tbuckley/cabot-search huggingface dataset:
A DNA Methylation Prognostic Signature of Glioblastoma: Identification of NPTX2-PTEN-NF-κB Nexus
Authors: Sudhanshu Shukla, Irene Rosita Pia Patric, Sivaarumugam Thinagararjan, Sujaya Srinivasan, Baisakhi Mondal, Alangar S. Hegde, Bangalore A. Chandramouli, Vani Santosh, Arimappamagan Arivazhagan, Kumaravel Somasundaram
Journal: Cancer Research (2013)

Abstract Glioblastoma (GBM) is the most common, malignant adult primary tumor with dismal patient survival, yet the molecular determinants of patient survival are poorly characterized. Global methylation profile of GBM samples (our cohort; n = 44) using high-resolution methylation microarrays was carried out. Cox regression analysis identified a 9-gene methylation signature that predicted survival in GBM patients. A risk-score derived from methylation signature predicted survival in univariate analysis in our and The Cancer Genome Atlas (TCGA) cohort. Multivariate analysis identified methylation risk score as an independent survival predictor in TCGA cohort. Methylation risk score stratified the patients into low-risk and high-risk groups with significant survival difference. Network analysis revealed an activated NF-κB pathway association with high-risk group. NF-κB inhibition reversed glioma chemoresistance, and RNA interference studies identified interleukin-6 and intercellular adhesion molecule-1 as key NF-κB targets in imparting chemoresistance. Promoter hypermethylation of neuronal pentraxin II (NPTX2), a risky methylated gene, was confirmed by bisulfite sequencing in GBMs. GBMs and glioma cell lines had low levels of NPTX2 transcripts, which could be reversed upon methylation inhibitor treatment. NPTX2 overexpression induced apoptosis, inhibited proliferation and anchorage-independent growth, and rendered glioma cells chemosensitive. Furthermore, NPTX2 repressed NF-κB activity by inhibiting AKT through a p53-PTEN-dependent pathway, thus explaining the hypermethylation and downregulation of NPTX2 in NF-κB-activated high-risk GBMs. Taken together, a 9-gene methylation signature was identified as an independent GBM prognosticator and could be used for GBM risk stratification. Prosurvival NF-κB pathway activation characterized high-risk patients with poor prognosis, indicating it to be a therapeutic target. Cancer Res; 73(22); 6563–73. ©2013 AACR.
Identifying recent Mycobacterium tuberculosis transmission in the setting of high HIV and TB burden
Authors: J. Mutsvangwa, K. A Millington, K. Chaka, T. Mavhudzi, Y.-B. Cheung, P. R Mason, A. E Butterworth, E. L Corbett, A. Lalvani
Journal: Thorax (2010)

<h3>Background</h3> Accurate diagnosis of latent tuberculosis infection (LTBI) in recently exposed HIV-infected tuberculosis (TB) contacts is a public health priority because of the high risk of progression to active TB but is hampered by the high background prevalence of LTBI in high-burden populations and poor sensitivity of tuberculin skin testing (TST) in HIV co-infection. <h3>Methods</h3> The prevalence of LTBI in 222 recent household contacts of TB cases and 176 household contacts of community controls without TB in Harare, Zimbabwe were compared using TST and interferon γ enzyme-linked immunospot (ELISpot) responses to ESAT-6 (early secretory antigenic target-6) and CFP-10 (culture filtrate protein-10). TST and ELISpot results were correlated with markers of recent TB exposure and the impact of HIV co-infection was assessed. <h3>Results</h3> In this high-incidence population, the proportion of ELISpot-positive contacts was not significantly different from community controls. However, ELISpot, unlike TST, revealed a higher prevalence of LTBI in recent contacts of sputum smear-positive cases than in contacts of controls. ELISpot results correlated significantly with positive sputum smear and culture status of the index case (adjusted OR 2.40, CI 1.12 to 5.14), even in the subgroup of HIV-infected contacts (adjusted OR 5.36, CI 1.11 to 25.93). and were independent of contacts9 HIV status. TST results were also associated with positive smear and culture status of the index case (adjusted OR 4.41, CI 1.82 to 10.67) but were negatively associated with contacts9 HIV status (adjusted OR 0.25, CI 0.10 to 0.60). <h3>Conclusions</h3> Contact investigations in high-burden populations should focus on contacts of sputum smear-positive cases in whom recent infection can be detected by ELISpot, even in the presence of HIV co-infection.
Effects of Intravenously Administered Recombinant Vesicular Stomatitis Virus (VSV ΔM51 ) on Multifocal and Invasive Gliomas
Authors: XueQing Lun, Donna L. Senger, Tommy Alain, Andra Oprea, Kelley Parato, Dave Stojdl, Brian Lichty, Anthony Power, Randal N. Johnston, Mark Hamilton, Ian Parney, John C. Bell, Peter A. Forsyth
Journal: JNCI Journal of the National Cancer Institute (2006)

Background: An ideal virus for the treatment of cancer should have effective delivery into multiple sites within the tumor, evade immune responses, produce rapid viral replication, spread within the tumor, and infect multiple tumors. Vesicular stomatitis virus (VSV) has been shown to be an effective oncolytic virus in a variety of tumor models, and mutations in the matrix (M) protein enhance VSV's effectiveness in animal models. Methods: We evaluated the susceptibility of 14 glioma cell lines to infection and killing by mutant strain VSV ΔM51 , which contains a single–amino acid deletion in the M protein. We also examined the activity and safety of this strain against the U87 and U118 experimental models of human malignant glioma in nude mice and analyzed the distribution of the virus in the brains of U87 tumor–bearing mice using fluorescence labeling. Finally, we examined the effect of VSV ΔM51 on 15 primary human gliomas cultured from surgical specimens. All statistical tests were two-sided. Results: All 14 glioma cell lines were susceptible to VSV ΔM51 infection and killing. Intratumoral administration of VSV ΔM51 produced marked regression of malignant gliomas in nude mice. When administered systemically, live VSV ΔM51 virus, as compared with dead virus, statistically significantly prolonged survival of mice with unilateral U87 tumors (median survival: 113 versus 46 days, P = .0001) and bilateral U87 tumors (median survival: 73 versus 46 days, P = .0025). VSV ΔM51 infected multifocal gliomas, invasive glioma cells that migrated beyond the main glioma, and all 15 primary human gliomas. There was no evidence of toxicity. Conclusions: Systemically delivered VSV ΔM51 was an effective and safe oncolytic agent against laboratory models of multifocal and invasive malignant gliomas, the most challenging clinical manifestations of this disease.
A Novel Mechanism of Action for Anti-Thymocyte Globulin
Authors: Marta Lopez, Michael R. Clarkson, Monica Albin, Mohamed H. Sayegh, Nader Najafian
Journal: Journal of the American Society of Nephrology (2006)

T cell–depleting agents are being tested as part of clinical tolerance strategies in humans with autoimmunity and transplantation. The immunosuppressive activity of anti-thymocyte globulin (ATG) has been thought to result primarily from depletion of peripheral lymphocytes. Herein is reported for the first time that ATG but not anti-CD52 mAb (alemtuzumab) or the IL-2R antagonists causes rapid and sustained expansion of CD4+CD25+ T cells when cultured with human peripheral blood lymphocytes. These cells display enhanced expression of the regulatory markers glucocorticoid-induced TNF receptor, cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), and forkhead box P3 and efficiently suppress a direct alloimmune response of the original responder lymphocytes. It is interesting that the cells do not suppress memory responses to the recall antigen mumps. Ex vivo expansion of regulatory T cells is due mainly to conversion of CD4+CD25− into CD4+CD25+ T cells and to a lesser degree to proliferation of natural CD4+CD25+ T cells. The induction of regulatory T cells depends on production of Th2 cytokines in the generating cultures. These novel data suggest that ATG not only may promote expansion/generation of regulatory T cells but also may be useful in future ex vivo expansion of these cells for cellular therapy in autoimmunity and clinical transplantation.
Some unusual cases of defibrination in pregnancy.
Authors: J. Willocks, J. MacVicar
Journal: BMJ (1965)

Eczema and Keratoconus-Copeman BIBDJTISH 979 cornea, (kerato)conus posticus, allows the condition of keratoconus to supervene.The common association of eczema and hay-fever with keratoconus may be explained by the assumption that these diseases provide the stimulus for eye-rubbing. SummaryThirty-two patients with eczema, half of whom had the atopic variety, were discovered among 100 patients with keratoconus-10 times the expected number.Many patients who develop keratoconus have an inherited defect of the posterior cornea-(kerato)conus posticus.Eczema, hay-fever, or emotional disturbance provides the stimulus that causes excessive eye-rubbing, -and this may result in conical distortion of the cornea-keratoconus.Keratoconus should be suspected in young eczematous patients whose vision suddenly deteriorates.I would like to thank Mr. Frederick
Strong Positive Selection and Habitat-Specific Amino Acid Substitution Patterns in Mhc from an Estuarine Fish Under Intense Pollution Stress
Authors: Sarah Cohen
Journal: Molecular Biology and Evolution (2002)

Population-level studies using the major histocompatibility complex (Mhc) have linked specific alleles with specific diseases, but data requirements are high and the power to detect disease association is low. A novel use of Mhc population surveys involves mapping allelic substitutions onto the inferred structural molecular model to show functional differentiation related to local selective pressures. In the estuarine fish Fundulus heteroclitus, populations experiencing strong differences in antigenic challenges show significant differences in amino acid substitution patterns that are reflected as variation in the structural location of changes between populations. Fish from a population genetically adapted to severe chemical pollution also show novel patterns of DNA substitution at a highly variable Mhc class II B locus including strong signals of positive selection at inferred antigen-binding sites and population-specific signatures of amino acid substitution. Heavily parasitized fish from an extreme PCB-contaminated (U.S. Environmental Protection Agency Superfund) site show enhanced population-specific substitutions in the a-helix portion of the inferred antigen-binding region. In contrast, fish from an unpolluted site show a significantly different pattern focused on the first strand of the B-pleated sheet. Whether Mhc population profile differences represent the direct effects of chemical toxicants or indirect parasite-mediated selection, the result is a composite habitat-specific signature of strong selection and evolution affecting the genetic repertoire of the major histocompatibility complex.
Soluble Interleukin-13Rα2 Decoy Receptor Inhibits Hodgkin’s Lymphoma Growth<b><i>in Vitro</i></b>and<b><i>in Vivo</i></b>
Authors: Young Trieu, Xiao-Yan Wen, Brian F. Skinnider, Mark R. Bray, Zhihua Li, Jaime O. Claudio, Esther Masih-Khan, Yuan-Xiao Zhu, Suzanne Trudel, J. Andrea McCart, Tak W. Mak, A. Keith Stewart
Journal: Cancer Research (2004)

Recent studies have demonstrated that the malignant Reed-Sternberg cells of Hodgkin's lymphoma (HL) secrete and are responsive to interleukin (IL)-13. We hypothesized that overexpression of a soluble IL-13 decoy receptor (sIL-13Ralpha2) via adenoviral-mediated gene transfer would inhibit IL-13-induced Reed-Sternberg cell proliferation. Western blot and ELISA analysis verified expression of sIL-13Ralpha2 in cell lysates and supernatants of AdsIL-13Ralpha2-transduced COS-7 cells. Treatment of two IL-13-responsive HL-derived cell lines, HDLM-2 and L-1236, with AdsIL-13Ralpha2-conditioned medium, resulted in the inhibition of cell proliferation, and down-regulated the phosphorylation of signal transducer and activator of transcription 6 (STAT6), an important mediator of IL-13 signaling. i.v. delivery of AdsIL-13Ralpha2 in NOD/SCID mice with s.c. implanted HDLM-2 cells delayed tumor onset and growth while enhancing survival compared with control mice. Intratumoral administration of AdsIL-13Ralpha2 led to the regression or stabilization of established tumors and was associated with diminished STAT6 phosphorylation. Our data demonstrate that AdsIL-13Ralpha2 can suppress HL growth in vitro and in vivo.
A Genomic Approach Reveals a Novel Mitotic Pathway in Papillomavirus Carcinogenesis
Authors: Françoise Thierry, Mohammed Abderrafi Benotmane, Caroline Demeret, Marcella Mori, Sébastien Teissier, Christian Desaintes
Journal: Cancer Research (2004)

Abstract More than 90% of cervical carcinomas are associated with human papillomavirus (HPV) infection. The two viral oncogenes E6 and E7 play a major role in transforming the cells by disrupting p53- and pRb-dependent cell cycle checkpoints. A hallmark of HPV-associated cervical carcinoma is loss of the expression of the viral E2 protein, often by disruption of E2-encoding gene. We showed previously that reintroduction of E2 in HPV18-associated cervical carcinoma cells induces cell cycle arrest in G1 because of the transcriptional repression of the viral oncogenes E6 and E7 and concomitant reactivation of the p53 and pRb pathways. Here we describe global gene profiling of HeLa cells expressing different HPV18 E2 mutants to study the effects of repression of the viral oncogenes. We identified 128 genes transcriptionally regulated by the viral oncogenes in cervical carcinoma. Surprisingly, E2 repressed a subset of E2F-regulated mitotic genes in an E6/E7-dependent pathway. This was corroborated by the observation that E2 delayed mitotic progression, suggesting the involvement of a mitotic pathway in HPV carcinogenesis. These mitotic genes constitute an as yet unrecognized set of genes, which were also found deregulated in other HPV-associated cervical carcinoma cell lines and therefore represent new targets for both diagnosis and therapeutic approaches in cervical cancer.
Zenon George Panos
Authors: M. Z. P. G. Z. Panos
Journal: BMJ (2015)

Zenon George Panos was born in the village of Stroumbi, Paphos. He was the son of the village school teacher George P Georgiades. He recalled that as a child he learnt to write at the village school by using a stick of charcoal on a slate. In his teens, he survived typhoid fever and in his 20s, pneumonia.

After qualifying from the University of Athens Medical School, he received postgraduate training in public health hygiene and environmental engineering, specialising in malaria control, at the Rockefeller Foundation in Athens. After his father’s untimely death in 1937, he returned to Paphos, where he was appointed medical officer in the colonial administration. He later gave fascinating accounts of house calls to remote hamlets, which were accessible only by a long mule ride.

In 1938 the then chief medical officer, Errol Neff, assigned him a pilot project, (which was later extended by Rex E Cheverton, Neff’s successor), for the control of malaria in the infested area of Limni, near Polis in the district of Paphos. This entailed identifying, draining, and systematic spraying of all stagnant water with petroleum products and Paris green (copper (II) acetate triarsenite), in order to destroy larvae of the Anopheles mosquito, and the use of the natural insecticide pyrethrin. The …
DEANER AN ADJUNCT FOR TREATMENT OF SCHIZOID AND SCHIZOPHRENIC PATIENTS
Authors: NINA TOLL
Journal: American Journal of Psychiatry (1958)

Despite the small number of patients included in this study, certain clinical impressions were formed: Deaner appears to merit further study in those conditions where CNS stimulation is needed. Its freedom from serious side-effects, and the dramatic response produced in some cases suggest that the drug is worthy of trial, especially in schizoid and schizophrenic patients who have not responded to other therapies.
Cost effectiveness of an outpatient multidisciplinary pulmonary rehabilitation programme
Authors: Timothy Leonard Griffiths, C. J. Phillips, S. Davies, Michael Leslie Burr, I. A. Campbell
Journal: Thorax (2001)

<h3>BACKGROUND</h3> Pulmonary rehabilitation programmes improve the health of patients disabled by lung disease but their cost effectiveness is unproved. We undertook a cost/utility analysis in conjunction with a randomised controlled clinical trial of pulmonary rehabilitation versus standard care. <h3>METHODS</h3> Two hundred patients, mainly with chronic obstructive pulmonary disease, were randomly assigned to either an 18 visit, 6 week rehabilitation programme or standard medical management. The difference between the mean cost of 12 months of care for patients in the rehabilitation and control groups (incremental cost) and the difference between the two groups in quality adjusted life years (QALYs) gained (incremental utility) were determined. The ratio between incremental cost and utility (incremental cost/utility ratio) was calculated. <h3>RESULTS</h3> Each rehabilitation programme for up to 20 patients cost £12 120. The mean incremental cost of adding rehabilitation to standard care was £ –152 (95% CI –881 to 577) per patient, p=NS. The incremental utility of adding rehabilitation was 0.030 (95% CI 0.002 to 0.058) QALYs per patient, p=0.03. The point estimate of the incremental cost/utility ratio was therefore negative. The bootstrapping technique was used to model the distribution of cost/utility estimates possible from the data. A high likelihood of generating QALYs at negative or relatively low cost was indicated. The probability of the cost per QALY generated being below £0 was 0.64. <h3>CONCLUSIONS</h3> This outpatient pulmonary rehabilitation programme produces cost per QALY ratios within bounds considered to be cost effective and is likely to result in financial benefits to the health service.
Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents
Authors: Amol M. Patwardhan, Armen N. Akopian, Nikita B. Ruparel, Anibal Diogenes, Susan T. Weintraub, Charis Uhlson, Robert C. Murphy, Kenneth M. Hargreaves
Journal: Journal of Clinical Investigation (2010)

The transient receptor potential vanilloid 1 (TRPV1) channel is the principal detector of noxious heat in the peripheral nervous system. TRPV1 is expressed in many nociceptors and is involved in heat-induced hyperalgesia and thermoregulation. The precise mechanism or mechanisms mediating the thermal sensitivity of TRPV1 are unknown. Here, we have shown that the oxidized linoleic acid metabolites 9- and 13-hydroxyoctadecadienoic acid (9- and 13-HODE) are formed in mouse and rat skin biopsies by exposure to noxious heat. 9- and 13-HODE and their metabolites, 9- and 13-oxoODE, activated TRPV1 and therefore constitute a family of endogenous TRPV1 agonists. Moreover, blocking these substances substantially decreased the heat sensitivity of TRPV1 in rats and mice and reduced nociception. Collectively, our results indicate that HODEs contribute to the heat sensitivity of TRPV1 in rodents. Because oxidized linoleic acid metabolites are released during cell injury, these findings suggest a mechanism for integrating the hyperalgesic and proinflammatory roles of TRPV1 and linoleic acid metabolites and may provide the foundation for investigating new classes of analgesic drugs.
Cytochrome P450 2J2 Promotes the Neoplastic Phenotype of Carcinoma Cells and Is Up-regulated in Human Tumors
Authors: Jian-Gang Jiang, Chun-Lian Chen, Jeffrey W. Card, Shilin Yang, Ji-Xiong Chen, Xiang-Ning Fu, Yao-Gui Ning, Xiao Xiao, Darryl C. Zeldin, Dao Wen Wang
Journal: Cancer Research (2005)

Abstract Cytochrome P450 (CYP) arachidonic acid epoxygenase 2J2 converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids, which exert diverse biological activities in cardiovascular system and endothelial cells. However, it is unknown whether this enzyme highly expresses and plays any role in cancer. In this study, we found that very strong and selective CYP2J2 expression was detected in human carcinoma tissues in 101 of 130 patients (77%) as well as eight human carcinoma cell lines but undetectable in adjacent normal tissues and nontumoric human cell lines by Western, reverse transcription-PCR, and immunohistochemical staining. In addition, forced overexpression of CYP2J2, and CYP BM3F87V or addition of epoxyeicosatrienoic acids (EET) in cultured carcinoma cell lines in vitro markedly accelerated proliferation by analyses of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, cell accounts, and cell cycle analysis, and protected carcinoma cells from apoptosis induced by tumor necrosis factor α (TNF-α) in cultures. In contrast, antisense 2J2 transfection or addition of epoxygenase inhibitors 17-ODYA inhibited proliferation and accelerated cell apoptosis induced by TNF-α. Examination of signaling pathways on the effects of CYP2J2 and EETs revealed activation of mitogen-activated protein kinases and PI3 kinase-AKT systems and elevation of epithelial growth factor receptor phosphorylation level. These results strongly suggest that CYP epoxygenase 2J2 plays a previously unknown role in promotion of the neoplastic cellular phenotype and in the pathogenesis of a variety of human cancers.
The next thing in prognostic molecular markers: microRNA signatures of cancer
Authors: W. M. Grady, M. Tewari
Journal: Gut (2010)

Cancer is known to be a consequence of the accumulation of mutations and epigenetic alterations of oncogenes and tumour suppressor genes, which cooperate to cause a normal cell to transform into a cancer cell. Thus, the clinical behaviour of cancer cells has been logically predicted to reflect the consequences of these mutated and altered genes. This hypothesis has led to the hope that measurement of gene activity or expression can be used as biomarkers to accurately determine which tumours will recur and which are likely to respond to specific treatments. Consequently, for over three decades, there has been an ongoing search to identify mutated or otherwise altered genes that can precisely predict the behaviour of tumours with regards to risk for recurrence and response to chemotherapy.

In the May issue of Gut , Li et al reported on the discovery of a microRNA gene expression signature that shows considerable promise for determining the prognosis of individuals with gastric cancer.1 Their identification of this panel of prognostic microRNAs for gastric cancer is one of several recent studies that have found this class of small non-coding RNAs to be useful for predicting the behaviour of a variety of different cancers, including acute myeloid leukaemia, chronic lymphocytic leukaemia, colon cancer, pancreatic cancer, and non-small cell lung cancer.2 These reports highlight that this relatively newly identified class of RNA molecules is showing substantial potential to be used as diagnostic and prognostic biomarkers for cancer. Beyond the promise that microRNAs hold as candidate biomarkers for the early detection and management of cancer, there is also considerable excitement for the use of miRNAs as a novel class of therapeutic targets and as an entirely new class of therapeutic agents for the treatment of cancers.

In order to appreciate where our understanding of microRNAs is …