tbuckley/cabot-search huggingface dataset:
Imbalance of stromelysin-1 and TIMP-1 in the mucosal lesions of children with inflammatory bowel disease
Authors: R B Heuschkel
Journal: Gut (2000)

<h3>BACKGROUND</h3> Degradation of the extracellular matrix and ulceration of the mucosa are major features of inflammatory bowel disease (IBD). One of the most important enzymes in degrading the matrix and produced in excess by cytokine activated stromal cells, is stromelysin-1. The activity of stromelysin-1 is controlled by tissue inhibitor of metalloproteinase (TIMP-1), its natural inhibitor. In model systems excess stromelysin-1 produces mucosal degradation. <h3>METHODS</h3> Quantitative competitive RT-PCR was used to analyse stromelysin-1 and TIMP-1 transcripts; western blotting was used to measure the amount of stromelysin-1 and TIMP-1 protein in biopsy samples from children with IBD. <h3>RESULTS</h3> In biopsies from patients with active Crohn9s disease (n=24), ulcerative colitis (n=23), and controls (n=16), TIMP-1 transcripts and protein were abundant and unchanged. Stromelysin-1 transcripts and protein were markedly elevated in mucosal biopsies obtained from inflamed sites of patients with active IBD but were not elevated in adjacent endoscopically normal mucosa (n=10). Elevated levels of stromelysin-1 transcripts in active Crohn9s disease (n=5) returned to normal levels following treatment with enteral nutrition. <h3>CONCLUSIONS</h3> Stromelysin-1 is markedly overexpressed at inflamed sites in patients with IBD whereas TIMP-1 remains unaltered. Excess stromelysin-1 is likely to be responsible for loss of mucosal integrity in IBD.
Growth Differentiation Factor 15, a Marker of Oxidative Stress and Inflammation, for Risk Assessment in Patients With Atrial Fibrillation
Authors: Lars Wallentin, Ziad Hijazi, Ulrika Andersson, John H. Alexander, Raffaele De Caterina, Michael Hanna, John D. Horowitz, Elaine M. Hylek, Renato D. Lopes, Signild Åsberg, Christopher B. Granger, Agneta Siegbahn
Journal: Circulation (2014)

Background— Growth differentiation factor 15 (GDF-15), high-sensitivity troponin, and N-terminal pro-brain natriuretic peptide levels are predictive of death and cardiovascular events in healthy elderly subjects, patients with acute coronary syndrome, and patients with heart failure. High-sensitivity troponin I and N-terminal pro-brain natriuretic peptide are also prognostic in patients with atrial fibrillation. We evaluated the prognostic value of GDF-15 alone and in addition to clinical characteristics and other biomarkers in patients with atrial fibrillation. Methods and Results— The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients. Efficacy and safety outcomes during 1.9 years of follow-up were compared across quartiles of GDF-15 by use of Cox analyses adjusted for clinical characteristics, randomized treatment, and other biomarkers. The GDF-15 level showed a median of 1383 ng/L (interquartile range, 977–2052 ng/L). Annual rates of stroke or systemic embolism ranged from 0.9% to 2.03% ( P &lt;0.001); of major bleeding, from 1.22% to 4.53% ( P &lt;0.001); and of mortality, from 1.34% to 7.19% ( P &lt;0.001) in the lowest compared with the highest GDF-15 quartile. The prognostic information provided by GDF-15 was independent of clinical characteristics and clinical risk scores. Adjustment for the other cardiac biomarkers attenuated the prognostic value for stroke, whereas the prognostic value for mortality and major bleeding remained. Apixaban consistently reduced stroke, mortality, and bleeding, regardless of GDF-15 levels. Conclusions— GDF-15 is a risk factor for major bleeding, mortality, and stroke in atrial fibrillation. The prognostic value for major bleeding and death remained even in the presence of N-terminal pro-brain natriuretic peptide and high-sensitivity troponin I. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00412984.
Change in Working Time in a Population-Based Cohort of Patients With Breast Cancer
Authors: Marie Høyer, Karin Nordin, Johan Ahlgren, Leif Bergkvist, Mats Lambe, Birgitta Johansson, Claudia Lampic
Journal: Journal of Clinical Oncology (2012)

Purpose We examined changes in working time 16 months after a breast cancer diagnosis and identified factors associated with job discontinuation and/or decreased working time. Patients and Methods This was a population-based cohort study with 735 patients identified in the Regional Breast Cancer Quality Register of Central Sweden. The study sample consisted of 505 women (age &lt; 63 years at diagnosis) who completed questionnaires at baseline and at follow-up (on average 4 and 16 months after diagnosis, respectively). Clinical register data and questionnaire data on sociodemographic factors were obtained at baseline. Self-reported work-related data were obtained at follow-up. Odds ratios were estimated by using logistic regression models. Results Compared with prediagnosis working time, 72% reported no change in working time, 2% reported an increase, 15% reported a decrease, and 11% did not work at follow-up. Chemotherapy increased the likelihood (odds ratio [OR], 2.45; 95% CI, 1.38 to 4.34) of job discontinuation/decreased working time. Among chemotherapy recipients, associated factors included full-time work prediagnosis (OR, 3.25; 95% CI, 1.51 to 7.01), cancer-related work limitations (OR, 5.26; 95% CI, 2.30 to 12.03), and less value attached to work (OR, 3.69; 95% CI, 1.80 to 7.54). In the nonchemotherapy group, older age (OR, 1.09; 95% CI, 1.02 to 1.17) and less value attached to work (OR, 5.00; 95% CI, 2.01 to 12.45) were associated with the outcome. Conclusion The majority of women treated for breast cancer returned to their prediagnosis working time. Chemotherapy and cancer-related work limitations are important factors to take into account in identifying women in need of support. Moreover, it is important to consider the woman's own valuation of labor market participation.
Women With Synchronous Primary Cancers of the Endometrium and Ovary: Do They Have Lynch Syndrome?
Authors: Pamela T. Soliman, Russell R. Broaddus, Kathleen M. Schmeler, Molly S. Daniels, Delia Gonzalez, Brian M. Slomovitz, David M. Gershenson, Karen H. Lu
Journal: Journal of Clinical Oncology (2005)

Lynch syndrome (hereditary nonpolyposis colorectal cancer; HNPCC) is an autosomal-dominant cancer predisposition syndrome that increases risk for multiple cancers, including colon, endometrial, and ovarian cancer. Revised Bethesda Criteria recommend that patients with two HNPCC-associated cancers undergo molecular evaluation to determine whether they have a mismatch repair (MMR) defect associated with HNPCC. The purpose of our study was to determine the likelihood of MMR defects (MSH2, MSH6, MLH1) in women with synchronous endometrial and ovarian cancer.Between 1989 and 2004, 102 women with synchronous endometrial and ovarian cancers were identified; 59 patients had tumor blocks available for analysis. Patients were divided into risk groups based on family history: high (met Amsterdam criteria), medium (personal history or first-degree relative with an HNPCC-associated cancer), and low (all others). Protein expression for MSH2, MSH6, and MLH1 was evaluated by immunohistochemistry. Microsatellite instability and MLH1 promoter methylation analyses were performed on a subset of cases.Median age was 50 years. Two patients met Amsterdam criteria for HNPCC. Five additional patients, all medium-risk, had molecular findings consistent with a germline mutation of either MSH2 or MLH1. None of the low-risk patients had molecular results consistent with a germline mutation.Overall, 7% of women in our cohort met either clinical or molecular criteria for Lynch syndrome. All of these women had a prior history or a first-degree relative with an HNPCC-associated cancer. Limiting genetic evaluation to women with synchronous endometrial and ovarian cancer who have a family history suggestive of HNPCC may appropriately identify women with Lynch syndrome.
The Study of Accrual to Clinical Trials: Can We Learn From Studying Who Enters Our Studies?
Authors: Otis W. Brawley
Journal: Journal of Clinical Oncology (2004)

Throughout the 1990s, less than 6% of all breast cancer patients and less than 3% of all adult cancer patients entered clinical trials in the United States. 1 At the same time, a number of well-designed, peer-reviewed clinical trials were accruing patients very slowly. The slow accrual is baffling, but even more concerning is the fact that few have studied the dynamics of clinical trials accrual in any cancer. At first glance, there are a number of reasons why a patient should want to enter a clinical trial. Clinical trials are mechanisms for testing new cancer therapies and for providing opportunities for patients to be exposed to state-ofthe-art treatments. 2 For the eligible patient, a cooperative group clinical trial and many cancer center-sponsored studies offer the patient a second or third opinion, as it is designed by a group of experts and is peer-reviewed. Unlike most cancer therapies, treatment in a clinical trial is given under conditions that are often audited, to assure it was given correctly. In contrast to adults, a high proportion of eligible children under 12 years of age are entered onto pediatric cancer studies. 3
The Chemical Biology of Naphthoquinones and Its Environmental Implications
Authors: Yoshito Kumagai, Yasuhiro Shinkai, Takashi Miura, Arthur K. Cho
Journal: The Annual Review of Pharmacology and Toxicology (2011)

Quinones are a group of highly reactive organic chemical species that interact with biological systems to promote inflammatory, anti-inflammatory, and anticancer actions and to induce toxicities. This review describes the chemistry, biochemistry, and cellular effects of 1,2- and 1,4-naphthoquinones and their derivatives. The naphthoquinones are of particular interest because of their prevalence as natural products and as environmental chemicals, present in the atmosphere as products of fuel and tobacco combustion. 1,2- and 1,4-naphthoquinones are also toxic metabolites of naphthalene, the major polynuclear aromatic hydrocarbon present in ambient air. Quinones exert their actions through two reactions: as prooxidants, reducing oxygen to reactive oxygen species; and as electrophiles, forming covalent bonds with tissue nucleophiles. The targets for these reactions include regulatory proteins such as protein tyrosine phosphatases; Kelch-like ECH-associated protein 1, the regulatory protein for NF-E2-related factor 2; and the glycolysis enzyme glyceraldehyde-3-phosphate dehydrogenase. Through their actions on regulatory proteins, quinones affect various cell signaling pathways that promote and protect against inflammatory responses and cell damage. These actions vary with the specific quinone and its concentration. Effects of exposure to naphthoquinones as environmental chemicals can vary with the physical state, i.e., whether the quinone is particle bound or is in the vapor state. The exacerbation of pulmonary diseases by air pollutants can, in part, be attributed to quinone action.
IL-33 Exacerbates Acute Kidney Injury
Authors: Ali Akcay, Quocan Nguyen, Zhibin He, Kultigin Turkmen, Dong Won Lee, Ana Andres Hernando, Christopher Altmann, Aysun Toker, Arijana Pacic, Danica Galesic Ljubanovic, Alkesh Jani, Sarah Faubel, Charles L. Edelstein
Journal: Journal of the American Society of Nephrology (2011)

Inflammation contributes to the pathogenesis of acute kidney injury (AKI). IL-33 is a proinflammatory cytokine, but its role in AKI is unknown. Here we observed increased protein expression of full-length IL-33 in the kidney following induction of AKI with cisplatin. To determine whether IL-33 promotes injury, we administered soluble ST2 (sST2), a fusion protein that neutralizes IL-33 activity by acting as a decoy receptor. Compared with cisplatin-induced AKI in untreated mice, mice treated with sST2 had fewer CD4 T cells infiltrate the kidney, lower serum creatinine, and reduced acute tubular necrosis (ATN) and apoptosis. In contrast, administration of recombinant IL-33 (rIL-33) exacerbated cisplatin-induced AKI, measured by an increase in CD4 T cell infiltration, serum creatinine, ATN, and apoptosis; this did not occur in CD4-deficient mice, suggesting that CD4 T cells mediate the injurious effect of IL-33. Wildtype mice that received cisplatin and rIL-33 also had higher levels of the proinflammatory chemokine CXCL1, which CD T cells produce, in the kidney compared with CD4-deficient mice. Mice deficient in the CXCL1 receptor also had lower serum creatinine, ATN, and apoptosis than wildtype mice following cisplatin-induced AKI. Taken together, IL-33 promotes AKI through CD4 T cell-mediated production of CXCL1. These data suggest that inhibiting IL-33 or CXCL1 may have therapeutic potential in AKI.
Cucurbitacin B Induces Apoptosis by Inhibition of the <i>JAK/STAT</i> Pathway and Potentiates Antiproliferative Effects of Gemcitabine on Pancreatic Cancer Cells
Authors: Nils H. Thoennissen, Gabriela B. Iwanski, Ngan B. Doan, Ryoko Okamoto, Patricia Lin, Sam Abbassi, Jee Hoon Song, Dong Yin, Melvin Toh, Wei Dong Xie, Jonathan W. Said, H. Phillip Koeffler
Journal: Cancer Research (2009)

Abstract Pancreatic cancer is an aggressive malignancy that is generally refractory to chemotherapy, thus posing experimental and clinical challenges. In this study, the antiproliferative effect of the triterpenoid compound cucurbitacin B was tested in vitro and in vivo against human pancreatic cancer cells. Dose-response studies showed that the drug inhibited 50% growth of seven pancreatic cancer cell lines at 10−7 mol/L, whereas clonogenic growth was significantly inhibited at 5 × 10−8 mol/L. Cucurbitacin B caused dose- and time-dependent G2-M-phase arrest and apoptosis of pancreatic cancer cells. This was associated with inhibition of activated JAK2, STAT3, and STAT5, increased level of p21WAF1 even in cells with nonfunctional p53, and decrease of expression of cyclin A, cyclin B1, and Bcl-XL with subsequent activation of the caspase cascade. Interestingly, the combination of cucurbitacin B and gemcitabine synergistically potentiated the antiproliferative effects of gemcitabine on pancreatic cancer cells. Moreover, cucurbitacin B decreased the volume of pancreatic tumor xenografts in athymic nude mice by 69.2% (P &amp;lt; 0.01) compared with controls without noticeable drug toxicities. In vivo activation of JAK2/STAT3 was inhibited and expression of Bcl-XL was decreased, whereas caspase-3 and caspase-9 were up-regulated in tumors of drug-treated mice. In conclusion, we showed for the first time that cucurbitacin B has profound in vitro and in vivo antiproliferative effects against human pancreatic cancer cells, and the compound may potentate the antiproliferative effect of the chemotherapeutic agent gemcitabine. Further clinical studies are necessary to confirm our findings in patients with pancreatic cancer. [Cancer Res 2009;69(14):5876–84]
Peripheral blood lymphocytes from psoriatic patients are hyporesponsive to β‐streptococcal superantigens
Authors: None Horiuchi, None Aiba, None Ozawa, None Sugawara, None Rikiishi, None Kumagai, None Tagami
Journal: British Journal of Dermatology (1998)

The strong association of acute guttate psoriasis and streptococcal throat infection, together with the preferential use of T cells expressing a particular T-cell receptor, has suggested a role for bacterial superantigens in the pathogenesis of psoriasis. We examined the proliferative responses of peripheral blood lymphocytes (PBLs), obtained from patients with psoriasis and from healthy controls, to streptococcal superantigens, cytoplasmic membrane-associated protein (CAP) and secretion-type CAP (SCAP), isolated from group A, β-haemolytic streptococci. PBLs from patients with psoriasis showed significantly less response to SCAP and CAP than those from healthy controls. Because there was no difference between psoriatic patients and controls in the proliferative response of PBLs to staphylococcal enterotoxin A or E (SEA, SEE) or the mitogen phytohaemagglutinin (PHA), these findings strongly suggest that the reduced reactivity to the streptococcal superantigens seems to reflect anergy of a population of PBLs to the superantigens. As the CAP used in the present study stimulates Vβ8 T cells selectively, we further examined the proliferation of Vβ8 T cells after such stimulation using flow cytometry. Vβ8 T cells obtained from three of four psoriatic patients failed to proliferate in the presence of CAP, whereas they proliferated vigorously in the presence of SEE, which activates Vβ8 T cells, confirming the specific hyporesponsiveness of PBLs from psoriatic patients to streptococcal superantigens. We then determined the effects of serum factors on the suppressed response of PBLs to the streptococcal superantigens with SCAP or CAP. It was partially restored when PBLs were cultured with sera obtained from healthy subjects, although the responses were still significantly lower than those of the healthy controls. In contrast, psoriatic sera markedly suppressed the proliferative response of PBLs from healthy controls to CAP or SCAP, but showed no suppression of the proliferative response of PBLs to SEA. Because these findings suggest the presence of specific inhibitory factors in psoriatic sera, we examined whether the inhibitory effect was caused by antisuperantigen antibody. However, no significant increase was detected in antibody titre to CAP in psoriatic sera, as has been noted in sera from patients with poststreptococcal glomerulonephritis. The present results show for the first time the hyporesponsiveness of PBLs to streptococcal superantigens and the presence of serum inhibitors that specifically inhibit T-cell response to the superantigens in psoriatic patients. These findings suggest a pathological role for streptococcal infections in the pathogenesis of psoriasis.
Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways
Authors: Yasuhito Onodera, Jin-Min Nam, Mina J. Bissell
Journal: Journal of Clinical Investigation (2013)

There is a considerable resurgence of interest in the role of aerobic glycolysis in cancer; however, increased glycolysis is frequently viewed as a consequence of oncogenic events that drive malignant cell growth and survival. Here we provide evidence that increased glycolytic activation itself can be an oncogenic event in a physiologically relevant 3D culture model. Overexpression of glucose transporter type 3 (GLUT3) in nonmalignant human breast cells activated known oncogenic signaling pathways, including EGFR, β1 integrin, MEK, and AKT, leading to loss of tissue polarity and increased growth. Conversely, reduction of glucose uptake in malignant cells promoted the formation of organized and growth-arrested structures with basal polarity, and suppressed oncogenic pathways. Unexpectedly and importantly, we found that unlike reported literature, in 3D the differences between "normal" and malignant phenotypes could not be explained by HIF-1α/2α, AMPK, or mTOR pathways. Loss of epithelial integrity involved activation of RAP1 via exchange protein directly activated by cAMP (EPAC), involving also O-linked N-acetylglucosamine modification downstream of the hexosamine biosynthetic pathway. The former, in turn, was mediated by pyruvate kinase M2 (PKM2) interaction with soluble adenylyl cyclase. Our findings show that increased glucose uptake activates known oncogenic pathways to induce malignant phenotype, and provide possible targets for diagnosis and therapeutics.
Deficient and Dysfunctional Regulatory T Cells in the Lungs of Chronic Beryllium Disease Subjects
Authors: Douglas G. Mack, Allison M. Lanham, Michael T. Falta, Brent E. Palmer, Lisa A. Maier, Andrew P. Fontenot
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Chronic beryllium disease (CBD) is a CD4+ T cell–mediated disorder characterized by persistent lung inflammation. Naturally occurring regulatory T (Treg) cells modulate adaptive immune responses. The role of this T-cell subset in beryllium-induced lung disease is unknown.Objectives: The aim of this study was to determine whether dysfunctional Treg cells in the lung contribute to the "unchecked" inflammatory response that characterizes CBD.Methods: Using blood and bronchoalveolar lavage (BAL) cells from normal control subjects and individuals with beryllium-induced disease, we determined the frequency and function of naturally occurring Treg cells.Measurements and Main Results: A significantly decreased percentage and expression of FoxP3 in BAL CD4+ T cells from CBD patients compared with beryllium-sensitized subjects was seen, and the percentage of FoxP3-expressing CD4+ Treg cells in BAL inversely correlated with disease severity. In contrast to blood Treg cells derived from beryllium-sensitized subjects and patients with CBD that completely suppressed blood responder T-cell proliferation, BAL FoxP3-expressing Treg cells from patients with CBD are unable to suppress anti–CD3-mediated BAL T-cell proliferation. Mixing studies showed that blood Treg cells are capable of suppressing autologous BAL responder T cells. Conversely, BAL CD4+ Treg cells are incapable of suppressing blood T cells, confirming that the failure of BAL Treg cells to suppress T-cell proliferation is caused by a dysfunctional Treg cell subset and not by resistance of BAL effector T cells to suppression.Conclusions: These findings suggest that the deficient and dysfunctional Treg cells in the lung of patients with CBD contribute to the persistent inflammatory response in this disease.
Psychological Impact of Prostate Biopsy: Physical Symptoms, Anxiety, and Depression
Authors: Julia Wade, Derek J. Rosario, Rhiannon C. Macefield, Kerry N.L. Avery, C. Elizabeth Salter, M. Louise Goodwin, Jane M. Blazeby, J. Athene Lane, Chris Metcalfe, David E. Neal, Freddie C. Hamdy, Jenny L. Donovan
Journal: Journal of Clinical Oncology (2013)

Purpose To investigate the psychological impact of prostate biopsy, including relationships between physical biopsy-related symptoms and anxiety and depression. Patients and Methods A prospective cohort of 1,147 men, nested within the Prostate Testing for Cancer and Treatment trial and recommended to receive prostate biopsy, completed questionnaires assessing physical and psychological harms after biopsy in the Prostate Biopsy Effects study. Psychological impact was measured using the Hospital Anxiety and Depression Scale, and scores were compared according to experiences of biopsy-related symptoms at biopsy, and at 7 and 35 days afterward, and in relation to biopsy results. Results A total of 1,144 men (99.7%) returned questionnaires at biopsy, with 1,090 (95.0%) and 1,016 (88.6%) responding at 7 and 35 days postbiopsy. Most men experienced biopsy-related symptoms as no problem or a minor problem, and overall levels of anxiety and depression were low and similar to normative levels. Of men receiving a negative biopsy result (n = 471), anxiety was greater in those experiencing problematic biopsy-related symptoms compared with those experiencing nonproblematic symptoms at 7 days for the following symptoms: pain (P &lt; .001), shivers, (P = .020), hematuria (P &lt; .001), hematochezia (P &lt; .001), and hemoejaculate (P &lt; .001). Anxiety was reduced, although symptoms were not, after 35 days. Overall levels of anxiety were low across all time points except at the 35-day assessment among men who had received a cancer diagnosis. Conclusion Problematic postbiopsy symptoms can lead to increased anxiety, distinct from distress related to diagnosis of prostate cancer. Men and doctors need to consider these additional potential harms of biopsy when deciding whether to initiate prostate-specific antigen testing.