGF) were correlated with time to tumor progression and overall survival. CONCLUSION: Thalidomide is a generally well-tolerated drug that may have antitumor activity in a minority of patients with recurrent high-grade gliomas. Future studies will better define the usefulness of thalidomide in newly diagnosed patients with malignant gliomas and in combination with radiotherapy and chemotherapy. Additionally, studies will be needed to confirm the potential utility of changes in serum bFGF as a marker of antiangiogenic activity and/or glioma growth.
Impact of Preoperative Chemotherapy After Neoadjuvant Chemoradiation on Tumor Down Staging in Patients with Locally Advanced Rectal Cancer: a Retrospective Study
Authors: A. Yaren, B. Yapar Taskoylu, A.G. Demiray, D. Herek, G.G. Dogu, S. Degirmencioglu, U. Sungurtekin, N. Callı Demirkan, B. Baltalarli
Journal: Annals of Oncology (2014)
Health Care Professionals’ Responses to Religious or Spiritual Statements by Surrogate Decision Makers During Goals-of-Care Discussions
Authors: Natalie C. Ernecoff, Farr A. Curlin, Praewpannarai Buddadhumaruk, Douglas B. White
Journal: JAMA Internal Medicine (2015)

Although many patients and their families view religion or spirituality as an important consideration near the end of life, little is known about the extent to which religious or spiritual considerations arise during goals-of-care conversations in the intensive care unit.To determine how frequently surrogate decision makers and health care professionals discuss religious or spiritual considerations during family meetings in the intensive care unit and to characterize how health care professionals respond to such statements by surrogates.A multicenter prospective cohort study was conducted between October 8, 2009, and October 24, 2012, regarding 249 goals-of-care conversations between 651 surrogate decision makers and 441 health care professionals in 13 intensive care units across the United States. Audio-recorded conversations between surrogate decision makers and health care professionals were analyzed, transcribed, and qualitatively coded. Data analysis took place from March 10, 2012, through May 24, 2014.Goals-of-care conferences.Constant comparative methods to develop a framework for coding religious and spiritual statements were applied to the transcripts. Participants completed demographic questionnaires that included religious affiliation and religiosity.Of 457 surrogate decision makers, 355 (77.6%) endorsed religion or spirituality as fairly or very important in their life. Discussion of religious or spiritual considerations occurred in 40 of 249 conferences (16.1%). Surrogates were the first to raise religious or spiritual considerations in most cases (26 of 40). Surrogates' statements (n=59) fell into the following 5 main categories: references to their religious or spiritual beliefs, including miracles (n=34); religious practices (n=19); religious community (n=8); the notion that the physician is God's instrument to promote healing (n=4); and the interpretation that the end of life is a new beginning for their loved one (n=4). Some statements fell into more than 1 category. In response to surrogates' religious or spiritual statements, health care professionals redirected the conversation to medical considerations (n=15), offered to involve hospital spiritual care providers or the patient's own religious or spiritual community (n=14), expressed empathy (n=13), acknowledged surrogates' statements (n=11), or explained their own religious or spiritual beliefs (n=3). In only 8 conferences did health care professionals attempt to further understand surrogates' beliefs, for example, by asking questions about the patient's religion.Among a cohort of surrogate decision makers with a relatively high degree of religiosity, discussion of religious or spiritual considerations occurred in fewer than 20% of goals-of-care conferences in intensive care units, and health care professionals rarely explored the patient's or family's religious or spiritual ideas.
The global risk of dying from multidrug-resistant tuberculosis (MDR-TB)
Authors: Luciana Brondi, Dennis Falzon, Charalambos Sismanidis, Philippe Glaziou, Matteo Zignol, Katherine Floyd, Harry Campbell, Harish Nair
Journal: European Respiratory Journal (2014)

In 2012, 8.6 million persons developed tuberculosis (TB) and 1.3 million of them died. Some 5.7% of TB patients were infected with bacteria resistant to at least isoniazid and rifampicin (multidrug-resistance; MDR-TB). Among TB patients on treatment, MDR-TB is associated with increased risk of dying. We estimated the global number of deaths due to MDR-TB.  Deaths attributed to MDR-TB in a given year are a product of the total TB deaths that year, the overall % MDR-TB among TB cases, and the risk ratio (RR) of dying among MDR-TB vs. non-MDR-TB patients. Data from vital statistics (sparse), mortality surveys, drug-resistance surveillance, and a meta-analysis of published estimates of RR of death in MDR-TB patients were used for the estimation.  A literature review of Medline, EMBASE, Global Health, and LILACS identified 25 articles out of 6,231 from 1999 to 2013 which cited an exploitable value of the RR of mortality in MDR-TB cases.  Studies had broad geographical coverage and included countries with both high and low burden of TB, MDR-TB and HIV. The meta-estimate of global RR of MDR-TB mortality was 2.36 (95% range, 1.67-3.05). Using TB data for 2012 collected by WHO it was estimated that 170,000 (95% range, 100,000-240,000) deaths from MDR-TB occurred in the world that year.  MDR-TB causes a sizeable proportion of TB deaths in the world. Available data precluded the differentiation of RR by geographic region or patient subgroups (eg, children).
Mitochondrial function and quality control is altered by low-dose cigarette smoke exposure
Authors: Korbinian Ballweg, Oliver Eickelberg, Silke Meiners
Journal: European Respiratory Journal (2014)

Mitochondrial function is reduced in aged tissue and upon exposure to environmental challenges. However, little is known on the adaptive response of lung cell mitochondria to non-toxic doses of cigarette smoke mimicking a realistic exposure scenario. Depending on the stress, mitochondria either adapt using a sophisticated quality control or induce dysfunction, mitophagy and apoptotic cell death. The aim of our project is to investigate the effect of non-toxic cigarette smoke on lung cell mitochondrial function and quality control.

In order to analyze mitochondrial quality control in response to smoke exposure, we used a cell culture model of cigarette smoke extract (CSE) treated alveolar epithelial cells. Levels of proteins involved in mitochondrial dynamics, mitophagy and the proteasomal pathway were assessed using Western Blot analysis. Mitochondrial morphology was analyzed and mitochondrial function was determined by measuring membrane potential and activity. First data showed that non-toxic doses of CSE induced mitochondrial elongation accompanied by increased metabolic activity and membrane potential. Correspondingly, the mitochondrial fusion protein Mfn2 was found to be increased in CSE treated cells. Of note, Mfn2 levels were also increased in lungs of COPD patients. Furthermore, VCP/p97, which is proposed to extract proteins from the mitochondria and transport them to the proteasome, was upregulated in CSE treated cells as well as in COPD lungs.

These data give first evidence for adaptive alterations in mitochondrial dynamics and increased mitochondrial function and UPS-mediated quality control in alveolar epithelial cells in response to non-toxic and low dose cigarette smoke.
Why heart disease mortality is low in France: the time lag explanation Commentary: Alcohol and other dietary factors may be important Commentary: Intrauterine nutrition may be important Commentary: Heterogeneity of populations should be taken into account Authors' response
Authors: M. Law, N. Wald, M. Stampfer, E. Rimm, D J P Barker, J. P Mackenbach, A. E Kunst
Journal: BMJ (1999)

Immune system activation can be elicited in viral infections, active immunization, or cancer immunotherapy, leading to the final common phenotype of increased glycolytic use by immune cells and subsequent detection by <sup>18</sup>F-FDG PET. Because <sup>18</sup>F-FDG is also used in baseline staging PET/CT scans and in tumor response assessment, physicians are faced with a unique challenge when evaluating tumor response in patients receiving cancer immunotherapy. The burgeoning field of cancer immunotherapy and the paucity of PET probes that can reliably differentiate activated immune cells from metabolically active cancer cells underscore the pressing need to identify and develop additional molecular imaging strategies. In an effort to address this concern, investigators have taken several molecular imaging approaches for cancer immunotherapy. Direct ex vivo labeling of T lymphocytes with radioactive probes before reinfusion represents the earliest attempts but has proven to be clinically limited because of significant PET probe dilution from proliferation of activated immune cells. Another approach is the indirect in vivo labeling of immune cells via PET reporter gene expression and involves the ex vivo genetic engineering of T lymphocytes with a reporter gene, reinfusion into the host, and the subsequent use of a PET probe specific for the reporter gene. The most recent approach involves the direct in vivo labeling of immune cells by targeting endogenous immune cell biochemical pathways that are differentially expressed during activation. In conclusion, these novel PET-based imaging approaches have demonstrated promise toward the goal of in vivo, noninvasive immune monitoring strategies for evaluating cancer immunotherapy.
Tracheal sound level as a potential diagnostic tool for pulmonary obstructive syndromes
Authors: Tudor Andrei Cernomaz, Daniela Boisteanu, Raluca Vasiluta, Traian Mihaescu
Journal: European Respiratory Journal (2011)

Aim and objectives: to asses the possibility of developing a tracheal sound analysis tool capable of diagnosing obstructive syndromes.

Material and methods: 34 subjects were stratified to the obstructive or control group. Tracheal sound was recorded during a forced expiratory maneuver; acquired signals were analyzed in terms of sound level vs time and a linear regression model was computed. The obstructive subgroup included 21 vs 13 controls. We found statistically significant between group differences for expiratory duration and for the linear regression and negative significant correlations between slope and expiratory duration, FEV1 and FEV1/VC. Building the ROC curve a threshold value of -19.67 for the slope of the linear regression model will associate a sensitivity of 95% and a specificity of 84.6% for this test.

Conclusion: Available data suggests that tracheal sound level analysis could be developed into a diagnostic and monitoring tool; additional mathematical approaches are probably necessary.
Abstract 9827: Acute Rosiglitazone Treatment is Cardioprotective Against Ischemia/Reperfusion Injury by Modulating AMPK, Akt, and JNK Signaling in Non-Diabetic Mice
Authors: Alex Morrison, Xiaoyan Yan, Ji Li
Journal: Circulation (2011)

Background: Rosiglitazone (RGZ), a PPAR-γ agonist, has been demonstrated to possess cardioprotective properties during ischemia/reperfusion (I/R). However, this concept remains controversial as recent evidence has suggested an increased risk of cardiac events associated with long-term use of RGZ in patients with type 2 diabetes. In this study, we tested the hypothesis that acute RGZ treatment is beneficial during I/R by modulating cardioprotective signaling pathways in a non-diabetic mouse model. Methods and Results: Non-diabetic FVB/NJ mice were subjected to left anterior descending coronary artery occlusion for 20 min followed by 4 h of reperfusion and given RGZ (1 µg/g i.v.) 5 min before reperfusion. Myocardial infarction was significantly reduced in mice treated with RGZ compared to vehicle controls (9% ± 1% vs. 20% ± 4%, P &lt;0.05) and post-ischemic recovery in isolated perfused hearts (no flow ischemia 20 min, reperfusion 30 min) was significantly improved with RGZ administered at reperfusion compared to vehicle ( P &lt;0.001). To investigate the signaling mechanisms of RGZ-induced cardioprotection, mice were subjected to 20 min of in vivo regional ischemia and 10 min of reperfusion. The levels of both p-AMPK (Thr 172 ) and p-Akt (Ser 473 ) were significantly increased when RGZ was given 5 min before reperfusion compared to vehicle ( P &lt;0.01 and P &lt;0.05, respectively). On the other hand, p-JNK (Thr 183 /Tyr 185 ) was significantly decreased as a result of RGZ treatment compared to vehicle ( P &lt;0.05). Pre-treatment with the selective PPAR-γ inhibitor GW-9662 (1 µg/g i.v.) 10 min before reperfusion significantly decreased both p-AMPK and p-Akt levels and did not decrease p-JNK levels in the heart during I/R. Moreover, mice pre-treated with the AMPK inhibitor compound C (10 μ g/g i.p.) and given RGZ 5 min before reperfusion did not exhibit a significant decrease in infarct size compared to RGZ alone. Conclusions: Taken together, acute treatment with RGZ can reduce ischemic injury in a non-diabetic mouse heart via modulating AMPK, Akt, and JNK signaling pathways. Although the use of RGZ pertains exclusively to patients with type 2 diabetes, the use of acute RGZ therapy to non-diabetic patients may be a potential beneficial treatment for I/R injury.
Attenuated Transforming Growth Factor β Signaling Promotes Nuclear Factor-κB Activation in Head and Neck Cancer
Authors: Jonah Cohen, Zhong Chen, Shi-Long Lu, Xin Ping Yang, Pattatheyil Arun, Reza Ehsanian, Matthew S. Brown, Hai Lu, Bin Yan, Oumou Diallo, Xiao-Jing Wang, Carter Van Waes
Journal: Cancer Research (2009)

Although constitutively activated nuclear factor-kappaB (NF-kappaB), attenuated transforming growth factor beta (TGFbeta) signaling, and TP53 mutations frequently occur in human cancers, how these pathways interact and together contribute to malignancy remains uncertain. Here, we found an association between overexpression of NF-kappaB-related genes, reduced expression of TGFbeta receptor (TbetaR) subunits and downstream targets, and TP53 genotype in head and neck squamous cell carcinoma (HNSCC). In response to recombinant TGFbeta1, both growth inhibition and TGFbeta target gene modulation were attenuated or absent in a panel of human HNSCC lines. However, in HNSCC cells that retained residual TGFbeta signaling, TGFbeta1 inhibited both constitutive and tumor necrosis factor alpha-stimulated NF-kappaB activity. Furthermore, HNSCC lines overexpressing mutant (mt) TP53 and human tumor specimens with positive TP53 nuclear staining exhibited reduced TbetaRII and knocking down mtTP53 induced TbetaRII, increasing TGFbeta downstream gene expression while inhibiting proinflammatory NF-kappaB target gene expression. Transfection of ectopic TbetaRII directly restored TGFbeta signaling while inhibiting inhibitor kappaBalpha degradation and suppressing serine-536 phosphorylation of NF-kappaB p65 and NF-kappaB transcriptional activation, linking these alterations. Finally, experiments with TbetaRII conditional knockout mice show that abrogation of TGFbeta signaling promotes the sustained induction of NF-kappaB and its proinflammatory target genes during HNSCC tumorigenesis and progression. Together, these findings elucidate a regulatory framework in which attenuated TGFbeta signaling promotes NF-kappaB activation and squamous epithelial malignancy in the setting of altered TP53 status.
Cytotoxicity Mediated by Soluble Macrophage Product(s)
Authors: K K Sethi, H Brandis
Journal: JNCI Journal of the National Cancer Institute (1975)

The soluble macrophage product(s) released by nonimmune mouse peritoneal macrophages exposed to endotoxin or from listeria-immune macrophages after incubation with specific antigen mediated cytotoxic activity against malignant cell types and, to a lesser extent, against normal cells. Only undiluted supernatants from nonimmune or listeria-immune macrophages cultured with medium 199 alone exerted some degree of cytotoxicity on the different target cell types tested. The macrophage product(s) retained cytotoxic activity storage at minus 20 degrees C, was stable when heated at 56 degrees C for 30 minutes, but was completely inactivated when exposed at 100 degrees C for 5 minutes. In the presence of 15 mug exogenous lysozyme/ml, the cytotoxic activity of the macrophage product(s) was significantly enhanced.
Primary giant mediastinal liposarcoma: Two case reports
Authors: Milda Nanushi, Jolanda Nikolla, Rezart Oketa, Dafina Todri, Alma Teferici
Journal: European Respiratory Journal (2013)

Liposarcoma comprises approximately 1% of all malignancies. Primary liposarcoma of the mediastinum is extremely rare, less than 1% of mediastinal tumors. It usually occurs in adults, commonly in the posterior mediastinum. Liposarcoma of the anterior mediastinum is very rare.

Mediastinal liposarcomas may extend into the pleural spaces and achieve a large size before detection. The presenting signs and symptoms are related to size and direct invasion of contiguous structures. Most patients present with dyspnea, chest discomfort, cough, or constitutional symptoms. Patients may present with superior vena cava syndrome. 15% of patients may be asymptomatic.

On conventional chest radiography mediastinal liposarcoma presents as a widened mediastinum. On CT varies from a predominantly fat-containing mass to a solid mass.

The recommended treatment for mediastinal liposarcoma is surgical excision. Radiotherapy and chemotherapy may follow the surgical excision. Approximately 40% of mediastinal liposarcomas recur after surgery.

We have 2 case reports of primary giant liposarcomas of mediastinum treated surgicallly in Albania in 2009 and 2012.

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Review of the 90th Annual Meeting of the British Association of Dermatologists, 6-8 July 2010, Manchester, U.K.
Authors: R.Y. Prasad Hunasehally, A.V. Anstey
Journal: British Journal of Dermatology (2011)

This is a synopsis of the main research and clinical findings presented at the British Association of Dermatologists meeting held during 6-8 July 2010 in Manchester, U.K. The conference highlighted the biological, epidemiological and therapeutic advances that have been made recently in the field of dermatology. This synopsis is a selection of the major findings from the meeting; it is not intended to be a substitute for reading the conference proceedings and related references quoted in this article.