tbuckley/cabot-search huggingface dataset:
PGE2-Induced CXCL12 Production and CXCR4 Expression Controls the Accumulation of Human MDSCs in Ovarian Cancer Environment
Authors: Nataša Obermajer, Ravikumar Muthuswamy, Kunle Odunsi, Robert P. Edwards, Pawel Kalinski
Journal: Cancer Research (2011)

Abstract Signals mediated by CXCL12 (SDF1) and its receptor CXCR4 are centrally involved in cancer progression, both directly by activating cancer cells and indirectly by inducing angiogenesis plus recruiting T regulatory and plasmacytoid dendritic immune cells. Here, we show that in ascites isolated from ovarian cancer patients, both CXCL12 and CXCR4 are controlled by the tumor-associated inflammatory mediator prostaglandin E2 (PGE2), which attracts myeloid-derived suppressor cells (MDSC) into the ascites microenvironment. In this setting, PGE2 was essential both for expression of functional CXCR4 in cancer-associated MDSCs and for production of its ligand CXCL12. Frequencies of CD11b+CD14+CD33+CXCR4+ MDSCs closely correlated with CXCL12 and PGE2 levels in patient ascites. MDSCs migrated toward ovarian cancer ascites in a CXCR4-dependent manner that required COX2 activity and autocrine PGE2 production. Inhibition of COX2 or the PGE2 receptors EP2/EP4 in MDSCs suppressed expression of CXCR4 and MDSC responsiveness to CXCL12 or ovarian cancer ascites. Similarly, COX2 inhibition also blocked CXCL12 production in the ovarian cancer environment and its ability to attract MDSCs. Together, our findings elucidate a central role for PGE2 in MDSC accumulation triggered by the CXCL12-CXCR4 pathway, providing a powerful rationale to target PGE2 signaling in ovarian cancer therapy. Cancer Res; 71(24); 7463–70. ©2011 AACR.
Dose escalation of infliximab in clinical practice: improvements seen may be explained by a regression-like effect
Authors: R F van Vollenhoven
Journal: Annals of the Rheumatic Diseases (2004)

To determine whether increased infliximab doses result in better clinical outcome in rheumatic diseases.Subjects were 124 patients with rheumatoid arthritis treated with biological agents at a single institute. Index cases were 44 patients whose infliximab doses had been increased. Controls were patients treated with infliximab without dose increase (n = 44), and patients treated with etanercept (n = 36). Disease activity score (DAS28), ACR28 swollen joint counts, and numerical ACR responses were compared before and after dose increases. For the controls, the point at which the DAS28 value showed any increase (despite infliximab/etanercept treatment) was used as the reference time point. Comparisons were made between three sets of outcomes: best outcome achieved before the dose increase (cases) or before the reference time point (controls); outcomes at this point; and best outcomes after this point.Following dose increase, disease activity showed modest but statistically significant improvements. The improvement achieved after dosage escalation was equal to, but not better than, the best values before dose escalation. While this finding could be interpreted as "recapturing" the previous response, similar improvements were seen in both control groups. Thus the same pattern of worsening and subsequent improvement was seen with or without the infliximab dose increase.Clinical improvement with increased infliximab dose, and the impression that a previous response can be "recaptured" with higher doses, cannot be taken at face value, as similar improvements occurred in two control groups. The use of infliximab at doses higher than 3 mg/kg needs to be evaluated further.
Physical Activity and the Metabolic Syndrome in Elderly German Men and Women
Authors: Valerie Hahn, Martin Halle, A. Schmidt-Trucksäss, W. Rathmann, C. Meisinger, A. Mielck
Journal: Diabetes Care (2008)

OBJECTIVE—The purpose of this study is to determine the optimal duration and intensity of exercise for elderly people for the prevention of the metabolic syndrome. RESEARCH DESIGN AND METHODS—The population-based Cooperative Research in the Region of Augsburg (KORA) S4 Survey with 1,653 participants aged 55–74 years was used to investigate the relationship between the metabolic syndrome and physical activity. RESULTS—Fifty-seven percent of men and 48% of women showed clinical symptoms of the metabolic syndrome. Leisure activities were common (&amp;gt;80% walked &amp;gt;30 min/day). Sports activities performed regularly for ≤1 h per week reduced the odds of having the metabolic syndrome (odds ratio 0.70 [95% CI 0.49–1.02] for men and 0.74 [0.53–1.04] for women), and sports activities &amp;gt;2 h per week were even more effective (0.62 [0.42–0.92] for men and 0.59 [0.39–0.89] for women). In contrast, activities such as walking and cycling did not have an additional influence. CONCLUSIONS—Intense physical activity by the elderly should be promoted in addition to leisure physical activity for the prevention of the metabolic syndrome.
Cytosine arabinoside, etoposide and aclarubicin (AVA) for the treatment of acute myeloid leukemia (AML) in elderly patients
Authors: P. Staib, B. Lathan, S. Knöppel-Schwark, H. Tesch, D. Voliotis, H.T. Steinmetz, M. Schwonzen, P.D. Wickramanayake, V. Diehl
Journal: Annals of Oncology (1998)
EFFECT ON BEHAVIOR IN HUMANS WITH THE ADMINISTRATION OF TARAXEIN
Authors: ROBERT G. HEATH, STEN MARTENS, BYRON E. LEACH, MATTHEW COHEN, CHARLES ANGEL
Journal: American Journal of Psychiatry (1957)

Work in progress centered about the isolation of taraxein from the serum of schizophrenic patients and its administration to monkeys and human volunteers is presented. The taraxein was extracted from a variety of schizophrenic patients in 4 institutions and administered on 17 occasions to nonpsychotic human volunteers and on one occasion to a schizophrenic patient in remission. Several additional studies are planned or in progress and we expect that in the near future it will be possible to present considerably more information.
The Emergency Medical Service and the Future
Authors: J. B. Hunter
Journal: BMJ (1941)

The threatening clouds disappeared and we for a time relaxed, but the memory of those days had left a bitter taste in the mouth, and the medical profession stirred uneasily at the thought of what might have been, and what perhaps was to come. As the months passed no signs could be seen of any attempt to deal with the casualty problem on the part of those in authority. Early in 1939 a meeting of representatives of the staff of the London teaching hospitals was arranged under the title of the Hospitals War Committee. It was decided then to ask the Voluntary Hospitals Committee to combine and meet the Ministry of Health to hear what arrangements were being made in connexion with the medical services if war should break out. As a result of deliberation the Ministry put forward tentatively its Sector scheme whereby twelve members, one from each of the teaching hospitals, should be selected to advise the Ministry on hospital arrangements in the London area in the event of war, and link the teaching hospitals to its casualty scheme.
A molecular map of mesenchymal tumors.
Authors: Stephen R Henderson, David Guiliano, Nadege Presneau, Sean McLean, Richard Frow, Sonja Vujovic, John Anderson, Neil Sebire, Jeremy Whelan, Nick Athanasou, Adrienne M Flanagan, Chris Boshoff
Journal: Genome biology (2005)

Abstract Background Bone and soft tissue tumors represent a diverse group of neoplasms thought to derive from cells of the mesenchyme or neural crest. Histological diagnosis is challenging due to the poor or heterogenous differentiation of many tumors, resulting in uncertainty over prognosis and appropriate therapy. Results We have undertaken a broad and comprehensive study of the gene expression profile of 96 tumors with representatives of all mesenchymal tissues, including several problem diagnostic groups. Using machine learning methods adapted to this problem we identify molecular fingerprints for most tumors, which are pathognomonic (decisive) and biologically revealing. Conclusion We demonstrate the utility of gene expression profiles and machine learning for a complex clinical problem, and identify putative origins for certain mesenchymal tumors.
Pachyonychia Congenita in Pediatric Patients
Authors: Sonal Shah, Monica Boen, Brandi Kenner-Bell, Mary Schwartz, Alfred Rademaker, Amy S. Paller
Journal: JAMA Dermatology (2013)

IMPORTANCE Nail dystrophy in early childhood often suggests a diagnosis of pachyonychia congenita (PC). No previous investigation has focused on the early signs of PC and the natural course of the disease. OBJECTIVES To determine the course of pediatric PC, correlate the disease course with the clinical appearance and specific gene mutations, and assess the effect of pediatric PC on quality of life. DESIGN, SETTING, AND PARTICIPANTS One hundred one patients or families with genetically confirmed PC from the International Pachyonychia Congenita Research Registry who completed a survey on the general clinical features of PC and an auxiliary questionnaire on the clinical presentation and quality-of-life issues related to pediatric PC. EXPOSURE Individuals with pachyonychia congenita. MAIN OUTCOMES AND MEASURES Completion of both surveys. RESULTS At birth, toenail changes were present in 47.5% of patients; fingernail changes in 40.6%; and plantar keratoderma in 6.9%. By 5 years of age, these 3 key manifestations were found in 81.2%, 74.2%, and 75.3%, respectively, of individuals with genotype-confirmed PC. The correct diagnosis was made during the first year of life in 26.7% of patients despite the presence of toenail dystrophy in more than 65.3%. Clinical differences that distinguished PC subtypes included (1) later onset and less frequent occurrence of nail dystrophy and keratoderma in PC-K6b, PC-K6c, and PC-K16; (2) concurrent fingernail and toenail thickening in PC-K6a and PC-K17; (3) more palmar keratoderma in PC-K16; (4) cysts primarily in PC-K17 and follicular hyperkeratoses primarily in PC-K6a; (5) hoarseness and/or oral leukokeratoses in the first year of life most often in PC-K6a; and (6) natal teeth exclusively in PC-K17. Among pediatric patients, PC affected the social interactions and function of adolescents most profoundly. CONCLUSIONS AND RELEVANCE Among patients with a detectable mutation, PC manifests with nail thickening and plantar keratoderma before school age in more than three-quarters of affected children, allowing early diagnosis. The highly visible nail changes and painful plantar thickening exert a psychosocial effect on most affected adolescents. Phenotype-genotype correlations in children with PC validate the new classification based on the affected gene.
Association Among Posttraumatic Stress Disorder, Adverse Birth Outcomes, and Domestic Violence
Authors: Hind Khalifeh, Gene Feder, Louise M. Howard
Journal: JAMA Psychiatry (2015)

To the Editor Research on perinatal mental disorders other than postnatal depression is long overdue; therefore, we were pleased to see the study by Yonkers et al, 1 which reported a 4-fold elevated risk for preterm birth in women who had a likely diagnosis of posttraumatic stress disorder or a major depressive episode. However, we were concerned by the omission of any measure of domestic violence in the study, as domestic violence is a correlate of posttraumatic stress disorder and major depression in pregnancy 2 and of adverse pregnancy outcomes including preterm birth. 3 The prevalence of antenatal domestic violence is about 4% to 9% in high-income settings. 4 In a systematic review of domestic violence and perinatal mental disorders, we reported that women with antenatal depression and posttraumatic stress disorder had high prevalence (15%-30%) and raised odds (3fold to 6-fold) of domestic violence experiences within the past year or during pregnancy. There were a few longitudinal studies, confined to postpartum depression, providing evidence for a bidirectional relationship between domestic violence and postpartum depression. Therefore, domestic violence is potentially important both as a trigger and a consequence of antenatal and postnatal mental disorders. The mechanisms linking domestic violence with adverse pregnancy outcomes 3 include poor antenatal care; chronic gynecological problems; behavioral risk factors, such as substance misuse; direct effects of physical trauma; and poor mental health. 3 Domestic violence has broader implications for mother and child beyond poor pregnancy outcomes including increased risks for maternal death and child abuse. 3,4 The high prevalence of domestic violence among preg
Domestic gas appliances and lung disease
Authors: A. Fuhlbrigge, S. Weiss
Journal: Thorax (1997)

Background.There is evidence from some studies that people living in homes with gas stoves and other unvented gas appliances experience more respiratory symptoms than those who use other fuels for cooking and heating, but other studies have found no such association.We have investigated whether the use of gas appliances is associated with an increased risk of respiratory symptoms and whether sensitisation to common environmental allergens modifies any such association.Methods.A stratified random sample of 15 000 adults aged 20-44 years, living in three towns in East Anglia, UK, were sent a questionnaire on asthma and hayfever.From those who responded, a random sample of 1864 were invited to complete an extended questionnaire that included questions on use of gas appliances, to give blood samples for measurement of total IgE and specific IgE to common allergens, and to undergo tests of respiratory function.659 women and 500 men agreed to an interview.The association of the use of gas appliances with respiratory symptoms, total IgE, specific IgE, and respiratory function was assessed by logistic and multiple regression models.Findings.Women who reported they mainly used gas for cooking had an increased risk of several asthma-like symptoms during the past 12 months including wheeze (odds ratio 2. 07 [95% CI 1.41-3.05]),waking with shortness of breath (2.32 [1.25-4.34]),and asthma attacks (2.60 [1.20-5.65]).Gas cooking increased the risk of symptoms more in women who were atopic than in non-atopic women but the difference did not reach significance (p>0.05).Women who used a gas stove or had an open gas fire had reduced lung function (forced expiratory volume in 1 s [FEV 1 ]) and increased airways obstruction (FEV 1 as a percentage of forced vital capacity) compared with women who did not.These associations were not observed in men.Interpretation.In East Anglia, the use of gas cooking is significantly associated with subjective and objective markers of respiratory morbidity in women but not in men.Women may be more susceptible than men to the products of gas combustion or they may have greater exposure to high concentrations of these products because they cook more frequently than men.(
Mammary Tumors and Mammary-Gland Development in Hybrid Mice Treated With Diethylstilbestrol for Varying Periods&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Flavia L. Richardson, Georgia Hall
Journal: JNCI Journal of the National Cancer Institute (1960)

Journal Article Mammary Tumors and Mammary-Gland Development in Hybrid Mice Treated With Diethylstilbestrol for Varying Periods Get access Flavia L. Richardson, Flavia L. Richardson Roscoe B. Jackson Memorial Laboratory, Bar Harbor, Maine Search for other works by this author on: Oxford Academic PubMed Google Scholar Georgia Hall Georgia Hall Roscoe B. Jackson Memorial Laboratory, Bar Harbor, Maine Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 25, Issue 5, November 1960, Pages 1023–1039, https://doi.org/10.1093/jnci/25.5.1023 Published: 01 November 1960 Article history Received: 09 May 1960 Published: 01 November 1960
CD4+ T cell-mediated immunological control of enterochromaffin cell hyperplasia and 5-hydroxytryptamine production in enteric infection
Authors: H. Wang, J. Steeds, Y. Motomura, Y. Deng, M. Verma-Gandhu, R. T El-Sharkawy, J. T McLaughlin, R. K Grencis, W. I Khan
Journal: Gut (2007)

Enterochromaffin (EC) cells are dispersed throughout the gastrointestinal (GI) mucosa and are the main source of 5-hydroxytryptamine (5-HT) in the gut. 5-HT has been implicated in the pathophysiology of several GI disorders, but the mechanisms regulating 5-HT production in the gut are unknown.To investigate the role of CD4(+) T cells in the production of 5-HT using a model of enteric parasitic infection.Severe combined immunodeficient (SCID) mice and their wild-type controls were infected with the nematode Trichuris muris and killed on various days after infection to study colonic EC cells and 5-HT production. The number of EC cells and the amount of 5-HT produced were significantly higher in infected wild-type mice than in non-infected mice. The number of EC cells and the amount of 5-HT after infection were significantly lower in SCID mice after infection than in wild-type mice. The number of EC cells and the amount of 5-HT was significantly increased after reconstitution of SCID mice with CD4(+) T cells from infected mice and this was accompanied by an upregulation of colonic CD3 T cells and T helper 2 (Th2) cytokines. Laser capture microdissection-based molecular and immunofluorescence techniques revealed the presence of interleukin 13 receptor alpha1-chain on EC cells.These results show an important immunoendocrine axis in the gut, where secretory products from CD4(+) T cells interact with EC cells to enhance the production of 5-HT in the gut via Th2-based mechanisms. These results show new insights into the mechanisms of gut function, which may ultimately lead to improved therapeutic strategies in functional and inflammatory disorders of the GI tract.
HIV-1 fusion peptide targets the TCR and inhibits antigen-specific T cell activation
Authors: Francisco J. Quintana, Doron Gerber, Sally C. Kent, Irun R. Cohen, Yechiel Shai
Journal: Journal of Clinical Investigation (2005)

The fusion peptide (FP) in the N terminus of the HIV envelope glycoprotein, gp41, functions together with other gp41 domains to fuse the virion with the host cell membrane. We now report that FP colocalizes with CD4 and TCR molecules, coprecipitates with the TCR, and inhibits antigen-specific T cell proliferation and proinflammatory cytokine secretion in vitro. These effects are specific: T cell activation by PMA/ionomycin or mitogenic antibodies is not affected by FPs, and FPs do not interfere with antigen-presenting cell function. In vivo, FPs inhibit the activation of arthritogenic T cells in the autoimmune disease model of adjuvant arthritis and reduce the disease-associated IFN-γ response. Hence, FPs might play 2 roles in HIV infection: mediating membrane fusion while downregulating T cell responses to itself that could block infection. Disassociated from HIV, however, the FP molecule provides a novel reagent for downregulating undesirable immune responses, exemplified here by adjuvant arthritis.
ACE2 of the heart: From angiotensin I to angiotensin (1–7)
Authors: S KEIDAR, M KAPLAN, A GAMLIELLAZAROVICH
Journal: Cardiovascular Research (2006)

Angiotensin II (Ang II), a bioactive peptide of the renin-angiotensin system (RAAS), plays an important role in the development of cardiovascular diseases (CVD). Pharmacological inhibition of angiotensin-converting enzyme (ACE), the Ang II forming enzyme, or specific blockade of Ang II binding to angiotensin type 1 receptor (AT1R) through which it exerts its deleterious effects, were shown to provide some protection against progression of CVD. The ACE-Ang II-AT1R axis has been challenged over the last few years with RAAS components able to counterbalance the effects of the main axis. The ACE homologue ACE2 efficiently hydrolyses Ang II to form Ang (1-7), a peptide that exerts actions opposite to those of Ang II. In contrast to the Ang II axis, the role of the ACE2-Ang (1-7) axis in cardiac function is largely obscure. Ang (1-7) is present in the viable myocardium, and its formation depends on Ang II as a substrate. The expression of this peptide is associated with cardiac remodeling: it is lost in the infarcted area and significantly increased in the border area. Low doses of Ang (1-7) improve cardiac output and antagonize Ang II-induced vasoconstriction. The type of Ang (1-7) biological activity is tissue specific and dose dependent. These findings point to a possible protective role for Ang (1-7) in abating the Ang II-induced actions. The elevated expression of Ang (1-7) in failing heart tissue paralleled the expression of its forming enzyme, ACE2. Several observations and experimental evidence suggest a beneficial role for ACE2 in cardiovascular function. Elevated ACE2 expression at the initial stage of several pathologies which decline with progression of disease might indicate a protective role for ACE2. Genetic manipulation of ACE2 expression, either targeted disruption or overexpression, point to the possible significance of this enzyme in cardiac function. Based on the above, a therapeutic approach that will amplify the ACE2-Ang (1-7) axis could provide further protection against the development of CVD. It turns out that the merits of currently used drugs--ACE inhibitors, AT1R blockers and mineralocorticoid receptor blockers (MRB) - lay beyond their direct effects on suppression of the ACE-Ang II-AT1R axis as they also increase cardiac ACE2 and Ang (1-7) significantly.
Optimal Cutoff Levels of More Sensitive Cardiac Troponin Assays for the Early Diagnosis of Myocardial Infarction in Patients With Renal Dysfunction
Authors: Raphael Twerenbold, Karin Wildi, Cedric Jaeger, Maria Rubini Gimenez, Miriam Reiter, Tobias Reichlin, Astrid Walukiewicz, Mathias Gugala, Lian Krivoshei, Nadine Marti, Zoraida Moreno Weidmann, Petra Hillinger, Christian Puelacher, Katharina Rentsch, Ursina Honegger, Carmela Schumacher, Felicitas Zurbriggen, Michael Freese, Claudia Stelzig, Isabel Campodarve, Stefano Bassetti, Stefan Osswald, Christian Mueller
Journal: Circulation (2015)

It is unknown whether more sensitive cardiac troponin (cTn) assays maintain their clinical utility in patients with renal dysfunction. Moreover, their optimal cutoff levels in this vulnerable patient population have not previously been defined.In this multicenter study, we examined the clinical utility of 7 more sensitive cTn assays (3 sensitive and 4 high-sensitivity cTn assays) in patients presenting with symptoms suggestive of acute myocardial infarction. Among 2813 unselected patients, 447 (16%) had renal dysfunction (defined as Modification of Diet in Renal Disease-estimated glomerular filtration rate <60 mL·min(-1)·1.73 m(-2)). The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including coronary angiography and serial levels of high-sensitivity cTnT. Acute myocardial infarction was the final diagnosis in 36% of all patients with renal dysfunction. Among patients with renal dysfunction and elevated baseline cTn levels (≥99th percentile), acute myocardial infarction was the most common diagnosis for all assays (range, 45%-80%). In patients with renal dysfunction, diagnostic accuracy at presentation, quantified by the area under the receiver-operator characteristic curve, was 0.87 to 0.89 with no significant differences between the 7 more sensitive cTn assays and further increased to 0.91 to 0.95 at 3 hours. Overall, the area under the receiver-operator characteristic curve in patients with renal dysfunction was only slightly lower than in patients with normal renal function. The optimal receiver-operator characteristic curve-derived cTn cutoff levels in patients with renal dysfunction were significantly higher compared with those in patients with normal renal function (factor, 1.9-3.4).More sensitive cTn assays maintain high diagnostic accuracy in patients with renal dysfunction. To ensure the best possible clinical use, assay-specific optimal cutoff levels, which are higher in patients with renal dysfunction, should be considered.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587.