tbuckley/cabot-search huggingface dataset:
Serum Cytokine Profiling as a Diagnostic and Prognostic Tool in Ovarian Cancer: A Potential Role for Interleukin 7
Authors: Annechien J.A. Lambeck, Anne P.G. Crijns, Ninke Leffers, Wim J. Sluiter, Klaske A. ten Hoor, Mike Braid, Ate G.J. van der Zee, Toos Daemen, Hans W. Nijman, W. Martin Kast
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To evaluate if serum cytokine levels could be used as diagnostic or prognostic markers in ovarian cancer. Experimental Design: A cytokine bead array was done to simultaneously analyze 14 cytokines in the sera of 187 ovarian cancer patients with complete clinicopathologic data and follow-up, 45 patients with benign ovarian tumors, and 50 healthy controls. Serum levels of the well-known serum tumor marker CA-125 were routinely measured in all patients. Results: Serum levels of CA-125, interleukin 6 (IL-6), IL-7, and IL-10 were elevated in ovarian cancer patients compared with patients with benign ovarian tumors. Analyzing the cytokines in combination with CA-125 showed that a combination of IL-7 and CA-125 serum levels could accurately predict 69% of the ovarian cancer patients, without falsely classifying patients with benign pelvic mass. The cytokines IL-6, IL-7, IL-8, IL-10, monocyte chemotactic protein-1 (MCP-1), and IP-10 and CA-125 were associated with disease-free and overall survival in univariate analysis. In multivariate analysis, IL-7 and IP-10 were independent predictors of overall survival, although after inclusion of the clininopathologic parameters, only stage and residual disease remained as independent predictors of survival. Conclusions: IL-7 levels were found to be strongly associated with ovarian cancer and could be used in combination with CA-125 to distinguish between malignant and benign ovarian tumors.
Detection of circulating lymphoma cells in subcutaneous panniculitis-like T-cell lymphoma
Authors: W. Nishie, K. Yokota, D. Sawamura, K. Sato-Matsumura, S. Tanimura, R. Osawa, T. Kawashima, T. Yokota, H. Shimizu
Journal: British Journal of Dermatology (2003)

Sir, Subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL) is a rare variant of primary cutaneous T‐cell lymphoma.1 SPTCL clinically presents with high fever and tender multiple subcutaneous nodules which are often misdiagnosed as erythema nodosum. Systemic involvement including peripheral blood and visceral organs has been thought to be rare except in the terminal leukaemic stage. We report a case of SPTCL in which the same clonal T‐cell receptor (TCR) γ gene was detected in both skin and peripheral blood in spite of the lack of any apparent clinical involvement of extracutaneous organs. A 73‐year‐old Japanese woman was admitted to our hospital with a 4‐month history of high fever and subcutaneous tender nodules. Physical examination revealed indurated erythematous subcutaneous nodules and tumours on her legs, abdomen, and right breast (Fig. 1a). No lymphadenopathy or hepatosplenomegaly were noted. Serum levels of lactate dehydrogenase, C‐reactive protein, and soluble interleukin (IL)‐2 receptor were within normal limits. A skin biopsy taken from a subcutaneous nodule on her left thigh showed a diffuse infiltration of medium to large‐sized pleomorphic mononuclear cells throughout the subcutaneous fatty tissues with the characteristic feature of so‐called ‘rimming’ around fatty spaces (Fig. 1b–d). Immunohistochemically, these neoplastic cells were characterized as CD3+, CD4–, CD8+, CD20–, CD30– and CD56–. Cytotoxic markers including TIA‐1, granzyme B, and perforin were also positively stained. In situ hybridization for Epstein–Barr virus‐encoded small nuclear RNA was negative. Standard Southern blot analysis of TCR γ gene rearrangement from the subcutaneous tumour proved the monoclonal nature of the infiltrated T lymphocytes. From these findings, the final diagnosis of SPTCL was made. Further analysis including peripheral blood cytology, bone marrow biopsy, computed tomography and gallium scintigraphy confirmed that the disease was limited to the skin.
The Bcl-2/Bcl-XL Family Inhibitor ABT-737 Sensitizes Ovarian Cancer Cells to Carboplatin
Authors: James Witham, Melanie R. Valenti, Alexis K. De-Haven-Brandon, Susanne Vidot, Suzanne A. Eccles, Stan B. Kaye, Alan Richardson
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The effective treatment of ovarian cancer is hampered by the development of drug resistance, which may be mediated by members of the Bcl-2 family of apoptosis regulators. ABT-737 is a recently described inhibitor of members of this family. We investigated whether this compound could sensitize ovarian cancer cells to chemotherapeutic agents. Experimental Design: The sensitivity of ovarian cancer cell lines to ABT-737 in combination with either carboplatin or paclitaxel was tested either in vitro by assessing cell growth/survival and apoptosis or in xenograft studies. Results: As a single agent, ABT-737 inhibited the growth of eight ovarian cancer cell lines, although with relatively poor potency. However, ABT-737, but not a less active enantiomer, increased the sensitivity of several cell lines to carboplatin. The increased sensitivity to carboplatin was accompanied by a decrease in time at which apoptosis was observed when assessed according to the number of attached cells, PARP cleavage, and nucleosome formation. ABT-737 was more effective at sensitizing IGROV-1 cells when ABT-737 was administered after carboplatin. In addition, ABT-737 significantly enhanced the activity of carboplatin in one of three primary cultures derived directly from ascitic tumor cells in patients recently treated with chemotherapy. Small interfering RNA directed to Bcl-XL also increased the sensitivity of ovarian cancer cell lines to carboplatin. ABT-737 was also able to augment the inhibition of IGROV-1 tumor xenograft growth beyond that obtained with carboplatin alone. Conclusions: These data suggest that ABT-737, in combination with carboplatin, may find utility in the treatment of patients with ovarian cancer.
Visualizing B cell capture of cognate antigen from follicular dendritic cells
Authors: Kazuhiro Suzuki, Irina Grigorova, Tri Giang Phan, Lisa M. Kelly, Jason G. Cyster
Journal: The Journal of Experimental Medicine (2009)

The prominent display of opsonized antigen by follicular dendritic cells (FDCs) has long favored the view that they serve as antigen-presenting cells for B cells. Surprisingly, however, although B cell capture of antigen from macrophages and dendritic cells has been visualized, acquisition from FDCs has not been directly observed. Using two-photon microscopy, we visualized B cell capture of cognate antigen from FDCs. B cell CXCR5 expression was required, and encounter with FDC-associated antigen could be detected for &amp;gt;1 wk after immunization. B cell–FDC contact times were often brief but occasionally persisted for &amp;gt;30 min, and B cells sometimes acquired antigen together with FDC surface proteins. These observations establish that FDCs can serve as sites of B cell antigen capture, with their prolonged display time ensuring that even rare B cells have the chance of antigen encounter, and they suggest possible information transfer from antigen-presenting cell to B cell.
The Newest Mania: Seeing Disease Mongering Everywhere
Authors: S. Nassir Ghaemi
Journal: PLoS Medicine (2006)

I am a disease monger.I teach primary care doctors how to identify bipolar disorder.Worse yet, I take money from pharmaceutical companies for doing so.I use it to subsidize my practice so that I can treat patients with no insurance, or little money, who now account for over a third of my patients-in part because the pharmaceutical companies have drained so much money out of the health-care system.Ironic, isn't it?My Web site PsychEducation.org(http:⁄⁄www.psycheducation.org) is number one on Google for searches on "bipolar II."See if you think it looks like disease mongering.Hundreds of people have written thanking me for explaining bipolar II and the concept of a bipolar spectrum, indicating that this new perspective really helps them understand their long-standing symptoms.To my immediate recall, none have complained about being led astray by an overbroad interpretation of bipolarity.Notice that, just like Mr. Moynihan, one of the guest editors of your April 2006 series of articles on disease mongering [1], I could be mongering even now, as I too have a new book.At least I'm not trying to attract attendees to my conference.Tricky, isn't it.Has there been an oversimplifi cation in this analysis?(PsychEducation.org
CNS myelin induces regulatory functions of DC-SIGN–expressing, antigen-presenting cells via cognate interaction with MOG
Authors: J.J. García-Vallejo, J.M. Ilarregui, H. Kalay, S. Chamorro, N. Koning, W.W. Unger, M. Ambrosini, V. Montserrat, R.J. Fernandes, S.C.M. Bruijns, J.R.T. van Weering, N.J. Paauw, T. O’Toole, J. van Horssen, P. van der Valk, K. Nazmi, J.G.M. Bolscher, J. Bajramovic, C.D. Dijkstra, B.A. ’t Hart, Y. van Kooyk
Journal: The Journal of Experimental Medicine (2014)

Myelin oligodendrocyte glycoprotein (MOG), a constituent of central nervous system myelin, is an important autoantigen in the neuroinflammatory disease multiple sclerosis (MS). However, its function remains unknown. Here, we show that, in healthy human myelin, MOG is decorated with fucosylated N-glycans that support recognition by the C-type lectin receptor (CLR) DC-specific intercellular adhesion molecule-3–grabbing nonintegrin (DC-SIGN) on microglia and DCs. The interaction of MOG with DC-SIGN in the context of simultaneous TLR4 activation resulted in enhanced IL-10 secretion and decreased T cell proliferation in a DC-SIGN-, glycosylation-, and Raf1-dependent manner. Exposure of oligodendrocytes to proinflammatory factors resulted in the down-regulation of fucosyltransferase expression, reflected by altered glycosylation at the MS lesion site. Indeed, removal of fucose on myelin reduced DC-SIGN–dependent homeostatic control, and resulted in inflammasome activation, increased T cell proliferation, and differentiation toward a Th17-prone phenotype. These data demonstrate a new role for myelin glycosylation in the control of immune homeostasis in the healthy human brain through the MOG–DC-SIGN homeostatic regulatory axis, which is comprised by inflammatory insults that affect glycosylation. This phenomenon should be considered as a basis to restore immune tolerance in MS.
Association Between Age-Related Decline in Brain Dopamine Activity and Impairment in Frontal and Cingulate Metabolism
Authors: Nora D. Volkow, Jean Logan, Joanna S. Fowler, Gene-Jack Wang, Ruben C. Gur, Christopher Wong, Christoph Felder, S. John Gatley, Yu-Shin Ding, Robert Hitzemann, Naomi Pappas
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: Despite the well-documented loss of brain dopamine activity with age, little is known about its functional consequences in healthy individuals. This study investigates the relationship between measures of brain dopamine D2 receptors (molecules that transmit dopamine signals) and regional brain glucose metabolism (a marker of brain function) in healthy individuals. METHOD: Thirty-seven healthy volunteers aged 24–86 years underwent positron emission tomography scans after injection of [11C]raclopride to assess dopamine D2 receptors and [18]fluorodeoxyglucose to assess regional brain glucose metabolism. Two methods used to assess the correlations between metabolism and dopamine D2 receptors—pixel-by-pixel correlations and correlations in preselected regions of interest—were then compared. RESULTS: D2 receptors as well as frontal and cingulate metabolism declined with age. Regardless of the method used, significant correlations between metabolism and D2 receptors were found in the frontal cortex (Brodmann's areas 6, 7, 8, 9, 10, 11, 44, 45, 47), anterior cingulate gyrus (areas 24, 32), temporal cortex (area 21), and caudate. These correlations remained significant after removing age effects (partial correlation). CONCLUSIONS: These results provide the first link between age-related declines in brain dopamine activity and frontal and cingulate metabolism, which supports the need to investigate the therapeutic utility of interventions that enhance dopamine function in the elderly. The fact that correlations remained significant after removing age effects suggests that dopamine may influence frontal, cingulate, and temporal metabolism regardless of age.
Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) Study
Authors: Martin R. Wilkins, Gideon A. Paul, Julian W. Strange, Nina Tunariu, Wendy Gin-Sing, Winston A. Banya, Mark A. Westwood, Alexander Stefanidis, Leong L. Ng, Dudley J. Pennell, Raad H. Mohiaddin, Petros Nihoyannopoulos, J. Simon R. Gibbs
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Phosphodiesterase type 5 (PDE5) inhibition has been proposed for the treatment for pulmonary arterial hypertension (PAH).This study compared adding sildenafil, a PDE5 inhibitor, to conventional treatment with the current practice of adding bosentan, an endothelin receptor antagonist.Twenty-six patients with PAH, idiopathic or associated with connective tissue disease, World Health Organization (WHO) functional class III, were randomized in a double-blind fashion to receive sildenafil (50 mg twice daily for 4 weeks, then 50 mg three times daily) or bosentan (62.5 mg twice daily for 4 weeks, then 125 mg twice daily) over 16 weeks.Changes in right ventricular (RV) mass (using cardiovascular magnetic resonance), 6-minute walk distance, cardiac function, brain natriuretic peptide, and Borg dyspnea index.When analyzed by intention to treat, there were no significant differences between the two treatment groups. One patient on sildenafil died suddenly. Patients on sildenafil who completed the protocol showed significant changes from baseline, namely, reductions in RV mass (-8.8 g; 95% confidence interval [CI], -2, -16; n = 13, p = 0.015) and plasma brain natriuretic peptide levels (-19.4 fmol x ml(-1); 95% CI, -5, -34; p = 0.014) and improvements in 6-minute walk distance (114 m; 95% CI, 67, 160; p = 0.0002), cardiac index (0.3 L x min(-1) x m(-2); 95% CI, 0.1, 0.4; p = 0.008), and systolic left ventricular eccentricity index (-0.2; 95% CI, -0.02, -0.37; p = 0.031). Bosentan improved 6-minute walk distance (59 m; 95% CI, 29, 89; n = 12, p = 0.001) and cardiac index (0.3; 95% CI, 0.1, 0.4; p = 0.008).Sildenafil added to conventional treatment reduces RV mass and improves cardiac function and exercise capacity in patients with PAH, WHO functional class III. Safety monitoring is important until more experience is obtained.
Heart cells keep the rhythm
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2006)

Cytokine therapy post–heart attack restores the expression of gap junction proteins and thus restores electrical connections between heart cells, according to a new study by Kuhlmann and colleagues (page 87). These heart cells, with better electrical connections, are able to pump with a more normal rhythm.






Figure 1

G-CSF treatment restores the expression of connexin 43 on cardiomyocytes near areas of heart attack–induced damage (arrows).




Restoring the function of damaged heart tissue is a new approach to the treatment of myocardial infarctions, or heart attacks. The scar tissue from heart attacks creates a roadblock for electrical conduction and can cause the heart to beat erratically. Indeed, erratic heartbeats—or arrhythmias—are the primary cause of death in patients who have had heart attacks.

Heart attack treatments range from blood-thinning and cholesterol-lowering drugs, which reduce the likelihood of developing blocked arteries, to implanted defibrillators that shock erratically beating hearts into line. But the idea of repairing damaged heart tissue is new. One promising repair approach involves the intravenous injection of two cytokines—G-CSF (granulocyte colony-stimulating factor) and SCF (stem cell factor)—which mobilize stem cells from the bone marrow (BM). Early studies suggested that these stem cells travel to the damaged heart and differentiate into functional heart cells called cardiomyocytes. Other studies, however, found no evidence that stem cells can become cardiomyocytes.

Kuhlmann and colleagues now confirm that G-CSF/SCF treatment in mice with heart damage causes BM-derived cells to enter the heart, but they show that virtually none of these cells become bona fide heart cells. The benefit of this treatment—which improved the heart's pump function and protected against induced arrhythmias—instead correlated with enhanced expression of the gap junction protein connexin 43 on the surface of heart cells adjacent to the injured tissue. The expression of connexin 43, which provides the electrical connection between neighboring cells, is decreased after heart injury, thus reducing the conductive capacity between cells.

The connexin-inducing effect of G-CSF might be direct, as cardiomyocyte expression of the G-CSF receptor was increased in response to injury. But this possibility is difficult to test in vitro, as mouse cardiomyocytes grow poorly in culture. The authors are also investigating G-CSF–independent signaling pathways that induce the expression of connexin 43 in other cell types.
Alterations of myocardial blood flow associated with experimental canine left ventricular hypertrophy secondary to valvular aortic stenosis.
Authors: D Alyono, R W Anderson, D G Parrish, X Z Dai, R J Bache
Journal: Circulation Research (1986)

Experimental renovascular hypertension or supravalvular aortic constriction results in left ventricular hypertrophy and impaired minimum coronary vascular resistance. However, these experimental models expose the coronary arteries to increased intra-arterial pressure, so that hypertensive vascular changes might be responsible for the impaired minimum coronary resistance. This study was performed to test the hypothesis that left ventricular hypertrophy in the absence of increased coronary pressure results in abnormalities of myocardial perfusion. Aortic valve stenosis was produced by plication of the noncoronary aortic cusp of 11 dogs at 6-8 weeks of age. Studies were carried out when the animals reached adulthood; mean left ventricular:body weight ratio was 7.1 +/- 0.4 as compared to 4.4 +/- 0.3 g/kg in 11 normal dogs (P less than 0.01). Under quiet resting conditions, myocardial blood flow measured with microspheres was significantly greater than normal in dogs with aortic stenosis. However, during maximum coronary vasodilation with adenosine, mean left ventricular blood flow in dogs with hypertrophy (3.29 +/- 0.39) was substantially less than in normal dogs (6.19 +/- 0.54 ml/min per g; P less than 0.01), whereas minimum coronary resistance was increased from 14.1 +/- 1.7 in normal dogs to 23.7 +/- 5.4 mmHg. min X g/ml (P less than 0.01). To examine the response of myocardial perfusion to cardiac stress, blood flow was measured during pacing at 200 and 250 beats/min. Compared with normal dogs, animals with hypertrophy had a subnormal increase in myocardial blood flow during tachycardia; this perfusion deficit was most marked in the subendocardium. These data demonstrate that left ventricular hypertrophy alone, without increased coronary artery pressure, is associated with impaired minimum coronary vascular resistance and with abnormalities of myocardial blood flow during pacing stress.
Active immunisation of human interferon α transgenic mice with a human interferon α Kinoid induces antibodies that neutralise interferon α in sera from patients with systemic lupus erythematosus
Authors: Alexis Mathian, Zahir Amoura, Estelle Adam, Fabien Colaone, Marco F M Hoekman, Olivier Dhellin, Pierre Vandepapelière, Julien Haroche, Jean-Charles Piette, Pierre Lebon, Géraldine Grouard-Vogel
Journal: Annals of the Rheumatic Diseases (2011)

Objectives Interferon α (IFNα) plays a central role in the pathogenesis of systemic lupus erythematosus (SLE) and is considered a target for its treatment. In the current study, the ability of active immunisation with a human (hu) IFNα2b Kinoid (IFN-K) to break B cell tolerance to IFNα and to induce huIFNα-neutralising antibodies in mice immunotolerant to huIFNα2b was assessed. Methods IFN-K was manufactured by crosslinking huIFNα2b to keyhole limpet haemocyanin (KLH). Transgenic mice expressing huIFNα2b received by intramuscular injection either saline or polymerised huIFNα2b as controls, or IFN-K, emulsified in ISA51vg adjuvant. Results All of the huIFNα2b-expressing mice immunised with IFN-K generated neutralising antibodies against huIFNα2b. In addition, these antibodies neutralised all 13 subtypes of huIFNα. They also neutralised IFNα activity in sera collected from 10 different patients with active SLE. However, the antibodies did not bind to huIFNγ or huIFNβ. Finally, cellular activation assays showed that immunisation with IFN-K did not induce memory T cells reactive to native huIFNα2b, whereas it did induce memory cells reactive to KLH. Conclusion These results show that active immunisation with IFN-K induces polyclonal antibodies that neutralise all subtypes of huIFNα as well as IFNα in sera from patients with SLE by breaking humoral but not cellular tolerance to IFNα. This suggests that immunisation with IFN-K is a promising new therapeutic strategy for the treatment of SLE.
BRCA1 Represses Amphiregulin Gene Expression
Authors: Ekaterina P. Lamber, Andrew A. Horwitz, Jeffrey D. Parvin
Journal: Cancer Research (2010)

BRCA1, the breast cancer- and ovarian cancer-specific tumor suppressor, can be a transcriptional repressor or a transcriptional activator, depending on the promoter context. To identify the genes activated or repressed by BRCA1, we have analyzed microarray results from cells depleted of BRCA1 and revealed a number of genes regulated by BRCA1 on the level of transcription. Among the genes repressed by BRCA1, we have identified amphiregulin (AREG) and early growth response-1 (EGR1). Results indicate that BRCA1 regulates AREG transcription directly through binding to the AREG promoter, however, we could not detect BRCA1 on the EGR1 promoter, suggesting that EGR1 is indirectly regulated by BRCA1. In an attempt to identify the mechanism of the AREG transcriptional repression by BRCA1, we have mapped two independent BRCA1 response elements on the AREG located at positions -202/-182 and +19/+122. BRCA1 depletion leads to induction of the AREG protein. Taken together, our data build the connection between BRCA1 loss of function and AREG upregulation-a change in gene expression often observed in breast cancer.
What is top of the charts? BPIFB1/LPLUNC1 localises to the bronchiolised epithelium in the honeycomb cysts in UIP
Authors: Colin D Bingle, Bianca Araujo, William A Wallace, Nik Hirani, Lynne Bingle
Journal: Thorax (2013)

Transcriptomic analyses are increasingly being used to define the molecular phenotype of complex diseases and may yet allow the identification of novel diagnostic and prognostic markers. Yang et al 1 are to be congratulated for their meticulous application of this technology to the systematic study of gene signatures from patients with Idiopathic Pulmonary Fibrosis (IPF). This study, which appears to be the largest data set yet published, identifies two distinct gene signatures with high expression of ‘cilium-associated genes’ being shown to be associated with cases that exhibit microscopic honeycombing, which is commonly observed in, but not specific to, ‘Usual Interstitial Pneumonia’ (UIP), the pathological pattern of remodelling seen in IPF. This metaplastic bronchial type epithelium within the honeycomb spaces has recently been the …