tbuckley/cabot-search huggingface dataset:
Abstract 2831: Studies on the mechanistic basis of the anticancer activity of 2,4-disulfonyl-PBN (OKN-007)
Authors: Robert A. Floyd, Hema Chandru, Charles Stewart, Rheal A. Towner
Journal: Cancer Research (2012)

Abstract Sulfatase 2 (Sulf2) is a protein which resides in the extracellular matrix of cancer cells and enzymatically removes sulfate from the 6-O-sulfate esters of heparin. Several tumors have been shown to be enriched in Sulf2 in comparison to normal tissues where it is either absent or present at very low levels. The action of Sulf2 alters growth factor binding to the extracellular matrix of cells and has been shown to be important in the development of many cancers including breast, lung, liver, colon, and pancreas. Sulf2 mobilizes fibroblast growth factors (FGFs), vascular endothelial growth factor (VEGF) and stromal derived growth factor-1 (SDF-1) bound to heparin. We found that OKN-007 acts to weakly inhibit the aryl sulfatase activity of Sulf2 acting on the substrate 4-methylumbelliferyl-sulfate (4-MUS) and to more effectively inhibit the enzymatic activity of Sulf2 when it acts upon its natural substrate the 6-O-sulfate ester of heparin. The Sulf2 enzymatic activity was potently inhibited by suramin, a compound that has 6 phenyl-sulfonyl groups as part of its chemical structure and has been shown to have anti-cancer activity. Utilizing the natural substrate we have shown that other sulfonyl-phenyl compounds act to suppress the activity of Sulf2. We have conducted preliminary studies to see if OKN-007 has anti-cancer activity in a breast cancer mouse xenograph model. Balb/c female ovariectomized Estradiol pellet-implanted nude mice were implanted with MCF-7 breast cancer cells and OKN-007 was administered at 250mg/kg/day in the drinking water. The experiment was terminated at week 5 at which time the data showed that OKN-007 decreased the average tumor volume by 33%. OKN-007 has been shown to have anti-cancer activity in the rat C6 model of glioma. The anti-cancer mechanism of action of OKN-007 is still unknown. Recently we have explored the potential of OKN-007 to alter cancer cell migration in a gradient involving the chemokine SDF-1 and its cellular receptor CXCR4. The CXCL4/SDF-1 gradient is considered to be important in the metastasis of primary cancers. Results with rat C6 glioma cells, U87MG human glioma cells as well as MCF-7 breast cancer cells indicate that OKN-007 at low concentrations inhibits cancer migration in a CXCR4/SDF-1 gradient. These observations need to be explored in more depth utilizing animal models of cancer metastasis. Research supported in part by US Army Concept Grant W81XWH-09-1-0352. Dr. Floyd holds the Merrick Foundation Chair in Aging Research. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2831. doi:1538-7445.AM2012-2831
Manufacturer's Response to Case Reports of PML
Authors: Marianne T. Sweetser, Katherine T. Dawson, Carmen Bozic
Journal: New England Journal of Medicine (2013)

On December 7, we noticed signs of an immune reconstitution inflammatory syndrome (IRIS) on MRI, with indications becoming more evident on December 13 (Fig. 1).We initiated treatment with intravenous methylprednisolone.Her clinical condition stabilized in early January 2013, and we observed the first signs of recovery on January 31.We believe that treatment with Psorinovo contributed to the development of PML in our patient.First, lymphopenia developed during treatment with Psorinovo and is a well known side effect. 1 Second, our patient had used no immunosuppressive medication before the onset of PML, and she was seronegative for HIV.Finally, the occurrence of IRIS after the discontinuation of Psorinovo argues in favor of a causal link.We think this case report is of special relevance since preparations of fumaric acid esters, including dimethyl fumarate, are emerging drugs that may have a broader range of therapeutic indications in the near future.
Abstract 962: Prolonged antiangiogenic therapy with oral metronomic topotecan and pazopanib in pediatric solid tumor mouse model.
Authors: Sushil Kumar, Reza Bayat Mokhtari, Syed Islam, Herman Yeger, Sylvain Baruchel
Journal: Cancer Research (2013)

Abstract Background: We have previously observed that the combination of daily oral Low Dose Metronomic (LDM) Topotecan (TP) and Pazopanib (PZ) significantly delayed the tumor growth and enhanced the survival in neuroblastoma (NB) mouse models (Kumar et al, 2011). However, this combination (TP+PZ) did not stop tumor growth and the animals eventually died due to disease during the course of therapy. Therefore, we planned to investigate the factors contributing to resistance to this antiangiogenic therapy in NB mouse model. Objectives: To investigate the effect of prolonged TP+PZ therapy on angiogenesis by testing the effect of therapy at different durations in NB mice xenograft model. Methods: Mice bearing subcutaneous SK-N-BE(2) NB xenografts were treated with either of the four regimens, daily, orally: vehicle (untreated), PZ (150 mg pazopanib), TP (1.0 mg/Kg topotecan), TP+PZ (combination of topotecan and pazopanib, same doses as single agents). Durations of treatment planned for each regimen were 28 days, 56 days and 80 days. Animals were sacrificed after these durations or upon end point, whichever was earlier. The criteria for end point are tumor sizes exceeding 2.0 cms in diameter or animals showing signs of morbidity. Results: The animals in control, PZ, TP reached the end point after 23d, 28d and 46d respectively. TP+PZ halted the tumor growth for up to 40 days, after which gradual growth was observed. The mean tumor diameters in the third TP+PZ group reached 1.8 cms at the day 80. CD31 immunofluorescence revealed that all the three durations of TP+PZ significantly lowered microvessel densities compared to the control (P= 0.02, 0.04 and 0.009 respectively for 28, 56 and 80 days respectively). However the ratio of CD31 to α- smooth muscle actin (pericyte marker) stained areas were significantly higher in animals treated with TP+PZ for 56 and 80days, compared to control (P=0.0006; 56d and 0.004; 80d) indicating higher pericyte coverage. TP+PZ (28d) showed signs of necrosis and cell cycle arrest (Ki67 staining), which were not observed in later durations (56 and 80 days) with TP+PZ. Long-term TP+PZ therapy also increased the levels of HIF-1 alpha, VEGF and Oct-4 within the tumor tissue. Conclusion: This study indicates that even though prolonged TP+PZ therapy demonstrates sustained antiangiogenic activity, it encounters resistance in NB, potentially mediated by pericyte coverage. Long-term TP+PZ therapy may also increase tumor stemness. Citation Format: Sushil Kumar, Reza Bayat Mokhtari, Syed Islam, Herman Yeger, Sylvain Baruchel. Prolonged antiangiogenic therapy with oral metronomic topotecan and pazopanib in pediatric solid tumor mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 962. doi:10.1158/1538-7445.AM2013-962
Gender of Offspring after Oral-Contraceptive Use
Authors: Kenneth J. Rothman, Jane Liess
Journal: New England Journal of Medicine (1976)

We examined the sex of offspring born after oral-contraceptive use according to duration of contraceptive use and the interval between cessation of use and conception for 6109 live births. The overall proportion of male births (with 90 per cent confidence) falls between 0.491 and 0.512. These data exclude with high probability a shift in the sex distribution of the magnitude previously hypothesized, and are not consistent with even a moderate shift in sex distribution. Sex of offspring was not related to total duration of oral-contraceptive use, duration of use since any previous pregnancy or interval between termination of use and conception. It appears that oral contraceptives have no bearing on the sex of subsequent offspring. (N Engl J Med 295.859–861, 1976)
Metabolic Acidosis Resulting from Intravenous Alimentation Mixtures Containing Synthetic Amino Acids
Authors: William C. Heird, Ralph B. Dell, John M. Driscoll, Burton Grebin, Robert W. Winters
Journal: New England Journal of Medicine (1972)

Abstract Hyperchloremic metabolic acidosis was observed in 11 infants receiving total parenteral nutrition containing mixtures of synthetic L-amino acids. The observed acidosis was not due to excessive gastrointestinal or renal losses of base as judged by the stool undetermined anion content and the urinary net acid excretion, nor was it due to infusion of preformed hydrogen ion as judged by the titratable acidity of the synthetic amino acid mixtures. Instead, the synthetic amino acid mixtures contain an excess of cationic amino acids in relation to anionic amino acids or other organic anions. Metabolism of these cationic amino acids results in a net excess of hydrogen ion, explaining the observed acidosis.
Clinical significance of CD95, Bcl-2 and Bax expression and CD95 function in adult de novo acute myeloid leukemia in context of P-glycoprotein function, maturation stage, and cytogenetics
Authors: C Wuchter, L Karawajew, V Ruppert, T Büchner, C Schoch, T Haferlach, R Ratei, B Dörken, W-D Ludwig
Journal: Leukemia (1999)
Axial and Appendicular Bone Mineral Density in Patients with Long-Term Deficiency or Excess of Calcitonin
Authors: Daniel L. Hurley, Robert D. Tiegs, Heinz W. Wahner, Hunter Heath
Journal: New England Journal of Medicine (1987)

Whether calcitonin deficiency causes and calcitonin excess prevents bone loss is controversial. We therefore measured plasma calcitonin levels and bone mineral density at the radius (by single photon absorptiometry) and lumbar spine (dual photon absorptiometry) in patients with an excess or deficiency of calcitonin. We studied 21 patients who had undergone subtotal thyroidectomy 6.8 to 29 years previously and had no calcitonin secretory reserve, and 11 patients who had received a diagnosis of medullary thyroid carcinoma 6.8 to 23 years previously and had chronic hyper-calcitoninemia. Bone-density values, expressed as Z-scores (i.e., as the number of standard deviations above or below the normal means adjusted for age and sex), were indistinguishable from normal in the patients who had undergone thyroidectomy (means ±SE: radius, 0.36±0.15; spine, 0.27±0.17). In the patients with medullary thyroid cancer, radial bone-density values were normal (-0.26±0.39), but spinal density was significantly reduced (-0.75±0.17, P<0.01). There were no significant correlations between the duration of calcitonin excess or deficiency and the bone density at either site. Bone mineral density was not affected by whether or not thyroxine replacement therapy was given. We conclude that skeletal mass is not affected by endogenous plasma calcitonin in adults. (N Engl J Med 1987; 317:537–41.)
AB0581 The Estimated Annual Incidence Rate of Polyarteritis Nodosa in Slovenia: Table 1.
Authors: R. Jese, Z. Rotar, S. Praprotnik, A. Hocevar, M. Tomsic
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Polyarteritis nodosa (PAN) is a necrotising vasculitis of medium and small sized muscular arteries. It is a rare disease, with reported annual incidence rate of 1–8 cases per 10<sup>6</sup> adults.<sup>1,2</sup> In areas where hepatitis B virus (HBV) infection is hyperendemic however, the annual incidence rate is much higher, i.e. up to 77 per 10<sup>6</sup> adults.<sup>3</sup> <h3>Objectives</h3> To determine the annual incidence rate of PAN within a well-defined adult population of the Ljubljana region of Slovenia. <h3>Methods</h3> A retrospective chart review of adult patients diagnosed with PAN was performed at the Department of Rheumatology of University Medical Centre Ljubljana, which is a part of an integrated secondary/tertiary university teaching hospital, that is the only referral rheumatology centre in the Ljubljana region, which represents about a quarter of Slovenian population. Potential cases were identified by searching the electronic medical records for ICD-10 codes M30.0. The electronic and paper records of patients who were residents of the Ljubljana region at the time of diagnosis were then thoroughly reviewed. Cases fulfilling the ACR 1990 classification criteria for PAN with either histologically proven vasculitis or characteristic arteriographic abnormalities were included in the analysis. The annual incidence rate of PAN was then calculated. <h3>Results</h3> Between January 1, 2003 and December 31, 2012 (10 years of observation) five new cases (3 male, 2 female, male:female ratio=1,5; median age 49 (range 27–72) years) of PAN were identified in the Ljubljana region with a population of 527,000 aged 18 years or above. Patients9 clinical characteristics at the time of diagnosis are presented in Table 1. Four patients complained of myalgias and all male patients had testicular pain. Peripheral nerve lesions were identified in two. Three patients had arteriographic abnormalities; two of them had the characteristic microaneurysms. One patient had an active HBV infection. One had a localized cutaneous form of PAN on the basis of nodular skin changes with typical histological picture and no other organ system involvement (Case 1*). During the follow up one patient developed AA amyloidosis. <h3>Conclusions</h3> The estimated annual incidence rate of PAN was 0.95 per 10<sup>6</sup> adults. <h3>References</h3> Gonzalez-Gay, MA, et al. Arthrit Care Res, 2003, 49.3: 388-93. Watts, RA, et al. Arthritis Rheum, 2000, 43.2: 414-19. McMahon, BJ, et al. Hepatology, 1989, 9.1: 97-101. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2564
A9.03 Exploring the potential of haeme-oxygenase 1 (HO-1) as a therapeutic target for pah associated with CTD
Authors: J Elies, C Peers C, F Del Galdo
Journal: Annals of the Rheumatic Diseases (2016)

<h3></h3> Pulmonary arterial hypertension (PAH) is a complex, multifactorial disease characterised by endothelial cells (EC) dysfunction and subsequent uncontrolled proliferation of vascular smooth muscle cells (VSMC), leading to a progressive increase in pulmonary vascular resistance and ultimately right heart failure. PAH is frequently associated with connective tissue diseases (CTD). The most common cause of CTD associated PAH is Systemic Sclerosis or Scleroderma (SSc), an autoimmune condition characterised by tissue fibrosis and endothelial cell dysfunction. While tissue fibrosis is the hallmark of SSc, EC dysfunction is a very early pathological manifestation and it causes PAH in 40% of patients during the course of the disease. The most important profibrotic growth factor involved in SSc is transforming growth factor (TGF)-β, however the putative link between aberrant TGF-β signalling and EC dysfunction is still not clear. Heme oxygenase 1 (HO-1) is an inducible enzyme (under hypoxia) with important antioxidant, anti-proliferative, and anti-inflammatory properties in VSMC and ECand its expression can be supressed by TGF-β. Here we explored whether inhibitory effect of TGF-β on HO-1 expression could be the link between aberrant TGF-β signalling and the endothelial dysfunction associated with the pathogenesis of PAH. Using immunohistochemistry we examined the expression of HO-1 in both skin and lung biopsies from healthy controls and patients with SSc. HO-1 expression was less dominant in the skin of SSc patients. By contrast, HO-1 was only detected in the infiltrated areas of SSc lung biopsies. Expression of HO-1 was assessed by&nbsp;<i>western blotting</i> (n = 4) and quantitative PCR&nbsp;(n = 3) in skin fibroblasts isolated from SSc patients and healthy subjects under Normoxia (control),chronic hypoxia (CH, <i>in vitro</i> model of PAH), TGF-β (5 ng/mL), and the combination of CH + TGF-β. Basal HO-1 expression was downregulated in SSc fibroblasts compared with healthy controls. HO-1 expression was upregulated by CH and not significantly affected by TGF-β. By contrast, TGF-β reversed the CH-dependent upregulation of HO-1 expression under CH. Importantly our results show that aberrant TGF-β signalling within SSc is responsible for the downregulation of HO-1, and might be responsible for the endothelial dysfunction associated with the pathogenesis of PAH.
Letter to the Editor: Leptospirosis versus hantavirus infections in the Netherlands and in Belgium, 2000 to 2014
Authors: J Clement, M Van Esbroeck, K Lagrou, J Verschueren, N P Sunil-Chandra, M Van Ranst
Journal: Eurosurveillance (2014)

Preview this article: Letter to the Editor: Leptospirosis versus hantavirus infections in the Netherlands and in Belgium, 2000 to 2014, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/19/38/art20912-en-1.gif
Research Facing Imminent Deficit Of Minority Scientists
Authors: K. Ruddon
Journal: JNCI Journal of the National Cancer Institute (1988)

Journal Article Research Facing Imminent Deficit Of Minority Scientists Get access Kate Ruddon Kate Ruddon Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 80, Issue 16, 19 October 1988, Page 1272, https://doi.org/10.1093/jnci/80.16.1272 Published: 19 October 1988
Giant colonic ulcer and pseudopolyps in an immunodepressed patient
Authors: G. Mavrogenis, D. Coumaros, D. Bazin, C. Renard, B. Moulin, J. Bellocq
Journal: Endoscopy (2011)

We read with interest the case report by Colaiacovo et al. describing a case of disseminated histoplasmosis in an immunodepressed patient [1]. We had a similar case of a 55-year-old African man who was evaluated for leucopenia and a persisting inflammatory syndrome. He had received a cadaveric renal allograft 2 years earlier because of glomerulonephritis, after which he had been treated with an immunosuppressive regimen of prednisone, tacrolimus, and mycophenolate mofetil. He had 1-month history of intermittent rectal bleeding, abdominal pain, and weight loss. Physical examination was unremarkable. Blood, urine, and stool cultures, chest radiograph, and testing for Clostridium difficile toxin, cytomegalovirus (CMV), Epstein–Barr virus, HIV, and parvovirus B19 infection were all negative. Abdominal computed tomography (CT) scan revealed a 5-cm thickened, stenotic segment of the right colon and enlarged mesenteric lymph nodes suggestive of carcinoma ([Fig. 1]).
Abstract 3466: Tumor pericytes: A novel target for immune therapy in renal cell carcinoma
Authors: Nina Chi, Jennifer Taylor, Jodie Maranchie, Walter Storkus
Journal: Cancer Research (2011)

Abstract Tumor vasculature is classified by leaky, chaotic blood vessels consisting of several components including vascular endothelial cells (VEC) and mural cells (smooth muscle cells and pericytes), as well as immune regulatory cells, stem cells and vascular progenitors. Irregular tumor vasculature limits immune effector cell access to the tumor, and may in part be responsible for the modest success observed in many current anti-cancer immunotherapies. Certain drugs targeting tyrosine kinase receptors expressed on tumor stromal cells induce a Type-1 proinflammatory skewing of the tumor microenvironment (TME) with a coordinate reduction in the number of immune regulatory cell populations. A transient normalization of the vasculature may also occur in association with enhanced leukocyte recruitment. We have shown that vaccination against tumor-associated stromal antigens leads to the activation of VCAM-1 expression on tumor vascular endothelial cells and the enhanced recruitment of protective Type-1 T cells into the TME. Currently little is known regarding pericyte biology and their behavior in the TME, with no existing treatments specifically targeting pericytes. We hypothesize that pericytes residing in the TME differentially express antigens that distinguish them from pericytes in healthy tissue, and vaccination specifically targeting tumor pericyte antigens will result in vascular normalization and improved delivery of protective Type-1 T cells into the TME. To address these hypotheses, we examined mRNA expression of pericytes and VEC that have been flow-sorted from human renal cell carcinoma (RCC) tumors and patient-matched normal adjacent kidney (NAK) tissue. We have identified antigens that are differentially expressed by pericytes and/or by VEC in the TME versus NAK (such as RGS5). We are currently investigating the therapeutic efficacy of genetic (lentiviral) vaccines encoding tumor-associated stromal antigens in murine tumor models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3466. doi:10.1158/1538-7445.AM2011-3466
Abstract 4383: Transglutaminase-2 mediates the pro-malignant effects of oncostatin-M receptor overexpression in cervical squamous cell carcinoma.
Authors: Maria M. Caffarel, Anasuya Chattopadhyay, Cinzia G. Scarpini, Nicholas Coleman
Journal: Cancer Research (2013)

Abstract An important feature of cervical squamous carcinogenesis is genomic instability caused by deregulated expression of HPV oncogenes in proliferating epithelial cells. A genomic imbalance that is commonly selected in advanced cervical squamous cell carcinoma (SCC) is copy number gain of chromosome 5p. One gene that is likely to drive selection of this abnormality is the oncostatin-M receptor (OSMR; located at 5p13.1), which is commonly up-regulated in cervical SCC and produces a significantly worse clinical outcome when over-expressed. Cervical SCC cells that over-expressed OSMR showed enhanced responsiveness to the major ligand OSM, which induced multiple pro-malignant effects, including increased cell migration and invasiveness. We now show that transglutaminase-2 (TGM2) is an important mediator of the ligand-dependent phenotypic effects of OSMR over-expression in cervical carcinoma cells. TGM2 expression correlated with disease progression and with OSMR levels in clinical samples of SCC of the cervix and head and neck. TGM2 depletion in cervical SCC cells abrogated the increased migration and invasiveness induced by OSM. TGM2 was shown to interact with integrin-α5β1 and fibronectin in cervical SCC cells, with OSM treatment strengthening the interaction. Importantly, integrin-α5β1 and fibronectin were over-expressed in cervical SCC samples, where levels correlated with those of OSMR. We conclude that an OSMR-TGM2-integrin-α5β1 pathway is of biological significance in cervical SCC and a candidate for therapeutic targeting. Citation Format: Maria M. Caffarel, Anasuya Chattopadhyay, Cinzia G. Scarpini, Nicholas Coleman. Transglutaminase-2 mediates the pro-malignant effects of oncostatin-M receptor overexpression in cervical squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4383. doi:10.1158/1538-7445.AM2013-4383