tbuckley/cabot-search huggingface dataset:
Matrix Metalloproteinase-9 Functions as a Tumor Suppressor in Colitis-Associated Cancer
Authors: Pallavi Garg, Dittakavi Sarma, Sabrina Jeppsson, Neal R. Patel, Andrew T. Gewirtz, Didier Merlin, Shanthi V. Sitaraman
Journal: Cancer Research (2010)

Abstract There is a well-documented association of matrix metalloproteinase-9 (MMP-9) and receptor Notch-1 overexpression in colon cancer. We recently showed that MMP-9 is also upregulated in colitis, where it modulates tissue damage and goblet cell differentiation via proteolytic cleavage of Notch-1. In this study, we investigated whether MMP-9 is critical for colitis-associated colon cancer (CAC). Mice that are wild type (WT) or MMP-9 nullizygous (MMP-9−/−) were used for in vivo studies and the human enterocyte cell line Caco2-BBE was used for in vitro studies. CAC was induced in mice using an established carcinogenesis protocol that involves exposure to azoxymethane followed by treatment with dextran sodium sulfate. MMP-9−/− mice exhibited increased susceptibility to CAC relative to WT mice. Elevations in tumor multiplicity, size, and mortality were associated with increased proliferation and decreased apoptosis. Tumors formed in MMP-9−/− mice exhibited expression of p21WAF1/Cip1 and increased expression of β-catenin relative to WT mice. In vitro studies of MMP-9 overexpression showed increased Notch-1 activation with a reciprocal decrease in β-catenin. Notch and β-catenin/Wnt signaling have crucial roles in determining differentiation and carcinogenesis in gut epithelia. Despite being a mediator of proinflammatory responses in colitis, MMP-9 plays a protective role and acts as a tumor suppressor in CAC by modulating Notch-1 activation, thereby resulting in activation of p21WAF1/Cip1 and suppression of β-catenin. Cancer Res; 70(2); 792–801
Elevated citrate in pediatric astrocytomas with malignant progression
Authors: S. Bluml, A. Panigrahy, M. Laskov, G. Dhall, M. D. Krieger, M. D. Nelson, J. L. Finlay, F. H. Gilles
Journal: Neuro-Oncology (2011)

In vivo magnetic resonance spectroscopy (MRS) provides information about metabolite concentrations in tissue. Recently citrate was detected by MRS in subgroups of pediatric brain tumors. Citrate is an intermediate in the tricarboxylic acid (TCA) cycle and accumulates in tissue when the glycolytic rate exceeds the TCA cycle activity, a feature of malignant tumors. Currently, no practical indicators allow clinicians to predict risk for malignant progression of pediatric astrocytomas (World Health Organization [WHO] grade II). Medical records and citrate concentrations measured with in vivo MRS of 29 pediatric astrocytomas were reviewed. This included 6 patients with astrocytomas (WHO II) who had stable disease (indolent LGA) for >2 years, 7 with aggressive grade II astrocytomas (aggressive LGA), 13 with anaplastic astrocytomas (WHO III), and 3 with glioblastoma (WHO IV) with disease progression within 2 years. Citrate was observed in all patients with aggressive LGA, and the mean citrate concentration was significantly higher in this group than among those with indolent LGA (mean ± standard deviation, 4.1 ± 1.1 vs 0.6 ± 0.8 mmol/kg; P < .0001). There was no consistent pattern for citrate in anaplastic astrocytoma and glioblastoma, with citrate prominent in some lesions whereas undetectable in others. It is unclear whether citrate accumulation occurred because of fundamental defects of citrate regulation or was secondary to altered physiological conditions. Nonetheless, prominent citrate identified a subgroup of pediatric grade II astrocytomas destined for aggressive behavior. Citrate was not specific for poor outcome because it was not detectable in all high-grade astrocytomas. In high-grade astrocytoma, tumors with prominent citrate may constitute a metabolic subclass.
Methylation of the oestrogen receptor gene in non-neoplastic epithelium as a marker of colorectal neoplasia risk in longstanding and extensive ulcerative colitis
Authors: S Fujii
Journal: Gut (2005)

<b>Background:</b> Surveillance colonoscopy is widely recommended in patients with longstanding and extensive ulcerative colitis (UC) in order to detect colorectal neoplasia at an early stage. However, it still remains questionable whether surveillance colonoscopy effectively enables early detection of UC associated neoplasia. There is a great need for sensitive markers to identify individuals at increased risk of neoplasia. The oestrogen receptor (OR) gene shows age related methylation in the colorectal epithelium and is methylated frequently in sporadic colorectal neoplasia, suggesting that OR methylation may predispose to colorectal neoplasia. <b>Aim:</b> To clarify whether analysis of methylation of the OR gene in non-neoplastic epithelium can contribute to prediction of increased neoplasia risk in UC patients. <b>Materials and methods:</b> A total of 165 non-neoplastic colorectal epithelia from 30 patients with longstanding and extensive UC, including 13 UC patients with neoplasia and 17 patients without, were evaluated. Methylation specific polymerase chain reaction was performed to determine the methylation status of the OR gene. <b>Results:</b> Methylation of the OR gene was detected in 54 of 70 (77.1%) non-neoplastic colorectal epithelia in UC with neoplasia but in only 23 of 95 (24.2%) without neoplasia. Methylation of the OR gene was significantly more frequent in non-neoplastic epithelium from UC with neoplasia than in chronic colitic epithelium from UC without neoplasia. Furthermore, in UC with neoplasia, the OR gene was extensively methylated in non-neoplastic epithelia throughout the colorectum compared with those in UC without neoplasia. <b>Conclusion:</b> These results suggest that analysis of OR gene methylation may have potential as a useful marker for identifying individuals at increased risk of neoplasia among those with longstanding and extensive UC.
Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: a population-based study
Authors: R McGready, SJ Lee, J Wiladphaingern, EA Ashley, MJ Rijken, M Boel, JA Simpson, MK Paw, M Pimanpanarak, Oh Mu, P Singhasivanon, NJ White, FH Nosten
Journal: The Lancet Infectious Diseases (2011)

The effects of malaria and its treatment in the first trimester of pregnancy remain an area of concern. We aimed to assess the outcome of malaria-exposed and malaria-unexposed first-trimester pregnancies of women from the Thai-Burmese border and compare outcomes after chloroquine-based, quinine-based, or artemisinin-based treatments.We analysed all antenatal records of women in the first trimester of pregnancy attending Shoklo Malaria Research Unit antenatal clinics from May 12, 1986, to Oct 31, 2010. Women without malaria in pregnancy were compared with those who had a single episode of malaria in the first trimester. The association between malaria and miscarriage was estimated using multivariable logistic regression.Of 48,426 pregnant women, 17,613 (36%) met the inclusion criteria: 16,668 (95%) had no malaria during the pregnancy and 945 (5%) had a single episode in the first trimester. The odds of miscarriage increased in women with asymptomatic malaria (adjusted odds ratio 2·70, 95% CI 2·04-3·59) and symptomatic malaria (3·99, 3·10-5·13), and were similar for Plasmodium falciparum and Plasmodium vivax. Other risk factors for miscarriage included smoking, maternal age, previous miscarriage, and non-malaria febrile illness. In women with malaria, additional risk factors for miscarriage included severe or hyperparasitaemic malaria (adjusted odds ratio 3·63, 95% CI 1·15-11·46) and parasitaemia (1·49, 1·25-1·78 for each ten-fold increase in parasitaemia). Higher gestational age at the time of infection was protective (adjusted odds ratio 0·86, 95% CI 0·81-0·91). The risk of miscarriage was similar for women treated with chloroquine (92 [26%] of 354), quinine (95 [27%) of 355), or artesunate (20 [31%] of 64; p=0·71). Adverse effects related to antimalarial treatment were not observed.A single episode of falciparum or vivax malaria in the first trimester of pregnancy can cause miscarriage. No additional toxic effects associated with artesunate treatment occurred in early pregnancy. Prospective studies should now be done to assess the safety and efficacy of artemisinin combination treatments in early pregnancy.
The specific interaction of helper T cells and antigen-presenting B cells. IV. Membrane and cytoskeletal reorganizations in the bound T cell as a function of antigen dose.
Authors: A Kupfer, S J Singer
Journal: The Journal of Experimental Medicine (1989)

We have used double-immunofluorescence labeling to determine the surface distributions of LFA-1 and CD4, and the intracellular distributions of the cytoskeletal protein talin and of the microtubule organizing center (MTOC) of cloned Th cells in 1:1 cell couples with antigen (Ag)-specific APC of the B cell type (B-APC). The Th cell was directed to a peptide fragment of the Ag OVA in the context of IAd. The B-APC was the transfected A20 B hybridoma cell A20-HL, bearing on its surface a surface Ig specific for the hapten TNP, and pulsed with different concentrations of DNP-OVA. At sufficiently high doses of DNP-OVA (greater than 100 ng/ml), in essentially all couples, LFA-1, CD4, and talin were each concentrated at the Th cell membrane where it was in contact with the B-APC, and the MTOC inside the Th cell was reoriented to face the contact region. At lower doses of DNP-OVA (between 50 and 10 ng/ml), in all couples, LFA-1 and talin were concentrated at the Th/B-APC contact region, but the extent of CD4 clustering, MTOC reorientation, and Th cell proliferation all decreased with decreasing Ag dose. With no Ag, none of these effects was observed. These and other data indicate that two distinct signals are received by the Th cell that is specifically bound to its B-APC. The first signal, at low Ag doses, stimulates a linkage of LFA-1 and talin in the Th cell, and a specific LFA-1-mediated intercellular adhesion; the second signal, at higher Ag doses, is required to induce Th cell proliferation, with which the Th-MTOC reorientation and CD4 clustering are correlated.
Platelet Glycoprotein IIb/IIIa Antagonists
Authors: Robert M. Scarborough, Neal S. Kleiman, David R. Phillips
Journal: Circulation (1999)

Abstract —During the last decade, intensive efforts have been made to evaluate the role of the platelet glycoprotein (GP) IIb/IIIa complex in platelet-mediated thrombus formation. Significant efforts have also been made to design potent antagonists of this “final common pathway” of platelet aggregation to be used as novel therapeutic strategies to treat acute coronary syndromes. Although several different GP IIb/IIIa antagonists have convincingly demonstrated the usefulness of this platelet-directed therapeutic strategy, a number of lingering unsolved and sometimes misunderstood issues concerning the pharmacology and optimal clinical usefulness of these agents remain to be explored. This article reviews these issues, which include antagonist affinity, reversibility, and receptor specificity. Other issues are related to the effects of GP IIb/IIIa receptor availability, neoepitopes induced by antagonist binding with the potential to mediate thrombocytopenia, optimal methods of platelet monitoring and, perhaps ultimately, the potential therapeutic index of the oral class of GP IIb/IIIa antagonists. All of these specific issues are likely to be illuminated in the next several years, which will greatly determine the breadth of this therapeutic class.
Vitamins A and E: Further Clues for Prostate Cancer Prevention
Authors: Karin B. Olson, Kenneth J. Pienta
Journal: JNCI Journal of the National Cancer Institute (1998)

682–5. (16) Mao L, Lee JS, Kurie JM, Fan YH, Lippman SM, Lee JJ, et al. Clonal genetic alterations in the lungs of current and former smokers. J Natl Cancer Inst 1997;89:857–62. (17) Muller CY, O’Boyle JD, Fong KM, Wistuba II, Biesterveld E, Ahmadian M, et al. Abnormalities of fragile histidine triad genomic and complementary DNAs in cervical cancer: association with human papillomavirus subtype. J Natl Cancer Inst 1998;90:433–9. (18) Otterson GA, Xiao GH, Geradts J, Jin F, Chen WD, Niklinska W, et al. Protein expression and functional analysis of the FHIT gene in human tumor cells. J Natl Cancer Inst 1998;90:426–32. (19) Siprashvili Z, Sozzi G, Barnes LD, McCue P, Robinson AK, Eryomin V, et al. Replacement of Fhit in cancer cells suppresses tumorigenicity. Proc Natl Acad Sci U S A 1997;94:13771–6. (20) Lee MP, Feinberg AP. Aberrant splicing but not mutations of TSG101 in human breast cancer. Cancer Res 1997;57:3131–4. (21) Sigalas I, Calvert AH, Anderson JJ, Neal DE, Lunec J. Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer. Nat Med 1996;2: 912–7.
mTOR Complex 2 Controls Glycolytic Metabolism in Glioblastoma through FoxO Acetylation and Upregulation of c-Myc
Authors: Kenta Masui, Kazuhiro Tanaka, David Akhavan, Ivan Babic, Beatrice Gini, Tomoo Matsutani, Akio Iwanami, Feng Liu, Genaro R. Villa, Yuchao Gu, Carl Campos, Shaojun Zhu, Huijun Yang, William H. Yong, Timothy F. Cloughesy, Ingo K. Mellinghoff, Webster K. Cavenee, Reuben J. Shaw, Paul S. Mischel
Journal: Cell Metabolism (2013)
P243 Influenza A outbreak in a UK respiratory centre
Authors: A Aujayeb, S West, S Waugh, J Samuel, A Russel, R Fagg, S Gray, C Walton, G Meachery
Journal: Thorax (2013)

<h3>Introduction</h3> In March 2013, 12 patients on a single ward in a tertiary respiratory transplant centre contracted influenza within 72 hours. There was no corresponding community outbreak. Staff with symptoms went off sick. Trust policies outlining respiratory infection and isolation existed but there were no guidelines for this specific novel situation. We found no published reports of such an event in England. <h3>Methods</h3> Patients quickly developed pyrexias and respiratory symptoms. All had throat swabs and blood cultures. Influenza A, H3N2 variant, was identified. A team of infection control and respiratory physicians, nurses and managers met regularly to implement these measures: Closure of ward and cohorting of bays Ward avoidance for non-essential personnel and anyone with symptoms Cancellation of non-essential procedures Strict hand hygiene and use of PPE and FFP3 masks Stockage of oseltamivir for treatment for all affected high risk staff and patients and prophylaxis offered to all ward patients and exposed high risk staff. No crossover of ward staff to transplant patients. Contact tracing of all immunocompromised patients on ward up to one week and all high risk patients 48 hours prior to the index case; advice on prophylaxis and their GPs contacted. Writing an information sheet for staff and GPs Increased and terminal ward cleaning <h3>Results</h3> On the respiratory ward, 151 bed days were lost and 53 on two other wards. Fourteen patients (including two on another ward) had positive swabs for H3N2. There were 27 symptomatic staff members; 15 had swabs, two were positive. All patients and two staff members were given treatment oseltamivir. Fourteen patients and two staff members had prophylaxis. No influenza complications or deaths occurred. The department staff had 45% influenza vaccination uptake in 2012/2013. All affected patients had been vaccinated. <h3>Conclusions</h3> Containment, pathogen identification, prompt treatment and contact tracing were priorities, to limit number of individuals affected. This is widely applicable. Our departmental staff vaccination rate is below Department of Health targets. Importance of vaccination needs emphasising, whilst recognising that vaccine effectiveness against all laboratory-confirmed influenza in primary care is 51% for 2012/2013.
Barriers and Strategies for Research in Arab Americans
Authors: Linda A. Jaber
Journal: Diabetes Care (2003)

Conducting clinical research in minority populations is challenging. Barriers to participation in research and strategies to overcome these barriers have been described by Fujimoto and other investigators (1–4). These reports and experiences have been invaluable in the planning and execution of a community-based epidemiological study in the Arab-American community. The study to determine the prevalence of diabetes in this largely unstudied minority population had been quite successful and achieved a participation rate of 87%.

It was clear from the beginning that the study’s success was dependent on community endorsement and support. Therefore, a proactive approach to exploring and addressing obstacles to participation was undertaken. We found similarities in issues related to participation in clinical research in this community and other minority populations.

The major barrier to research among community members was the general fear, suspicion, and distrust of large institutions and governmental agencies. Field testing of the consent form and the study questionnaires revealed potential obstacles to participation. The standard disclaimer of the consent form that data obtained were to be disclosed to the Food and Drug Administration and other governmental agencies was considered alarming and needed to be amended. The questionnaires eliciting perceived sensitive information related to religious convictions, sociocultural …
Modelling asthma in macaques: longitudinal changes in cellular and molecular markers
Authors: G. Ayanoglu, B. Desai, R.B. Fick, J. Grein, R. de Waal Malefyt, J. Mattson, T. McClanahan, S. Olmstead, S.P. Reece, M.R. Van Scott, R.L. Wardle
Journal: European Respiratory Journal (2010)

The aim of the present study was to determine whether systemic sensitisation and chronic aeroallergen challenge in macaques replicate the classical and emerging immunology and molecular pathology of human asthma. Macaques were immunised and periodically challenged over 2 yrs with house dust mite allergen. At key time-points, serum, bronchoalveolar lavage (BAL) and bronchial biopsies were assayed for genes, proteins and lymphocyte subpopulations relevant to clinical asthma. Immunisation and periodic airway challenge induced changes in immunoglobulin E, airway physiology and eosinophilia consistent with chronic, dual-phase asthma. Sensitisation increased interleukin (IL)-1β and -6 concentrations in serum, and IL-13 expression in BAL cells. Airway challenge increased: early expression of IL-5, -6, -13 and -19, and eotaxin; and variable late-phase expression of IL-4, -5 and -13, and thymus- and activation-regulated chemokine in BAL cells. CD4+ lymphocytes comprised 30% of the CD3+ cells in BAL, increasing to 50% in the late phase. Natural killer T-cells represented <3% of the CD3+ cells. Corticosteroid treatment reduced serum histamine levels, percentage of CD4+ cells and monocyte-derived chemokine expression, while increasing CD3+ and CD8+ cells in BAL. Sensitisation and periodic aeroallergen challenge of cynomolgus macaques results in physiological, cellular, molecular and protein phenotypes, and therapeutic responses observed in human asthma, providing a model system useful in target and biomarker discovery, and translational asthma research.
A systematic review of physicians' survival predictions in terminally ill cancer patients
Authors: P. Glare
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objective</b> To systematically review the accuracy of physicians9 clinical predictions of survival in terminally ill cancer patients. <b>Data sources</b> Cochrane Library, Medline (1996-2000), Embase, Current Contents, and Cancerlit databases as well as hand searching. <b>Study selection</b> Studies were included if a physician9s temporal clinical prediction of survival (CPS) and the actual survival (AS) for terminally ill cancer patients were available for statistical analysis. Study quality was assessed by using a critical appraisal tool produced by the local health authority. <b>Data synthesis</b> Raw data were pooled and analysed with regression and other multivariate techniques. <b>Results</b> 17 published studies were identified; 12 met the inclusion criteria, and 8 were evaluable, providing 1563 individual prediction-survival dyads. CPS was generally overoptimistic (median CPS 42 days, median AS 29 days); it was correct to within one week in 25% of cases and overestimated survival by at least four weeks in 27%. The longer the CPS the greater the variability in AS. Although agreement between CPS and AS was poor (weighted κ 0.36), the two were highly significantly associated after log transformation (Spearman rank correlation 0.60, P &lt; 0.001). Consideration of performance status, symptoms, and use of steroids improved the accuracy of the CPS, although the additional value was small. Heterogeneity of the studies9 results precluded a comprehensive meta-analysis. <b>Conclusions</b> Although clinicians consistently overestimate survival, their predictions are highly correlated with actual survival; the predictions have discriminatory ability even if they are miscalibrated. Clinicians caring for patients with terminal cancer need to be aware of their tendency to overestimate survival, as it may affect patients9 prospects for achieving a good death. Accurate prognostication models incorporating clinical prediction of survival are needed.
Preventing Complications of Central Venous Catheterization
Authors: David C. McGee, Michael K. Gould
Journal: New England Journal of Medicine (2003)

Central venous catheters permit the measurement of hemodynamic variables that cannot be measured accurately by noninvasive means. They also allow delivery of medications and nutritional support. More than 15 percent of patients, however, have a serious mechanical, infectious, or thrombotic complication related to the use of a central venous catheter. This review explains strategies for minimizing the frequency of such complications. An accompanying video shows techniques for catheter insertion by the internal jugular and subclavian routes.