tbuckley/cabot-search huggingface dataset:
Indoleamine 2,3-Dioxygenase Expression in Human Cancers: Clinical and Immunologic Perspectives
Authors: Jessica Godin-Ethier, Laïla-Aïcha Hanafi, Ciriaco A. Piccirillo, Réjean Lapointe
Journal: Clinical Cancer Research (2011)

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme with immune-regulating activities in many contexts, such as fetal protection, allograft protection, and cancer progression. Clinical trials are currently evaluating IDO inhibition with 1-methyltryptophan in cancer immunotherapy. However, the exact role of tryptophan catabolism by IDO in human cancers remains poorly understood. Here, we review several studies that correlate IDO expression in human cancer samples and tumor-draining lymph nodes, with relevant clinical or immunologic parameters. IDO expression in various histologic cancer types seems to decrease tumor infiltration of immune cells and to increase the proportion of regulatory T lymphocytes in the infiltrate. The impact of IDO on different immune cell infiltration leads to the conclusion that IDO negatively regulates the recruitment of antitumor immune cells. In addition, increased IDO expression correlates with diverse tumor progression parameters and shorter patient survival. In summary, in the vast majority of the reported studies, IDO expression is correlated with a less favorable prognosis. As we may see results from the first clinical trials with 1-methyltryptophan in years to come, this review brings together IDO studies from human studies and aims to help appreciate outcomes from current and future trials. Consequently, IDO inhibition seems a promising approach for cancer immunotherapy.
Microvascular function is impaired in ankylosing spondylitis and improves after tumour necrosis factor α blockade
Authors: I C van Eijk, M J L Peters, E H Serné, I E van der Horst-Bruinsma, B A C Dijkmans, Y M Smulders, M T Nurmohamed
Journal: Annals of the Rheumatic Diseases (2008)

Ankylosing spondylitis (AS) is associated with increased cardiovascular morbidity and mortality. Microvascular function has been linked to several risk factors for cardiovascular disease. Inflammation in AS may cause microvascular dysfunction. To test this, we assessed microvascular function in (a) patients with AS compared to healthy controls and (b) patients with AS before and after 1 month of anti-tumour necrosis factor (TNF)alpha treatment with etanercept.A total of 15 consecutive patients with AS, who were scheduled for etanercept treatment according to the Assessment in Ankylosing Spondylitis (ASAS) group guidelines, and 12 healthy controls matched for age and sex, were recruited. Endothelium-dependent and independent vasodilatation in skin were evaluated with laser Doppler fluxmetry after iontophoresis of acetylcholine and sodium nitroprusside, respectively. Videomicroscopy was used to measure recruitment of skin capillaries after arterial occlusion.Compared to healthy controls, patients with AS had impaired endothelium-dependent vasodilatation and capillary recruitment. Following anti-TNFalpha treatment, microvascular function improved significantly for endothelium-dependent vasodilatation (p = 0.03) and capillary recruitment (p = 0.006). A significant correlation was observed between changes in endothelium-dependent vasodilatation and changes in erythrocyte sedimentation rate (ESR) (r = -0.56; p = 0.03).Microvascular dysfunction is present in patients with AS with active disease, but improves as inflammation regresses after TNFalpha blockade.
Ferritin Contributes to Melanoma Progression by Modulating Cell Growth and Sensitivity to Oxidative Stress
Authors: Alfonso Baldi, Daniela Lombardi, Patrizia Russo, Emanuele Palescandolo, Antonio De Luca, Daniele Santini, Feliciano Baldi, Luigi Rossiello, Maria Lucia Dell'Anna, Arianna Mastrofrancesco, Vittoria Maresca, Enrica Flori, Pier Giorgio Natali, Mauro Picardo, Marco G. Paggi
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Employing an in vitro model system of human melanoma progression, we previously reported ferritin light chain (L-ferritin) gene overexpression in the metastatic phenotype. Here, we attempted to characterize the role of ferritin in the biology of human melanoma and in the progression of this disease. Experimental Design: Starting from the LM human metastatic melanoma cell line, we engineered cell clones in which L-ferritin gene expression was down-regulated by the stable expression of a specific antisense construct. These cells were then assayed for their growth capabilities, chemoinvasive properties, and sensitivity to oxidative stress. Additionally, ferritin protein content in primary and metastatic human melanomas was determined by immunohistochemistry. Results: Artificial L-ferritin down-regulation in the LM cells strongly inhibited proliferation and chemoinvasion in vitro and cell growth in vivo. In addition, L-ferritin down-regulated cells displayed enhanced sensitivity to oxidative stress and to apoptosis. Concurrently, immunohistochemical analysis of a human melanoma tissue array revealed that ferritin expression level in metastatic lesions was significantly higher (P &amp;lt; 0.0001) than in primary melanomas. Furthermore, ferritin expression was constantly up-regulated in autologous lymph node melanoma metastases when compared with the respective primary tumors in a cohort of 11 patients. Conclusions: These data suggest that high ferritin expression can enhance cell growth and improve resistance to oxidative stress in metastatic melanoma cells by interfering with their cellular antioxidant system. The potential significance of these findings deserves to be validated in a clinical setting.
Stress Management and Immune System Reconstitution in Symptomatic HIV-Infected Gay Men Over Time: Effects on Transitional Naive T Cells (CD4<sup>+</sup>CD45RA<sup>+</sup>CD29<sup>+</sup>)
Authors: Michael H. Antoni, Dean G. Cruess, Nancy Klimas, Kevin Maher, Stacy Cruess, Mahendra Kumar, Susan Lutgendorf, Gail Ironson, Neil Schneiderman, Mary Ann Fletcher
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Changes in immunologic status were evaluated in 25 HIV-infected men randomly assigned to a 10-week stress management intervention or a wait-list control condition. METHOD: The authors monitored changes in number of transitional naive T cells (CD4+CD45RA+CD29+) over 6–12 months after the completion of the intervention. RESULTS: Men receiving stress management had higher CD4+ CD45RA+CD29+ cell counts at follow-up than did the control subjects. This difference was independent of initial number of naive T cells and HIV virus load. CONCLUSIONS: Stress management is associated with immunologic reconstitution in HIV-positive gay men.
PWE-052 Phenotyping the early morning rush (EMR) in patients with diarrhoea predominant irritable bowel syndrome (IBS-D)
Authors: K Garsed, M Hastings, C Lam, P Whorwell, R Spiller
Journal: Gut (2012)

<h3>Introduction</h3> A proportion of patients with IBS-D describe frequent bowel movements first thing in the morning. While most clinicians recognise the phenomenon there is currently no definition of this "early morning rush" and no data describing the subgroup of patients who experience this disabling symptom which frequently impacts on their quality of life and ability to work. <h3>Methods</h3> 119 patients meeting the Rome 3 criteria for IBS-D and 20 age and sex matched healthy volunteers (HV) completed a 1-week stool diary, hospital anxiety and depression score (HADS), and personal health questionnaire (PHQ-12). They also completed an IBS severity score (IBSSS) and IBS quality of life score (IBSQOL) as part of entry into a clinical trial. Whole gut transit (WGT) was measured during the placebo arm using the radio-opaque marker method. EMR was defined as ≥2 bowel movements within 1 h, between midnight and midday. Patients and HV were divided into 3 subgroups, those with ≤2 days/week EMR = normal morning rush (NMR), those with 3–4 days/week EMR = moderate morning rush (MMR), and those with 5–7 days/week with EMR =severe morning rush (SMR). <h3>Results</h3> 16% of patients had MMR and 15% of patients had SMR, all HV had NMR. Those with SMR had greater psychological distress (sum of the HADS score) than those with NMR, 19.11 (±1.8) vs 13.48 (±0.8) p=0.021, and more somatic symptoms (PHQ-12), 9.2 (±0.9) vs 6.5 (±0.4) p=0.02. The SMR group had greater mean daily stool frequency than those with NMR and MMR 5.6 (3.5–8.2) vs 2.14 (1.7–3.0) and 3.7 (2.7–4.4) p&lt;0.0001 with a higher IBSSS 366 (±18.4) vs 296.6 (±9.4) and 295.9 (±17.2) p=0.005, this was accompanied by a lower IBSQOL 334.3 (±21.1) vs 467.3 (±17.9) and 467.3 (±33.4) p=0.004. WGT (in hours) was significantly faster in the SMR group 7 (5.5–15) vs 19 (10–39) in the NMR and 16 (8.5–24.5) in the MMR groups p=0.03. <h3>Conclusion</h3> Around 1/3 of IBS patients suffer from early morning rush. Those severely affected represent a group with a worse quality of life, greater psychological distress and more somatic symptoms. This is associated with faster whole gut transit and increased stool frequency. A third of the patients with SMR dropped out of the trial compared to &lt;10% in the other groups making this a challenging subgroup to study. <h3>Competing interests</h3> None declared.
Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers
Authors: Ryohei Katayama, Alice T. Shaw, Tahsin M. Khan, Mari Mino-Kenudson, Benjamin J. Solomon, Balazs Halmos, Nicholas A. Jessop, John C. Wain, Alan Tien Yeo, Cyril Benes, Lisa Drew, Jamal Carlos Saeh, Katherine Crosby, Lecia V. Sequist, A. John Iafrate, Jeffrey A. Engelman
Journal: Science Translational Medicine (2012)

Multiple mechanisms of crizotinib resistance were identified in lung cancer patients including new secondary ALK mutations and activation of receptor tyrosine kinases.
SOME ANTECEDENT FACTORS IN ARMY PRISONERS
Authors: ADOLF HAAS, EDMUND J. KURAS
Journal: American Journal of Psychiatry (1958)

This study of 543 consecutive admissions to the USAREUR Rehabilitation Center shows a certain concentration of negative antecedent developmental factors in the background of these men. I do not consider that the figures in this paper are by any means decisive enough for definitive conclusions, but I believe that they indicate an open field for additional sociopsychological research into the problems of the Armed Services abroad in peacetime. Additional data, should they be collected, could aid in a reevaluation of induction procedures presently in use. Such data could help in the selection of suitable personnel for overseas tours of duty in peacetime. They might also add some new and valuable insights which would aid in the leadership training of lower echelon commanders.
Establishment of T and B cell lines from patients with mycosis fungoides
Authors: K. KALTOFT, K. THESTRUP-PEDERSEN, J. R. JENSEN, SUSANNE BISBALLE, H. ZACHARIAE
Journal: British Journal of Dermatology (1984)

Eighteen patients with mycosis fungoides were studied in order to establish cell lines that might be associated with the human T cell leukaemia‐lymphoma virus (HTLV). Three T cell lines were established, two from affected skin and one from a lymph node showing dermatopahtic lymphadenopathy. The T cells expressed OKT3 and OKT4 antigens. They temporarily expressed an HTLV p19‐like antigen in up to 5% of the cells during culture. None of our patients had lymphocytosis or abnormal lymphocytes, except one patient with Sézary's syndrome. We could not establish T cell lines from peripheral blood, but five B lymphoblastoid cell lines were obtained, all positive for the Epstein–Barr virus nuclear antigen. Our finding that T cell lines can be established from skin biopsies and lymph nodes of patients with mycosis fungoides, but not from the blood, supports the concept of a malignant T lymphocyte primarily localized in the skin. The temporary expression of HTLV p19 antigen may indicate the presence of retrovirus, but further studies are needed.
Arsenic Trioxide Treatment Decreases the Oxygen Consumption Rate of Tumor Cells and Radiosensitizes Solid Tumors
Authors: Caroline Diepart, Oussama Karroum, Julie Magat, Olivier Feron, Julien Verrax, Pedro Buc Calderon, Vincent Grégoire, Philippe Leveque, Julie Stockis, Nicolas Dauguet, Bénédicte F. Jordan, Bernard Gallez
Journal: Cancer Research (2011)

Arsenic trioxide (As(2)O(3)) is an effective therapeutic against acute promyelocytic leukemia and certain solid tumors. Because As(2)O(3) inhibits mitochondrial respiration in leukemia cells, we hypothesized that As(2)O(3) might enhance the radiosensitivity of solid tumors by increasing tumor oxygenation [partial pressure of oxygen (pO(2))] via a decrease in oxygen consumption. Two murine models of radioresistant hypoxic cancer were used to study the effects of As(2)O(3). We measured pO(2) and the oxygen consumption rate in vivo by electron paramagnetic resonance oximetry and (19)fluorine-MRI relaxometry. Tumor perfusion was assessed by Patent blue staining. In both models, As(2)O(3) inhibited mitochondrial respiration, leading to a rapid increase in pO(2). The decrease in oxygen consumption could be explained by an observed decrease in glutathione in As(2)O(3)-treated cells, as this could increase intracellular reactive oxygen species that can disrupt mitochondrial membrane potential. When tumors were irradiated during periods of As(2)O(3)-induced augmented oxygenation, radiosensitivity increased by 2.2-fold compared with control mice. Notably, this effect was abolished when temporarily clamped tumors were irradiated. Together, our findings show that As(2)O(3) acutely increases oxygen consumption and radiosensitizes tumors, providing a new rationale for clinical investigations of As(2)O(3) in irradiation protocols to treat solid tumors.
Replication and Functional Genomic Analyses of the Breast Cancer Susceptibility Locus at 6q25.1 Generalize Its Importance in Women of Chinese, Japanese, and European Ancestry
Authors: Qiuyin Cai, Wanqing Wen, Shimian Qu, Guoliang Li, Kathleen M. Egan, Kexin Chen, Sandra L. Deming, Hongbing Shen, Chen-Yang Shen, Marilie D. Gammon, William J. Blot, Keitaro Matsuo, Christopher A. Haiman, Ui Soon Khoo, Motoki Iwasaki, Regina M. Santella, Lina Zhang, Alecia Malin Fair, Zhibin Hu, Pei-Ei Wu, Lisa B. Signorello, Linda Titus-Ernstoff, Kazuo Tajima, Brian E. Henderson, Kelvin Y.K. Chan, Yoshio Kasuga, Polly A. Newcomb, Hong Zheng, Yong Cui, Furu Wang, Ya-Lan Shieh, Hiroji Iwata, Loic Le Marchand, Sum Yin Chan, Martha J. Shrubsole, Amy Trentham-Dietz, Shoichiro Tsugane, Montserrat Garcia-Closas, Jirong Long, Chun Li, Jiajun Shi, Bo Huang, Yong-Bing Xiang, Yu-Tang Gao, Wei Lu, Xiao-Ou Shu, Wei Zheng
Journal: Cancer Research (2011)

We evaluated the generalizability of a single nucleotide polymorphism (SNP), rs2046210 (A/G allele), associated with breast cancer risk that was initially identified at 6q25.1 in a genome-wide association study conducted among Chinese women. In a pooled analysis of more than 31,000 women of East-Asian, European, and African ancestry, we found a positive association for rs2046210 and breast cancer risk in Chinese women [ORs (95% CI) = 1.30 (1.22-1.38) and 1.64 (1.50-1.80) for the AG and AA genotypes, respectively, P for trend = 1.54 × 10⁻³⁰], Japanese women [ORs (95% CI) = 1.31 (1.13-1.52) and 1.37 (1.06-1.76), P for trend = 2.51 × 10⁻⁴], and European-ancestry American women [ORs (95% CI) = 1.07 (0.99-1.16) and 1.18 (1.04-1.34), P for trend = 0.0069]. No association with this SNP, however, was observed in African American women [ORs (95% CI) = 0.81 (0.63-1.06) and 0.85 (0.65-1.11) for the AG and AA genotypes, respectively, P for trend = 0.4027]. In vitro functional genomic studies identified a putative functional variant, rs6913578. This SNP is 1,440 bp downstream of rs2046210 and is in high linkage disequilibrium with rs2046210 in Chinese (r(2) = 0.91) and European-ancestry (r² = 0.83) populations, but not in Africans (r² = 0.57). SNP rs6913578 was found to be associated with breast cancer risk in Chinese and European-ancestry American women. After adjusting for rs2046210, the association of rs6913578 with breast cancer risk in African Americans approached borderline significance. Results from this large consortium study confirmed the association of rs2046210 with breast cancer risk among women of Chinese, Japanese, and European ancestry. This association may be explained in part by a putatively functional variant (rs6913578) identified in the region.
The Mechanisms of Action of PPARs
Authors: Joel Berger, David E. Moller
Journal: Annual Review of Medicine (2002)

▪ Abstract The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPARγ, PPARα, and PPARδ, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we present the current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases.
Elastase secretion by stimulated macrophages. Characterization and regulation.
Authors: Z Werb, S Gordon
Journal: The Journal of Experimental Medicine (1975)

Thioglycolate-stimulated mouse peritoneal macrophages secrete a Proteinase which degrades insoluble elastin. There is little elastase activity in cell lysates but the bulk of the enzyme accumulates extracellularly during culture in serum-free medium. The secretion of elastase is sustained for over 12 days in culture and continued secretion of elastase requires protein synthesis. Unstimulated macrophages secrete very little elastase activity but can be triggered to secrete higher levels of this enzyme by phagocytosis and intracellular storage of latex particles. The macrophages elastase is a distinctive proteinase differing from the elastases of pancreas and granulocytes and is distinct from the other secreted proteinases of macrophages, namely, collagenase and plasminogen activator. The macrophages elastase is a serine proteinase and is inhibited by di-isopropyl phosphoro-fluoridate, ovoinhibitor, EDTA, dithiothretiol, and serum. Its activity is little affected by soybean trypsin inhibitor, turkey ovomucoid and chloromethyl ketones derived from tosyl lysine, tosyl phenylalanine, and acetyltetra alanine. Hydrolysis by macrophage elastase of chromogenic ester substrates for pancreatic elastase could not be detected. Elastase secretion by stimulated macrophages exceeds that by primary and established fibroblast cell strains. It is likely that elastase secretion by macrophages plays a major role in the pathogenesis of chronic destructive pulmonary diseases such as emphysema.
Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome
Authors: Daniel A. Dumesic, Sharon E. Oberfield, Elisabet Stener-Victorin, John C. Marshall, Joop S. Laven, Richard S. Legro
Journal: Endocrine Reviews (2015)

Polycystic ovary syndrome (PCOS) is a heterogeneous and complex disorder that has both adverse reproductive and metabolic implications for affected women. However, there is generally poor understanding of its etiology. Varying expert-based diagnostic criteria utilize some combination of oligo-ovulation, hyperandrogenism, and the presence of polycystic ovaries. Criteria that require hyperandrogenism tend to identify a more severe reproductive and metabolic phenotype. The phenotype can vary by race and ethnicity, is difficult to define in the perimenarchal and perimenopausal period, and is exacerbated by obesity. The pathophysiology involves abnormal gonadotropin secretion from a reduced hypothalamic feedback response to circulating sex steroids, altered ovarian morphology and functional changes, and disordered insulin action in a variety of target tissues. PCOS clusters in families and both female and male relatives can show stigmata of the syndrome, including metabolic abnormalities. Genome-wide association studies have identified a number of candidate regions, although their role in contributing to PCOS is still largely unknown.
Super-Suppression of Mitochondrial Reactive Oxygen Species Signaling Impairs Compensatory Autophagy in Primary Mitophagic Cardiomyopathy
Authors: Moshi Song, Yun Chen, Guohua Gong, Elizabeth Murphy, Peter S. Rabinovitch, Gerald W. Dorn
Journal: Circulation Research (2014)

Mitochondrial reactive oxygen species (ROS) are implicated in aging, chronic degenerative neurological syndromes, and myopathies. On the basis of free radical hypothesis, dietary, pharmacological, and genetic ROS suppression has been tested to minimize tissue damage, with remarkable therapeutic efficacy. The effects of mitochondrial-specific ROS suppression in primary mitophagic dysfunction are unknown.An in vivo dose-ranging analysis of ROS suppression in an experimental cardiomyopathy provoked by defective mitochondrial clearance.Mice lacking mitofusin 2 (Mfn2) in hearts have impaired parkin-mediated mitophagy leading to accumulation of damaged ROS-producing organelles and progressive heart failure. As expected, cardiomyocyte-directed expression of mitochondrial-targeted catalase at modest levels normalized mitochondrial ROS production and prevented mitochondrial depolarization, respiratory impairment, and structural degeneration in Mfn2 null hearts. In contrast, catalase expression at higher levels that supersuppressed mitochondrial ROS failed to improve either mitochondrial fitness or cardiomyopathy, revealing that ROS toxicity is not the primary mechanism for cardiac degeneration. Lack of benefit from supersuppressing ROS was associated with failure to invoke secondary autophagic pathways of mitochondrial quality control, revealing a role for ROS signaling in mitochondrial clearance. Mitochondrial permeability transition pore function was normal, and genetic inhibition of mitochondrial permeability transition pore function did not alter mitochondrial or cardiac degeneration, in Mfn2 null hearts.Local mitochondrial ROS (1) contribute to mitochondrial degeneration and (2) activate mitochondrial quality control mechanisms. A therapeutic window for mitochondrial ROS suppression should minimize the former while retaining the latter, which we achieved by expressing lower levels of catalase.
Oncostatin M Is Elevated in Mucosal Disease and May Mediate Epithelial Barrier Dysfunction in Vivo
Authors: Kathryn L. Pothoven, James E. Norton, Lydia Suh, Roderick G. Carter, Kathryn E. Hulse, Erin Rocci, Nirmala Gonsalves, Mark C. Liu, Anju T. Peters, Kathleen E. Harris, Stephanie Shintani Smith, David B. Conley, Leslie C. Grammer, Atsushi Kato, Robert C. Kern, Paul Bryce, Bruce Tan, Robert P. Schleimer
Journal: Journal of Allergy and Clinical Immunology (2015)