tbuckley/cabot-search huggingface dataset:
Urocanic acid isomers in patients with non-melanoma skin cancer
Authors: C. De Simone, C. Masini, M.S. Cattaruzza, C. Guerriero, D. Cerimele, M. Norval
Journal: British Journal of Dermatology (2001)

Background Cis-urocanic acid (cis-UCA), formed from the naturally occurring trans-isomer in the epidermis on ultraviolet (UV) radiation, initiates some of the changes leading to UV-induced immunosuppression, but its role in cutaneous carcinogenesis has not been fully investigated. Objectives To measure the concentration of UCA isomers in the photoexposed and non-photoexposed skin of patients with multiple non-melanoma skin cancer (NMSC), enrolled in different periods of the year, in comparison with control subjects. Patients/methods UCA isomers were determined by high-performance liquid chromatography analysis in samples from the outer arm (photoexposed site) and buttock (non-photoexposed site) obtained from 20 patients and 19 controls during the winter period (October to April), and from five patients and 11 controls during the summer period (June to September). Results In the winter months, no difference was found between patients and controls in the concentration of UCA or the percentage of cis-UCA in either site. In the summer months, the percentage of cis-UCA in the buttock of patients and controls was similar but it was significantly higher in the arm of the controls (42%) than in the patients (17%). Conclusions We conclude that different behaviour regarding sun exposure is the most likely explanation for these results, and that the concentration of UCA and its isomers does not reflect a tendency for individuals to develop NMSC.
β2 integrins modulate the initiation and progression of atherosclerosis in low-density lipoprotein receptor knockout mice
Authors: Aksam Merched, Katherine Tollefson, Lawrence Chan
Journal: Cardiovascular Research (2009)

β2 integrin-mediated adhesion is thought to be a key event in cardiovascular disease. However, results of clinical trials targeting these molecules have been disappointing. Here, we investigated the effect of inactivation of β2 integrins at different stages of atherosclerosis by timed bone marrow transplantation (BMT) of CD18−/− cells in low-density lipoprotein receptor knockout (LDLR−/−) mice. Early BMT before fatty streak formation revealed a short-term protective effect of CD18 (34% atherosclerotic lesion reduction). Once fatty streak lesions had developed (5-week atherogenic diet) before BMT, β2 integrin expression did not affect lesion progression. However, after the establishment of more mature lesions (pre-feeding mice the atherogenic diet for 10 weeks), CD18+/+ BMT enhanced atherosclerosis (36%) lesion progression compared with CD18−/− BMT. Furthermore, β2 integrins modulated the capacity of isolated peritoneal macrophages to take up acetylated LDL and native LDL and to phagocytose apoptotic cells, possibly via CD18-dependent mitogen-activated protein kinase signalling. Gene expression profile of CD18−/− and CD18+/+ macrophages revealed significant differences in putative protective as well as atherogenic functions. β2 integrin-mediated interaction between leucocytes and the vessel wall is a time-dependent and dynamic process. During the initiation phase, it protects against atherosclerotic lesion formation. However, with the evolution of the lesion and chronic exposure to dyslipidaemia, β2 integrins' pro-atherogenic action becomes dominant, accelerating the atherosclerotic process.
Accelerated Methotrexate, Vinblastine, Doxorubicin, and Cisplatin Is Safe, Effective, and Efficient Neoadjuvant Treatment for Muscle-Invasive Bladder Cancer: Results of a Multicenter Phase II Study With Molecular Correlates of Response and Toxicity
Authors: Elizabeth R. Plimack, Jean H. Hoffman-Censits, Rosalia Viterbo, Edouard J. Trabulsi, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Costas D. Lallas, Yu-Ning Wong, Jianqing Lin, Alexander Kutikov, Efrat Dotan, Timothy A. Brennan, Norma Palma, Essel Dulaimi, Reza Mehrazin, Stephen A. Boorjian, William Kevin Kelly, Robert G. Uzzo, Gary R. Hudes
Journal: Journal of Clinical Oncology (2014)

Purpose Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC); however, it is infrequently adopted in practice because of concerns regarding toxicity and delay to cystectomy. We hypothesized that three cycles of neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) would be safe, shorten the time to surgery, and yield similar pathologic complete response (pT0) rates compared with historical controls. Patients and Methods Patients with cT2-T4a and N0-N1 MIBC were eligible and received three cycles of AMVAC with pegfilgrastim followed by radical cystectomy with lymph node dissection. The primary end point was pT0 rate. Telomere length (TL) and p53 mutation status were correlated with response and toxicity. Results Forty-four patients were accrued; 60% had stage III to IV disease; median age was 64 years. Forty patients were evaluable for response, with 15 (38%; 95% CI, 23% to 53%) showing pT0 at cystectomy, meeting the primary end point of the study. Another six patients (14%) were downstaged to non–muscle invasive disease. Most (82%) experienced only grade 1 to 2 treatment-related toxicities. There were no grade 3 or 4 renal toxicities and no treatment-related deaths. One patient developed metastases and thus did not undergo cystectomy; all others (n = 43) proceeded to cystectomy within 8 weeks after last chemotherapy administration. Median time from start of chemotherapy to cystectomy was 9.7 weeks. TL and p53 mutation did not predict response or toxicity. Conclusion AMVAC is well tolerated and results in similar pT0 rates with 6 weeks of treatment compared with standard 12-week regimens. Further analysis is ongoing to ascertain whether molecular alterations in tumor samples can predict response to chemotherapy.
Visualization of Intrathoracically Disseminated Solid Tumors in Mice with Optical Imaging by Telomerase-Specific Amplification of a Transferred Green Fluorescent Protein Gene
Authors: Tatsuo Umeoka, Takeshi Kawashima, Shunsuke Kagawa, Fuminori Teraishi, Masaki Taki, Masahiko Nishizaki, Satoru Kyo, Katsuyuki Nagai, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara
Journal: Cancer Research (2004)

Abstract Currently available methods for detection of tumors in vivo such as X-ray, computed tomography, and ultrasonography are noninvasive and have been well studied; the images, however, are not specific for tumors. Direct optical imaging of tumor cells in vivo that can clearly distinguish them from surrounding normal tissues may be clinically useful. Here, we describe a new approach to visualizing tumors whose fluorescence can be detected using tumor-specific replication-competent adenovirus (OBP-301, Telomelysin) in combination with Ad-GFP, a replication-deficient adenovirus expressing green fluorescent protein (GFP). Human telomerase reverse transcriptase is the catalytic subunit of telomerase, which is highly active in cancer cells but quiescent in most normal somatic cells. We constructed an adenovirus 5 vector in which the human telomerase reverse transcriptase promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site and showed that OBP-301 replicated efficiently in human cancer cells, but not in normal cells such as human fibroblasts. When the human lung and colon cancer cell lines were infected with Ad-GFP at a low multiplicity of infection, GFP expression could not be detected under a fluorescence microscope; in the presence of OBP-301, however, Ad-GFP replicated in these tumor cells and showed strong green signals. In contrast, coinfection with OBP-301 and Ad-GFP did not show any signals in normal cells such as fibroblasts and vascular endothelial cells. We also found that established subcutaneous tumors could be visualized after intratumoral injection of OBP-301 and Ad-GFP. A549 human lung tumors and SW620 human colon tumors transplanted into BALB/c nu/nu mice were intratumorally injected with 8 × 105 plaque-forming units of Ad-GFP in combination with 8 × 106 plaque-forming units of OBP-301. Within 3 days of treatment, the fluorescence of the expressed GFP became visible by a three-chip color cooled charged-coupled device camera in these tumors, whereas intratumoral injection of Ad-GFP alone could not induce GFP fluorescence. Moreover, intrathoracic administration of Ad-GFP and OBP-301 could visualize disseminated A549 tumor nodules in mice after intrathoracic implantation. Our results indicate that intratumoral or intrathoracic injection of Ad-GFP in combination with OBP-301 might be a useful diagnostic method that provides a foundation for future clinical application.
Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer
Authors: Mark J. Smyth, Morgan E. Wallace, Stephen L. Nutt, Hideo Yagita, Dale I. Godfrey, Yoshihiro Hayakawa
Journal: The Journal of Experimental Medicine (2005)

The CD1d reactive glycolipid, α-galactosylceramide (α-GalCer), potently activates T cell receptor-α type I invariant NKT cells that secondarily stimulate the proliferation and activation of other leukocytes, including NK cells. Here we report a rational approach to improving the antitumor activity of α-GalCer by using delayed interleukin (IL)-21 treatment to mature the α-GalCer–expanded pool of NK cells into highly cytotoxic effector cells. In a series of experimental and spontaneous metastases models in mice, we demonstrate far superior antitumor activity of the α-GalCer/IL-21 combination above either agent alone. Superior antitumor activity was critically dependent upon the increased perforin-mediated cytolytic activity of NK cells. Transfer of α-GalCer–pulsed dendritic cells (DCs) followed by systemic IL-21 caused an even more significant reduction in established (day 8) metastatic burden and prolonged survival. In addition, this combination prevented chemical carcinogenesis more effectively. Combinations of IL-21 with other NK cell–activating cytokines, such as IL-2 and IL-12, were much less effective in the same experimental metastases models, and these cytokines did not substitute effectively for IL-21 in combination with α-GalCer. Overall, the data suggest that NK cell antitumor function can be enhanced greatly by strategies that are designed to expand and differentiate NK cells via DC activation of NKT cells.
Paracrine Signaling by Platelet-Derived Growth Factor-CC Promotes Tumor Growth by Recruitment of Cancer-Associated Fibroblasts
Authors: Charlotte Anderberg, Hong Li, Linda Fredriksson, Johanna Andrae, Christer Betsholtz, Xuri Li, Ulf Eriksson, Kristian Pietras
Journal: Cancer Research (2008)

Abstract Cancer results from the concerted performance of malignant cells and stromal cells. Cell types populating the microenvironment are enlisted by the tumor to secrete a host of growth-promoting cues, thus upholding tumor initiation and progression. Platelet-derived growth factors (PDGF) support the formation of a prominent tumor stromal compartment by as of yet unidentified molecular effectors. Whereas PDGF-CC induces fibroblast reactivity and fibrosis in a range of tissues, little is known about the function of PDGF-CC in shaping the tumor-stroma interplay. Herein, we present evidence for a paracrine signaling network involving PDGF-CC and PDGF receptor-α in malignant melanoma. Expression of PDGFC in a mouse model accelerated tumor growth through recruitment and activation of different subsets of cancer-associated fibroblasts. In seeking the molecular identity of the supporting factors provided by cancer-associated fibroblasts, we made use of antibody arrays and an in vivo coinjection model to identify osteopontin as the effector of the augmented tumor growth induced by PDGF-CC. In conclusion, we establish paracrine signaling by PDGF-CC as a potential drug target to reduce stromal support in malignant melanoma. [Cancer Res 2009;69(1):369–78]
New Insights into Epithelial-Mesenchymal Transition in Kidney Fibrosis
Authors: Youhua Liu
Journal: Journal of the American Society of Nephrology (2009)

Epithelial-mesenchymal transition (EMT), a process by which differentiated epithelial cells undergo a phenotypic conversion that gives rise to the matrix-producing fibroblasts and myofibroblasts, is increasingly recognized as an integral part of tissue fibrogenesis after injury. However, the degree to which this process contributes to kidney fibrosis remains a matter of intense debate and is likely to be context-dependent. EMT is often preceded by and closely associated with chronic interstitial inflammation and could be an adaptive response of epithelial cells to a hostile or changing microenvironment. In addition to tubular epithelial cells, recent studies indicate that endothelial cells and glomerular podocytes may also undergo transition after injury. Phenotypic alteration of podocytes sets them in motion to functional impairment, resulting in proteinuria and glomerulosclerosis. Several intracellular signal transduction pathways such as TGFβ/Smad, integrin-linked kinase (ILK) and Wnt/β-catenin signaling are essential in controlling the process of EMT and presently are potential targets of antifibrotic therapy. This review highlights the current understanding of EMT and its underlying mechanisms to stimulate further discussion on its role, not only in the pathogenesis of renal interstitial fibrosis but also in the onset of podocyte dysfunction, proteinuria, and glomerulosclerosis.
Nasal Challenge to Indoor Particulate Matter (PM) Does Not Lead to Local or Systemic Eosinophilia
Authors: M.C. Ong, P.N. Breysse, G.B. Diette, B.M. Thomas, P.J. Lenehan, J. Curtin-Brosnan, E.C. Matsui
Journal: Journal of Allergy and Clinical Immunology (2011)
Immune-driven recombination and loss of control after HIV superinfection
Authors: Hendrik Streeck, Bin Li, Art F.Y. Poon, Arne Schneidewind, Adrianne D. Gladden, Karen A. Power, Demetre Daskalakis, Suzane Bazner, Rosario Zuniga, Christian Brander, Eric S. Rosenberg, Simon D.W. Frost, Marcus Altfeld, Todd M. Allen
Journal: The Journal of Experimental Medicine (2008)

After acute HIV infection, CD8+ T cells are able to control viral replication to a set point. This control is often lost after superinfection, although the mechanism behind this remains unclear. In this study, we illustrate in an HLA-B27+ subject that loss of viral control after HIV superinfection coincides with rapid recombination events within two narrow regions of Gag and Env. Screening for CD8+ T cell responses revealed that each of these recombination sites (∼50 aa) encompassed distinct regions containing two immunodominant CD8 epitopes (B27-KK10 in Gag and Cw1-CL9 in Env). Viral escape and the subsequent development of variant-specific de novo CD8+ T cell responses against both epitopes were illustrative of the significant immune selection pressures exerted by both responses. Comprehensive analysis of the kinetics of CD8 responses and viral evolution indicated that the recombination events quickly facilitated viral escape from both dominant WT- and variant-specific responses. These data suggest that the ability of a superinfecting strain of HIV to overcome preexisting immune control may be related to its ability to rapidly recombine in critical regions under immune selection pressure. These data also support a role for cellular immune pressures in driving the selection of new recombinant forms of HIV.
Objectively measured physical capability levels and mortality: systematic review and meta-analysis
Authors: R. Cooper, D. Kuh, R. Hardy, None Mortality Review Group
Journal: BMJ (2010)

<b>Objective</b> To do a quantitative systematic review, including published and unpublished data, examining the associations between individual objective measures of physical capability (grip strength, walking speed, chair rising, and standing balance times) and mortality in community dwelling populations. <b>Design</b> Systematic review and meta-analysis. <b>Data sources</b> Relevant studies published by May 2009 identified through literature searches using Embase (from 1980) and Medline (from 1950) and manual searching of reference lists; unpublished results were obtained from study investigators. <b>Study selection</b> Eligible observational studies were those done in community dwelling people of any age that examined the association of at least one of the specified measures of physical capability (grip strength, walking speed, chair rises, or standing balance) with mortality. <b>Data synthesis</b> Effect estimates obtained were pooled by using random effects meta-analysis models with heterogeneity between studies investigated. <b>Results</b> Although heterogeneity was detected, consistent evidence was found of associations between all four measures of physical capability and mortality; those people who performed less well in these tests were found to be at higher risk of all cause mortality. For example, the summary hazard ratio for mortality comparing the weakest with the strongest quarter of grip strength (14 studies, 53 476 participants) was 1.67 (95% confidence interval 1.45 to 1.93) after adjustment for age, sex, and body size (I<sup>2</sup>=84.0%, 95% confidence interval 74% to 90%; P from Q statistic &lt;0.001). The summary hazard ratio for mortality comparing the slowest with the fastest quarter of walking speed (five studies, 14 692 participants) was 2.87 (2.22 to 3.72) (I<sup>2</sup>=25.2%, 0% to 70%; P=0.25) after similar adjustments. Whereas studies of the associations of walking speed, chair rising, and standing balance with mortality have only been done in older populations (average age over 70 years), the association of grip strength with mortality was also found in younger populations (five studies had an average age under 60 years). <b>Conclusions</b> Objective measures of physical capability are predictors of all cause mortality in older community dwelling populations. Such measures may therefore provide useful tools for identifying older people at higher risk of death.
Validation of the Diabetes Prevention Trial–Type 1 Risk Score in the TrialNet Natural History Study
Authors: Jay M. Sosenko, Jay S. Skyler, Jeffrey Mahon, Jeffrey P. Krischer, Craig A. Beam, David C. Boulware, Carla J. Greenbaum, Lisa E. Rafkin, Catherine Cowie, David Cuthbertson, Jerry P. Palmer
Journal: Diabetes Care (2011)

OBJECTIVE We assessed the accuracy of the Diabetes Prevention Trial–Type 1 Risk Score (DPTRS), developed from the Diabetes Prevention Trial–Type 1 (DPT-1), in the TrialNet Natural History Study (TNNHS). RESEARCH DESIGN AND METHODS Prediction accuracy of the DPTRS was assessed with receiver-operating characteristic curve areas. The type 1 diabetes cumulative incidence within the DPTRS intervals was compared between the TNNHS and DPT-1 cohorts. RESULTS Receiver-operating characteristic curve areas for the DPTRS were substantial in the TNNHS (P &amp;lt; 0.001 at both 2 and 3 years). The type 1 diabetes cumulative incidence did not differ significantly between the TNNHS and DPT-1 cohorts within DPTRS intervals. In the TNNHS, 2-year and 3-year risks were low for DPTRS intervals &amp;lt;6.50 (&amp;lt;0.10 and &amp;lt;0.20, respectively). Thresholds ≥7.50 were indicative of high risk in both cohorts (2-year risks: 0.49 in the TNNHS and 0.51 in DPT-1). CONCLUSIONS The DPTRS is an accurate and robust predictor of type 1 diabetes in autoantibody-positive populations.
Dose response of continuous positive airway pressure on nasal symptoms, obstruction and inflammation<i>in vivo</i>and<i>in vitro</i>
Authors: Mohammed D. AlAhmari, Raymond J. Sapsford, Jadwiga A. Wedzicha, John R. Hurst
Journal: European Respiratory Journal (2012)

Obstructive sleep apnoea is a common condition associated with cardiovascular risk. Continuous positive airway pressure (CPAP) is an effective treatment but is associated with nasal side-effects, which hinder compliance and may result from inflammation. We investigated whether CPAP was pro-inflammatory to human subjects in vivo , and to cultured bronchial epithelial cells in vitro . In vivo , we further investigated whether induction of nasal inflammation was associated with the development of systemic inflammation, nasal symptoms and changes in nasal mucociliary clearance. In vitro , CPAP resulted in cytokine release from cultured BEAS-2B cells in a time- and dose (pressure)-dependent manner. In vivo , CPAP resulted in dose-dependent upregulation of nasal inflammatory markers associated with the development of nasal symptoms, and reduced mucociliary clearance. CPAP also upregulated selected markers of systemic inflammation. CPAP results in dose-dependent release of inflammatory cytokines from human epithelial cells in vitro and in vivo . In vivo responses were associated with systemic inflammation, reductions in nasal mucociliary function and the development of nasal symptoms. This emphasises the need for novel strategies to reduce nasal inflammation and therefore aid compliance.
Inhibition of Prostate Tumor Growth and Bone Remodeling by the Vascular Targeting Agent VEGF121/rGel
Authors: Khalid A. Mohamedali, Ann T. Poblenz, Charles R. Sikes, Nora M. Navone, Philip E. Thorpe, Bryant G. Darnay, Michael G. Rosenblum
Journal: Cancer Research (2006)

Abstract The pathophysiology of tumor growth following skeletal metastases and the poor response of this type of lesion to therapeutic intervention remains incompletely understood. Vascular endothelial growth factor (VEGF)-A and its receptors play a role in both osteoclastogenesis and tumor growth. Systemic (i.v.) treatment of nude mice bearing intrafemoral prostate (PC-3) tumors with the vascular ablative agent VEGF121/recombinant gelonin (rGel) strongly inhibited tumor growth. Fifty percent of treated animals had complete regression of bone tumors with no development of lytic bone lesions. Immunohistochemical analysis showed that VEGF121/rGel treatment suppressed tumor-mediated osteoclastogenesis in vivo. In vitro treatment of murine osteoclast precursors, both cell line (RAW264.7) and bone marrow–derived monocytes (BMM), revealed that VEGF121/rGel was selectively cytotoxic to osteoclast precursor cells rather than mature osteoclasts. VEGF121/rGel cytotoxicity was mediated by Flt-1, which was down-regulated during osteoclast differentiation. Analysis by flow cytometry and reverse transcription-PCR showed that both BMM and RAW264.7 cells display high levels of Flt-1 but low levels of Flk-1. Internalization of VEGF121/rGel into osteoclast precursor cells was suppressed by pretreatment with an Flt-1 neutralizing antibody or by placenta growth factor but not with an Flk-1 neutralizing antibody. Thus, VEGF121/rGel inhibits osteoclast maturation in vivo and it seems that this process is important in the resulting suppression of skeletal osteolytic lesions. This is a novel and unique mechanism of action for this class of agents and suggests a potentially new approach for treatment or prevention of tumor growth in bone. (Cancer Res 2006; 66(22): 10919-28)