tbuckley/cabot-search huggingface dataset:
Abstract 1967: Multi-stage silicon vector-delivered tumor antigen and TLR ligands for dendritic cell-based cancer immunotherapy
Authors: Xiaojun Xia, Mauro Ferrari, Haifa Shen
Journal: Cancer Research (2012)

Abstract Immunotherapy has shown promise in cancer treatment but achieved limited success in clinic trials. With this strategy, eliciting strong antitumor immune response in vivo remains a challenge, largely due to the immunosuppressive tumor microenvironment and inefficient delivery of cancer vaccine. Nanoparticle-delivered antigen together with adjuvants provides a promising strategy to increase the vaccine delivery efficiency. Recently, our group developed a multi-stage silicon vector (MSV) system for protected and prolonged nano-scale drug delivery. MSV delivered siRNA in vivo induced sustained knockdown of target gene expression and subsequent anti-tumor efficacy in mice. Here we tested the effect of MSV-formulated antigen peptides and Toll-like receptor (TLR) ligands on dendritic cells. By formulating HER-2 antigen peptide together with TLR4 ligand (MPLA) and TLR9 ligand (CpG), we found that MSV-delivered antigen and TLR ligands were uptaken by mouse dendritic cells after 1h co-incubation, and started to be released inside the cells at 3 h after co-incubation. Moreover, MSV-delivered TLR ligands strongly activated mouse dendritic cell expression of co-stimulatory molecules such as CD80 and CD86. It also induced dendritic cells to produce large amount of pro-inflammatory cytokines, such as TNF-alpha, IL-6, and IL-12. In summary, MSV-delivered vaccine efficiently delivered antigen and immuno-activating TLR ligands together into dendritic cells, and promoted dendritic cell maturation and activation. Therefore, MSV formulation of tumor antigen and TLR ligands may serve as a nano-scale cancer vaccine with enhanced in vivo efficacy. Ongoing experiments include testing in vivo T cell responses to MSV-delivered HER-2 antigen peptide and TLR ligands, and determining the antitumor efficacy on mouse mammary gland tumor model. 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 1967. doi:1538-7445.AM2012-1967
MB-28 * GENOME-WIDE COPY NUMBER ANALYSIS, NEUROPATHOLOGICAL CLASSIFICATION AND ANALYSIS OF HEDGEHOG ACTIVATION: HISTOLOGY REFLECTS GENETICS AND BIOLOGY IN MEDULLOBLASTOMAS OF YOUNG CHILDREN
Authors: E. Kapitza, D. Denkhaus, A. z. Muhlen, S. Rutkowski, T. Pietsch
Journal: Neuro-Oncology (2015)

The identification of desmoplastic/nodular histology as an independent favourable prognostic marker in medulloblastoma (MB) of infancy has allowed the reduction of therapy in these patients to decrease longterm side-effects. Although we were able to demonstrate different origins and pathway activation of desmoplastic versus non-desmoplastic MB, the genomics and pathway activation has not been exactly related to the different histological MB subtypes. 168 MBs of children under 5 years of age were diagnosed according to the WHO 2007 classification, and FFPE material was analysed in detail by immunohistochemical techniques (including staining of hedgehog targets YAP-1 and p75-NGFR) as well as by molecular inversion profiling (MIP) to assess the genomic landscape of infant MB. GISTIC analysis was performed to identify significant copy number alterations in MB subtypes. MB with extensive nodularity (MBEN, n = 22) and desmoplastic MB (DMB, n = 42) were both characterized by LOH of chromosomal arms 9q or 10q (MBEN, 77% of cases; DMB, 76%), whereas classic MB (CMB, n = 90) and large cell or anaplastic MBs (LCA-MB, n = 14) frequently showed specific gains of chromosomal arm 17q (CMB, 67%; LCA-MB, 79%),partially occurring as isochromosome 17q (CMB, 30%; LCA-MB, 57%), and gains of OTX2 (CMB, 73%; LCA-MB, 79%). Moreover 10/14 (71%) of LCA-MB carried MYCC (n = 9) or MYCN (n = 1) amplifications. The overall frequency of chromosomal copy number aberrations was significantly lower in the desmoplastic/nodular subtypes compared to non-desmoplastic subtypes. Importantly, there was a high correlation between desmoplastic/nodular histology (MBEN and DMB) versus non-desmoplastic subtypes with hedgehog pathway activation shown by the expression of Yap-1 and p75-NGFR (concordance rate, >98%). In summary, histology of infant MB is associated with specific recurrent chromosomal alterations and reflects their biology determined by their cellular origin and developmental pathway activation. Immunohistological assessment of pathway markers and genomic profiling by MIP can help to classify infant MBs.
Sugar to Reduce a Prolapsed Ileostomy
Authors: Alexandra R M L Brandt, Olaf Schouten
Journal: New England Journal of Medicine (2011)

A 62-year-old man who had undergone ileostomy 2 years earlier for mesenteric ischemia requiring an extended right hemicolectomy presented to the ER with a prolapsed ileostomy. The prolapse had occurred 12 hours before presentation, with no known cause.
Relapse and Reinfection in Chronic Bacteriuria
Authors: Marvin Turck, Kenneth N. Anderson, Robert G. Petersdorf
Journal: New England Journal of Medicine (1966)

ONLY about 20 per cent of patients with chronic infections of the urinary tract remain free from significant bacteriuria after cessation of treatment, regardless of the type or duration of chemotherapy.1 2 3 One possible explanation for the refractoriness of chronic urinary-tract infections to both medical and surgical therapeutic measures is that the drug is unable to eradicate foci of infection within the renal parenchyma. In this sense, chronic urinary-tract infections and subacute bacterial endocarditis may be similar. In the latter a brief course of antibiotic therapy at times does not eliminate the causative pathogen, resulting in relapse, and elimination of infection . . .
A1.43 Autologous tolerogenic dendritic cells in rheumatoid and inflammatory arthritis
Authors: G Bell, A Anderson, R Harry, J Diboll, E McColl, A Dickinson, C Hilkens, J D Isaacs
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background and Objectives</h3> Current therapies used in the treatment of rheumatoid and inflammatory arthritis, although efficacious in treating symptoms, may non-specifically suppress the immune system with consequences such as increased risk of infection and malignancy. It is therefore desirable to develop more specific immune-modulatory therapies in order to specifically switch off the pathological immune response, inducing immune tolerance in an auto-antigen specific manner. Autologous tolerogenic dendritic cells are one such therapy, with promising results already noted in animal models of arthritis. We are performing an experimental phase Ia study of intra-articular tolerogenic dendritic cells in rheumatoid and inflammatory arthritis patients. Our primary and secondary objectives are to assess safety, tolerability and feasibility of treatment; exploratory objectives seek preliminary evidence of a beneficial therapeutic effect. <h3>Methods</h3> An experimental medicine phase Ia study is underway. Peripheral blood mononuclear cells are isolated via leukapheresis and transferred to a GMP Facility for 7days. CD11<sup>+</sup> monocytes are isolated using a Clinimacs<sup>®</sup> and differentiated to tolDC using a combination of Il-4, GM-CSF, vitamin D3 and dexamethasone. On day 7 the product is released and administered arthroscopically into the target knee joint, allowing concurrent synovial biopsy. There are 3 dosing cohorts of 1, 3 and 10 million tolDC with a control arm (arthroscopic washout only), in a 3:1 ratio. Dose escalation criteria have been defined and a Data Monitoring and Ethics Committee established. Subjects are closely observed until 5 days post tolDC administration for a treatment-induced flare in the target joint. At day 14 repeat arthroscopy enables examination of the target joint and repeat synovial biopsies. Escape treatment in the form of intra-articular steroid may be administered at any time for a knee flare or persistent disease activity. Patients are followed until day + 90. <h3>Results</h3> To date 10 subjects have been enrolled in study. Three subjects each have been treated with 1 and three million tolDC. A further subject has been treated with 10 million tolDC. Two patients have received placebo and in one further subject tolDC failed quality control. Overall patient acceptability has been high. All subjects have required intra-articular steroid at day 14 for persistent knee disease activity, apart from the subject in the high dose (10million tolDC) cohort. Two serious adverse events have been documented (pneumonia and systemic RA flare), in a patient who received one million tolDC. <h3>Conclusion</h3> In this ascending dose phase I study of intra-articular tolDC we have not seen evidence of acute toxicity. Our results to date suggest that the intra-articular administration of tolDC is safe (does not induce an acute flare of inflammatory arthritis) and is acceptable to patients.
P715Regulation of elastic fibers and smooth muscle cells in the mechanism of fibrosis found in patients with initial and intense varicose lesions: a clinical correlation
Authors: J Regadera, JP Velasco-Martin, G Espana-Caparros, LM Reparaz, LA Condezo-Hoyos, J Ancer-Rodriguez
Journal: Cardiovascular Research (2014)

Pathological changes of chronic venous insufficiency is characterized by intimal and medial fibrosis of venous wall. Our aim was to link the correlation between Doppler sonography data and the degree of intimal and medial lesions in varicose saphenous veins at different locations. Saphenous veins from ten patients were evaluated by Doppler sonography and inmunohistochemestry. smooth muscular actin, and vimentin were studied from normal to pathological vein lesions. Collagen fibers distribution and extracellular matrix were also studied by Red Sirius Stain. Elastogenesis was studied by confocal microscopy and orcein stain. The evaluation of each molecule was explored using almost two slides per case. Quantification of these molecules and structures were made by Image J software. In initial lesions of varicose vein, intimal layer double their size compared to normal wall vein. Present a progressive increase of extracellular matrix and myofibroblast (vimentin+ and SMA+) proliferation. At severe intimal varicose lesions, lumen of vein decreased, and Doppler sonography blood flow was lower. In this field we observed thickness in intimal wall, corresponding to significatilly increase of SMA+ cells and elastics fibers deposition. The morphometric data showed that SMA+ area at intimal layer is correlated negatively to intimal thickness. In addition, quantification of elastic fibers at intimal varicose veins is significantly high compared to normal vein. Correlation between elastics fibers area and intimal high were negative. In the intima, a deposition of elastic fibers, which were shorter and disorganized was observed. The vascular medial layer shows atrophy of smooth muscular cells and presence of fibrous tissue. The intimal and medial fibrotic changes were not related to mast cell or immunocompetent cells proliferation. These data suggest a progressive transformation from normal to pathological varicose vein. In the eco Doppler sonography area reflux of varicose veins, we found a well established intimal and medial lesions characterized by fibrotic tissue and loss of SMA cells. These lesions are an irreversible fibrotic process in patients with leg chronic venous insufficiency.
Case 24-2000
Authors: Edward B. Bromfield, Jean-Paul Vonsattel
Journal: New England Journal of Medicine (2000)

Presentation of CaseA 23-year-old man was admitted to the hospital because of complex partial seizures that had become generalized.The patient, who was from El Salvador, had been well until the age of 15 years, when he had three seizures during a two-month period. He was told that the seizures were caused by a “parasite.” A medication, which has not been identified, was prescribed, and there was no recurrence. At the age of 16 years, he had a series of episodes of “panic,” each lasting as long as three days. Soon after these episodes, he emigrated to the United . . .
Intravenous Beta-Blockade in Coronary Heart Disease
Authors: S. H. Taylor, B. Silke, P. S. Lee
Journal: New England Journal of Medicine (1982)

Beta-blocking drugs are increasingly prescribed in coronary heart disease, but controversy surrounds the hemodynamic relevance of their ancillary pharmacologic properties--cardioselectivity and intrinsic sympathomimetic activity. We therefore compared the effects of four intravenous beta-adrenoreceptor antagonists with different ancillary properties on left ventricular function in 24 patients with coronary heart disease. All four drugs depressed the relation between left ventricular filling pressure and cardiac output at rest and during exercise. However, practolol and oxprenolol, which have intrinsic sympathomimetic activity, induced significantly less depression of left ventricular function than either propranolol or metoprolol, which do not have this activity. Cardioselectivity, a property of both practolol and metoprolol, had no discernible hemodynamic advantage. Beta-blocking drugs that have intrinsic sympathomimetic activity appear to be more effective in maintaining cardiac function than drugs without this property, when given intravenously to patients with coronary heart disease.
Usefulness of 64Cu-ATSM in Head and Neck Cancer
Authors: Ilaria Grassi, Cristina Nanni, Gianfranco Cicoria, Claudio Blasi, Feisal Bunkheila, Egesta Lopci, Patrick M. Colletti, Domenico Rubello, Stefano Fanti
Journal: Clinical Nuclear Medicine (2013)

Aims 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) is a hypoxia-avid, positron emitter radiotracer. The primary aim of this study is to assess the efficacy of pretherapy 64Cu-ATSM PET/CT as a prognostic factor of response to therapy. The secondary aims are to investigate if there is a difference between early and late PET/CT scans and if there is a difference between the biologic tumor volume (BTV) in radiotherapy treatment planning calculated between 64Cu-ATSM and 18F-FDG, and to assess if 64Cu-ATSM is a prognostic marker of disease progression. Methods Eleven patients with head and neck cancer treated with chemoradiotherapy were enrolled prospectively; both 64Cu-ATSM and 18F-FDG PET/CT scans before and after treatment were obtained. The 64Cu-ATSM scans were performed after 1 hour (early) and 16 hours (late). Results All patients had stage III or IV squamous cell head and neck cancer; 7 of 11 patients had nodal metastasis, and 22 cancer foci were detected with 64Cu-ATSM. SUVmax was 16.2 ± 7.9, and there was no significant SUVmax difference between early and late imaging. 18F-FDG SUVmax before therapy was 15.6 ± 9.4, whereas 18F-FDG SUVmax after therapy was 1.5 ± 1.2. Sensitivity and specificity values of 64Cu-ATSM calculated with receiver operating characteristic curves were 100% and 50% considering the SUVmax and 100% and 33% considering the volume, respectively. No difference has been found between the BTV contoured with 64Cu-ATSM and 18F-FDG. Conclusions The 64Cu-ATSM scans showed high sensitivity but low specificity in predicting neoadjuvant chemoradiotherapy response. No difference was noted between early and late scans. 18F-FDG and 64Cu-ATSM provided similar results about delineation of BTV.
Development of Phenotypic and Transcriptional Biomarkers to Evaluate Relative Activity of Potentially Estrogenic Chemicals in Ovariectomized Mice
Authors: Sylvia C. Hewitt, Wipawee Winuthayanon, Brianna Pockette, Robnet T. Kerns, Julie F. Foley, Norris Flagler, Elizabeth Ney, Apichart Suksamrarn, Pawinee Piyachaturawat, Pierre R. Bushel, Kenneth S. Korach
Journal: Environmental Health Perspectives (2015)

Concerns regarding potential endocrine-disrupting chemicals (EDCs) have led to a need for methods to evaluate candidate estrogenic chemicals. Our previous evaluations of two such EDCs revealed a response similar to that of estradiol (E2) at 2 hr, but a less robust response at 24 hr, similar to the short-acting estrogen estriol (E3).Microarray analysis using tools to recognize patterns of response have been utilized in the cancer field to develop biomarker panels of transcripts for diagnosis and selection of treatments most likely to be effective. Biological effects elicited by long- versus short-acting estrogens greatly affect the risks associated with exposures; therefore, we sought to develop tools to predict the ability of chemicals to maintain estrogenic responses.We used biological end points in uterine tissue and a signature pattern-recognizing tool that identified coexpressed transcripts to develop and test a panel of transcripts in order to classify potentially estrogenic compounds using an in vivo system. The end points used are relevant to uterine tissue, but the resulting classification of the compounds is important for other sensitive tissues and species.We evaluated biological and transcriptional end points with proven short- and long-acting estrogens and verified the use of our approach using a phytoestrogen. With our model, we were able to classify the diarylheptanoid D3 as a short-acting estrogen.We have developed a panel of transcripts as biomarkers which, together with biological end points, might be used to screen and evaluate potentially estrogenic chemicals and infer mode of activity.
Abstract 296: 12-O-tetradecanoylphorbol-13-acetate (TPA) induces cell scattering by upregulating krüppel-like factor 4 (KLF4) through the PKCα-ERK signaling axis.
Authors: Jun-Kai Lai, Han-Chung Wu, Chia-Che Chang
Journal: Cancer Research (2013)

Abstract Krüppel-like factor 4 (KLF4) is a C2H2 zinc-finger transcription factor known to regulate multiple cellular processes including cell proliferation, differentiation and stemness. Cell scattering is characterized by disruption of E-cadherin-mediated intercellular adhesion and acquisition of fibroblast-like morphology with increased motility and invasiveness, a cellular process reminiscent of epithelial-to-mesenchymal transition (EMT). We have previously demonstrated the involvement of KLF4 in hepatocyte growth factor (HGF)-induced cell scattering (Lai et al., J. Cell Sci., in press). Still, the question as to whether KLF4 is generally involved in cell-scattered response induced by other stimuli such as 12-O-Tetradecanoylphorbol-13-Acetate (TPA) has never been formerly addressed and thus the main focus of this study. Using human hepatocellular carcinoma cell line HepG2 as the cellular model, we herein presented evidence that KLF4 was clearly up-regulated following TPA stimulation. RT-PCR analysis and luciferase reporter assay revealed that both the mRNA and promoter activity of KLF4 was markedly increased by TPA, indicating that TPA up-regulated KLF4 at the level of transcription. Of note, knockdown of KLF4 severely impaired the level of TPA-induced HepG2 cell scattering, highlighting the requirement of KLF4 in TPA-induced scattered response. Additionally, we found that the promoting effect of TPA on KLF4 expression was clearly blocked when cells were pre-treated with the pan-PKC inhibitor Gö6983 as well as the PKCα-specific inhibitor Gö6976. Likewise, TPA-induced cell scattering and KLF4 up-regulation were ablated when ERK activity was inhibited by U0126. Taken together, our results defined the involvement of KLF4 in TPA-induced cell scattered response. Particularly, TPA engages the PKCα-ERK signaling axis to induce transcriptional up-regulation of KLF4, leading to the initiation of cell scattering. Our findings further implicate the possible involvement of KLF4 in other TPA-induced cellular responses such as cell migration and invasion. Citation Format: Jun-Kai Lai, Han-Chung Wu, Chia-Che Chang. 12-O-tetradecanoylphorbol-13-acetate (TPA) induces cell scattering by upregulating krüppel-like factor 4 (KLF4) through the PKCα-ERK signaling axis. [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 296. doi:10.1158/1538-7445.AM2013-296
Immunoassay of Human Calcitonin
Authors: Armen H Tashjian, Barbara G. Howland, Kenneth E. W. Melvin, C. Stratton Hill
Journal: New England Journal of Medicine (1970)

A radioimmunoassay using 131I-labeled synthetic human calcitonin and antiserum to human calcitonin revealed normal basal levels of the peptide in serum of 0.02 to 0.4 ng per milliliter. Calcium infusion produced a twofold to threefold rise in serum calcitonin in most control subjects. Chronic hypercalcemia was not regularly associated with elevated serum calcitonin, and calcitonin levels were normal in six patients with chronic hypocalcemia. In medullary carcinoma of the thyroid gland basal serum calcitonin was 1 to 540 ng per milliliter. Calcitonin levels correlated with the extent of disease. In patients with medullary carcinoma, serum calcitonin responses to calcium and glucagon infusions tended to be greater than in control subjects. Results of family studies suggest that the immunoassay may prove useful in the early diagnosis of this tumor among high-risk persons. We conclude that calcitonin normally circulates in human serum, that its concentration may not always correlate directly with serum calcium, and that immunoassay is a useful method for measuring calcitonin in human disease.
PTU-113 Rifaximin in Non-Alcoholic Steatohepatitis: an Open-Label Pilot Study
Authors: J F Cobbold, S N Wai, J Stove, F Shojaee-Moradie, J Fitzpatrick, E L Thomas, J Bell, R D Goldin, S D Taylor-Robinson, M S Yee, Q M Anstee, M R Thursz
Journal: Gut (2013)

<h3>Introduction</h3> Mounting evidence implicates gut microbial dysbiosis in the pathogenesis of non-alcoholic steatohepatitis (NASH) by mechanisms including caloric salvage, lipopolysaccharide production, upregulation of proinflammatory cytokines, increased insulin resistance and consequent increases in body mass and hepatic steatosis. Rifaximin is a minimally-absorbed, gut-selective antibiotic with bactericidal activity against a broad spectrum of gut microbes, making it an attractive candidate therapy. We aimed to study the effect of Rifaximin on markers of hepatic inflammation, hepatic steatosis, hepatic and peripheral insulin sensitivity. <h3>Methods</h3> Patients with biopsy-proven NASH, elevated aminotransferase values and no hepatic comorbidities were included in this open-label, randomised, cross-over study, all receiving 6 weeks of Rifaximin 400mg twice daily, before or after one of two 6 week observation periods on standard therapy. The primary endpoint was change in alanine aminotransferase (ALT) values after Rifaximin therapy. Secondary endpoints were change in percentage hepatic lipid assessed by hepatic proton magnetic resonance spectroscopy and change in hepatic and peripheral insulin sensitivity assessed by the hyperinsulinaemic euglycaemic clamp. Patients also had anthropometrics, serum biochemistry and cytokine profiling at each timepoint. Stool and urine were collected for subsequent analysis. <h3>Results</h3> 15 patients, 13 male, 2 female, mean (SD) age 48(9.5) years were included. 7 had diabetes on oral hypoglycaemic medications and 8 did not have diabetes. After 6 weeks of therapy, there was no difference in ALT before, 69 (40)IU/L, and after, 71 (43)IU/L, treatment, p = 0.7. Hepatic lipid content was 23.3(12.8)% before and 26.5(15.9)% after Rifaximin, p = 0.16. Peripheral insulin sensitivity (Rd) was unchanged, 29.5 (6.5) to 29.4 (10.0) mmol/kg min, p = 0.91, hepatic insulin sensitivity (% suppression of endogenous glucose production) was unchanged (35.2(10.1)% to 31.2(13.2)%, p = 0.35). There were no significant differences in body mass index, waist and hip circumference, IL 1b, IL6, IL10, IL18, CD14, TNFa, Leptin, Resistin and Adiponectin values with treatment. <h3>Conclusion</h3> Treatment with Rifaximin was not associated with changes in markers of hepatocellular damage, hepatic lipid content, cytokine profile or insulin sensitivity in patients with NASH. <h3>Disclosure of Interest</h3> None Declared