tbuckley/cabot-search huggingface dataset:
A Phase I Trial of Imetelstat in Children with Refractory or Recurrent Solid Tumors: A Children's Oncology Group Phase I Consortium Study (ADVL1112)
Authors: Patrick A. Thompson, Rachid Drissi, Jodi A. Muscal, Eshini Panditharatna, Maryam Fouladi, Ashish M. Ingle, Charlotte H. Ahern, Joel M. Reid, Tong Lin, Brenda J. Weigel, Susan M. Blaney
Journal: Clinical Cancer Research (2013)

Imetelstat is a covalently-lipidated 13-mer thiophosphoramidate oligonucleotide that acts as a potent specific inhibitor of telomerase. It binds with high affinity to the template region of the RNA component of human telomerase (hTERC) and is a competitive inhibitor of telomerase enzymatic activity. The purpose of this study was to determine the recommended phase II dose of imetelstat in children with recurrent or refractory solid tumors.Imetelstat was administered intravenously more than two hours on days 1 and 8, every 21 days. Dose levels of 225, 285, and 360 mg/m(2) were evaluated, using the rolling-six design. Imetelstat pharmacokinetic and correlative biology studies were also performed during the first cycle.Twenty subjects were enrolled (median age, 14 years; range, 3-21). Seventeen were evaluable for toxicity. The most common toxicities were neutropenia, thrombocytopenia, and lymphopenia, with dose-limiting myelosuppression in 2 of 6 patients at 360 mg/m(2). Pharmacokinetics is dose dependent with a lower clearance at the highest dose level. Telomerase inhibition was observed in peripheral blood mononuclear cells at 285 and 360 mg/m(2). Two confirmed partial responses, osteosarcoma (n = 1) and Ewing sarcoma (n = 1), were observed.The recommended phase II dose of imetelstat given on days 1 and 8 of a 21-day cycle is 285 mg/m(2).
PWE-150 Transient Elastography (fibroscans) Success Rates Are Operator Dependent; Experience From The South West Liver Unit
Authors: L Vine, B Kershaw, P Figg, U Warshow
Journal: Gut (2014)

<h3>Introduction</h3> Transient Elastography (FibroScan<sup>®</sup>) is a well validated, easy to use, non-invasive method of assessing the stage of liver fibrosis, whilst avoiding potential complications of liver biopsy. Despite ease of use, operator success rates vary, there is a known failure rate and its accuracy at assessing the stage of fibrosis depends on a ‘valid’ reading being gained. The South West Liver Unit has been performing transient elastography since 2010 and receives referrals from regional hospitals where scanning is unavailable. The aim of this study was to review the overall numbers performed, the success rates of operators, and the percentage of valid scans obtained. <h3>Methods</h3> Data was collected and analysed retrospectively; and was obtained from the FibroScan<sup>®</sup> hard drive. Clinical information was obtained from clinical databases and clinical letters. Validation of scan was based on the three recognised validation criteria; (1) &gt;10 valid readings, (2) success rate &gt; 60% and (3) interquartile range to median ratio of &lt; 0.3. <h3>Results</h3> Between 2010 and 2012 inclusive, 1819 scans were undertaken. Multiple attempts (n = 247), including probe size change, were excluded. Of the remaining 1572 scans, (2010 = 537, 2011=544, 2012= 558), 74% were valid on above criteria (2010=72%, 2011=75%, 2012=74%). Overall doctors performed more scans than nurses, n = 856 versus n = 713, but nurses had a slightly higher mean success rate, 75.5% vs. 72.5%. Scans were performed by 14 different operators (registrars, consultants and nurses). Individual operator success rates varied widely from 43% to 87%; as did the number of scans performed, median = 70, range 15–373. Success rates were highest in those with formal training, with a weak correlation to number of scans performed (r<sup>2</sup>= 0.34, <i>p</i>=ns). The commonest scan indications included regional hospital referral (31%), non-alcohol related fatty liver disease (25%), viral hepatitis (13.5%) and alcohol related liver disease (11%). <h3>Conclusion</h3> Each year an increasing number of scans are performed, with good overall success rates; although a proportion of scans completed will meet ‘invalid’ criteria and this must be taken into account when interrupting the predicted fibrosis score. Inter-operator variability is evident and relates to prior formal training (undertaken by EchoSens) and total number of scans performed. Nurses undertake scans in dedicated clinics with a set time allowance and this may explain their higher success rates. Transient elastography should, therefore, be performed by those with formal training, undertaking regular scans in a dedicated clinic, to increase validity of results. <h3>Disclosure of Interest</h3> None Declared.
Human Renal Carcinoma Line Transfected With Interleukin-2 and/or Interferon Gene(s): Implications for Live Cancer Vaccines
Authors: A. Belldegrun, C.-L. Tso, T. Sakata, T. Duckett, M. J. Brunda, S. H. Barsky, J. Chai, R. Kaboo, R. S. Lavey, W. H. McBride, J. B. deKernion
Journal: JNCI Journal of the National Cancer Institute (1993)

Combination therapy with systemically administered interleukin-2 (IL-2) and interferon alpha (IFN-alpha) has resulted in long-term objective remissions in 30% of patients with metastatic renal cell carcinoma (RCC), but toxic effects are clinically significant.We have thus investigated an alternative therapeutic approach--continuous intratumoral production of IL-2 and/or IFN-alpha by a cytokine-transfected human RCC tumor cell line.Plasmid vectors were used to transfect the R11 RCC line with the genes for human IL-2 and/or IFN-alpha by the calcium phosphate precipitation method. Biologic characteristics of the cytokine-transfected tumor cells were determined by assays of thymidine incorporation and cytotoxicity, fluorescence-activated cell-sorter analysis, Northern blotting, and in vivo studies in C3Hf/Sed/Kam mice rendered T-cell deficient.The transfected cell lines produced the following amounts of cytokine per 10(6) cells per day: R11-IL-2 (220 U), R11-IFN-alpha (10,240 U), and R11-IL-2 + IFN-alpha (95 U + 1270 U, respectively). Gamma irradiation did not eliminate cytokine secretion. Morphology and growth rates were identical to those for the parental R11 cell line, except for IFN-alpha-producing clones, which showed significant growth inhibition. All cytokine-producing cells demonstrated increased susceptibility to cell killing by peripheral blood leukocytes (PBL). IFN-alpha producers exhibited enhanced HLA antigen expression and suppressed c-myc messenger RNA expression; when cocultured in vitro, they induced similar changes in parental R11 cells. IL-2 producers could stimulate growth and cytotoxicity of naive (i.e., freshly isolated, uncultured) and activated PBL. All cytokine-producing cells lost their tumorigenicity, as evidenced by failure to grow in the T-cell-depleted mice. When co-injected at a local site but not at a distant site, these cells prevented growth of parental R11 cells. Histologic examination of the injection sites revealed a substantial influx of macrophages. Intraperitoneal administration of IL-2 and/or IFN-alpha could not, however, prevent growth of the parental R11 tumors.Local production of high concentrations of IL-2 and IFN-alpha at the tumor site is more effective in preventing tumor growth than systemic administration.Continuous local delivery of cytokines via transfer of cytokine genes into tumor cells for use as live cancer vaccines is a novel strategy for manipulation of host-mediated antitumor immune response in patients with advanced RCC.
Association of Prostate Cancer Risk Variants with Clinicopathologic Characteristics of the Disease
Authors: Jianfeng Xu, Sarah D. Isaacs, Jielin Sun, Ge Li, Kathleen E. Wiley, Yi Zhu, Fang-Chi Hsu, Fredrik Wiklund, Aubrey R. Turner, Tamara S. Adams, Wennuan Liu, Bruce J. Trock, Alan W. Partin, Baoli Chang, Patrick C. Walsh, Henrik Grönberg, William Isaacs, Siqun Zheng
Journal: Clinical Cancer Research (2008)

Fifteen independent genetic variants have been implicated in prostate cancer risk by recent genome-wide association studies. However, their association with clinicopathologic features of prostate cancer is uncertain.We systematically evaluated these 15 variants in 1,563 prostate cancer patients undergoing radical prostatectomy, taking advantage of the uniform tumor stage and grade information available for each of these cases. Associations of these variants with aggressiveness, pathologic Gleason scores, pathologic stage, age at diagnosis, or serum prostate-specific antigen (PSA) levels were tested.After adjusting for multiple testing, none of the single nucleotide polymorphisms was individually or cumulatively associated with aggressiveness or individual clinicopathologic variables of prostate cancer such as Gleason scores, pathologic stage, or age at diagnosis of prostate cancer. The reported risk allele (G) for single nucleotide polymorphism rs2735839 in the KLK3 gene at 19q13 was more frequent in less aggressive prostate cancer patients (0.89) than in more aggressive prostate cancer patients (0.86; nominal P = 0.03) or in controls (0.86; nominal P = 0.04). Considering that this allele was also significantly associated with higher serum PSA levels among controls (nominal P = 0.003), the observed trend of higher frequency of this risk allele between less and more aggressive prostate cancer, or between less aggressive and controls may be due to detection bias of PSA screening.Prostate cancer risk variants recently discovered from genome-wide case-control association studies are not associated with clinicopathologic variables in this population. Case-case studies are urgently needed to discover genetic variants that predict tumor aggressiveness.
An Immune Response Enriched 72-Gene Prognostic Profile for Early-Stage Non–Small-Cell Lung Cancer
Authors: Paul Roepman, Jacek Jassem, Egbert F. Smit, Thomas Muley, Jacek Niklinski, Tony van de Velde, Anke T. Witteveen, Witold Rzyman, Arno Floore, Sjaak Burgers, Giuseppe Giaccone, Michael Meister, Hendrik Dienemann, Marcin Skrzypski, Miroslaw Kozlowski, Wolter J. Mooi, Nico van Zandwijk
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Current staging methods are imprecise for predicting prognosis of early-stage non–small-cell lung cancer (NSCLC). We aimed to develop a gene expression profile for stage I and stage II NSCLC, allowing identification of patients with a high risk of disease recurrence within 2 to 3 years after initial diagnosis. Experimental Design: We used whole-genome gene expression microarrays to analyze frozen tumor samples from 172 NSCLC patients (pT1-2, N0-1, M0) from five European institutions, who had undergone complete surgical resection. Median follow-up was 89 months (range, 1.2-389) and 64 patients developed a recurrence. A random two thirds of the samples were assigned as the training cohort with the remaining samples set aside for independent validation. Cox proportional hazards models were used to evaluate the association between expression levels of individual genes and patient recurrence-free survival. A nearest mean analysis was used to develop a gene-expression classifier for disease recurrence. Results: We have developed a 72-gene expression prognostic NSCLC classifier. Based on the classifier score, patients were classified as either high or low risk of disease recurrence. Patients classified as low risk showed a significantly better recurrence-free survival both in the training set (P &amp;lt; 0.001; n = 103) and in the independent validation set (P &amp;lt; 0.01; n = 69). Genes in our prognostic signature were strongly enriched for genes associated with immune response. Conclusions: Our 72-gene signature is closely associated with recurrence-free and overall survival in early-stage NSCLC patients and may become a tool for patient selection for adjuvant therapy.
Cell Type–Specific Angiotensin II–Evoked Signal Transduction Pathways
Authors: Yunzeng Zou, Issei Komuro, Tsutomu Yamazaki, Sumiyo Kudoh, Ryuichi Aikawa, Weidong Zhu, Ichiro Shiojima, Yukio Hiroi, Kazuyuki Tobe, Takashi Kadowaki, Yoshio Yazaki
Journal: Circulation Research (1998)

Abstract —Angiotensin II (Ang II) induces hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. To determine the molecular mechanism by which Ang II displayed different effects on cardiac myocytes and fibroblasts, we examined signal transduction pathways leading to activation of extracellular signal–regulated kinases (ERKs). Ang II–induced ERK activation was abolished by pretreatment with pertussis toxin and by overexpression of the G βγ subunit–binding domain of the β-adrenergic receptor kinase 1 in cardiac fibroblasts but not in cardiac myocytes. Inhibition of protein kinase C strongly inhibited activation of ERKs by Ang II in cardiac myocytes, whereas inhibitors of tyrosine kinases but not of protein kinase C abolished Ang II–induced ERK activation in cardiac fibroblasts. Overexpression of C-terminal Src kinase (Csk), which inactivates Src family tyrosine kinases, suppressed the activation of transfected ERK in cardiac fibroblasts. Ang II rapidly induced phosphorylation of Shc and association of Shc with Grb2. Cotransfection of the dominant-negative mutant of Ras or Raf-1 kinase abolished Ang II–induced ERK activation in cardiac fibroblasts. Overexpression of Csk or the dominant-negative mutant of Ras had no effects on Ang II–induced ERK activation in cardiac myocytes. These findings suggest that Ang II–evoked signal transduction pathways differ among cell types. In cardiac fibroblasts, Ang II activates ERKs through a pathway including the G βγ subunit of G i protein, tyrosine kinases including Src family tyrosine kinases, Shc, Grb2, Ras, and Raf-1 kinase, whereas G q and protein kinase C are important in cardiac myocytes.
Addition of Rituximab to Standard Chemotherapy Improves the Survival of Both the Germinal Center B-Cell–Like and Non–Germinal Center B-Cell–Like Subtypes of Diffuse Large B-Cell Lymphoma
Authors: Kai Fu, Dennis D. Weisenburger, William W.L. Choi, Kyle D. Perry, Lynette M. Smith, Xinlan Shi, Christine P. Hans, Timothy C. Greiner, Philip J. Bierman, R. Gregory Bociek, James O. Armitage, Wing C. Chan, Julie M. Vose
Journal: Journal of Clinical Oncology (2008)

Diffuse large B-cell lymphoma (DLBCL) includes at least two prognostically important subtypes (ie, germinal center B-cell-like [GCB] and activated B-cell-like [ABC] DLBCL), which initially were characterized by gene expression profiling and subsequently were confirmed by immunostaining. However, with the addition of rituximab to standard chemotherapy, the prognostic significance of this subclassification of DLBCL is unclear.We studied 243 patient cases of de novo DLBCL, which included 131 patient cases treated with rituximab plus standard chemotherapy (rituximab group) and 112 patient cases treated with only standard chemotherapy (control group). The cases were assigned to GCB or non-GCB subgroups (the latter of which included both ABC DLBCL and unclassifiable DLBCL) on the basis of immunophenotype by using the Hans method. Clinical characteristics and survival outcomes of the two patient groups were compared.The clinical characteristics of the patients in the rituximab and the control groups were similar. Compared with the control group, addition of rituximab improved the 3-year overall survival (OS; 42% v 77%; P < .001) of patients with DLBCL. Rituximab-treated patients in either the GCB or the non-GCB subgroups also had a significantly improved 3-year OS compared with their respective subgroups in the control group (P < .001). In the rituximab group, the GCB subgroup had a significantly better 3-year OS than the non-GCB subgroup (85% v 69%; P = .032). Multivariate analyses confirmed that rituximab treatment was predictive for survival in both the GCB and the non-GCB subgroups.In this retrospective study, we have shown that the subclassification of DLBCL on the basis of the cell of origin continues to have prognostic importance in the rituximab era.
Raynaud's phenomenon affecting the tongue of a patient with scleroderma
Authors: M J Bridges
Journal: Annals of the Rheumatic Diseases (2002)

Anterior and intermediate uveitis are inflammatory processes of diverse causes, including among others, infections, trauma, lymphoproliferative disorders, and ischaemia.The remainder are considered to have an immune pathogenesis with an autoimmune component.For example, uveitis is a common manifestation of spondyloarthropathy (SpA), a related group of disorders, with common clinical, biological, genetic, and therapeutic characteristics. 1 Within the SpA group of diseases, considerable overlap between the different disease entities can occur-for example, during the course of ankylosing spondylitis, 40% of the patients will develop acute anterior uveitis (AUU). 2 In addition, in patients with AUU, SpA is the most commonly identified systemic disease. 3 Moreover, as is true for other diseases within the SpA group, subclinical gut inflammation has been found in patients with AUU. 4 5 From a therapeutic perspective, the management of patients with AAU is targeted at stopping the inflammatory process, in the shortest time possible, as otherwise it might result in irreversible damage leading to impaired visual acuity.Most attacks can be managed by topical steroids and mydriatic agents; in severe episodes of iritis periocular injection of corticosteroids may be beneficial.Occasionally, oral administration of steroids is necessary, sometimes in combination with immunosuppressive agents.However, in some patients the uveitis appears to be treatment resistant; in others, the use of steroids is restricted owing to a lack of response, intolerance, or side effects.The beneficial effects of tumour necrosis factor α (TNFα) blockade with infliximab (Remicade) are well established in Crohn's disease and, more recently, open and placebo controlled studies indicated a significant improvement of articular symptoms of this treatment in patients with SpA. [6]7][8] Considering the disease overlap within the SpA group and the promising therapeutic results of TNFα blockade in this group of diseases, we suggested that this treatment might possibly provide a clinical benefit in SpA related uveitis.Here, we report the effect of TNFα blockade with infliximab on chronic treatment resistant uveitis in a patient with SpA.. . . .
Predicting Recurrence and Progression of Noninvasive Papillary Bladder Cancer at Initial Presentation Based on Quantitative Gene Expression Profiles
Authors: Marc Birkhahn, Anirban P. Mitra, Anthony J. Williams, Gitte Lam, Wei Ye, Ram H. Datar, Marija Balic, Susan Groshen, Kenneth E. Steven, Richard J. Cote
Journal: European Urology (2009)
Determining the quality and complexity of next-generation sequencing data without a reference genome
Authors: Seyed Yahya Anvar, Lusine Khachatryan, Martijn Vermaat, Michiel van Galen, Irina Pulyakhina, Yavuz Ariyurek, Ken Kraaijeveld, Johan T den Dunnen, Peter de Knijff, Peter AC ’t Hoen, Jeroen FJ Laros
Journal: Genome biology (2014)

We describe an open-source kPAL package that facilitates an alignment-free assessment of the quality and comparability of sequencing datasets by analyzing k-mer frequencies. We show that kPAL can detect technical artefacts such as high duplication rates, library chimeras, contamination and differences in library preparation protocols. kPAL also successfully captures the complexity and diversity of microbiomes and provides a powerful means to study changes in microbial communities. Together, these features make kPAL an attractive and broadly applicable tool to determine the quality and comparability of sequence libraries even in the absence of a reference sequence. kPAL is freely available at https://github.com/LUMC/kPAL webcite.
No Prevention of Ischemic Preconditioning by the Protein Kinase C Inhibitor Staurosporine in Swine
Authors: Christian Vahlhaus, Rainer Schulz, Heiner Post, Raouf Onallah, Gerd Heusch
Journal: Circulation Research (1996)

The delay of infarct size development by ischemic preconditioning involves the activation of protein kinase C in rats and rabbits. In dogs the role of protein kinase C in ischemic preconditioning is controversial. We investigated whether or not the activation of protein kinase C is a prerequisite for ischemic preconditioning in swine. Swine were used, since they are large mammals and since infarct development in this species, due to the lack of an innate collateral circulation, is similar to that in humans. In 20 enflurane-anesthetized swine, the proximal left anterior descending coronary artery was cannulated and perfused from an extracorporeal circuit. The impact of continuous intracoronary infusion of 10 −7 mol/L staurosporine, a potent protein kinase C inhibitor, on global and regional myocardial function (sonomicrometry), subendocardial blood flow (ENDO, microspheres), and infarct size (IS, triphenyltetrazolium chloride staining after 120 minutes of reperfusion) was analyzed. Staurosporine (10 −7 mol/L) abolished the 1.6-fold increase in coronary arterial resistance in response to 10 −6 mol/L IC 4β-phorbol 12-myristate 13-acetate, a potent protein kinase C activator. In the presence of staurosporine, 90 minutes of low-flow ischemia at an ENDO of 0.05±0.04 (mean±SD) mL·min −1 ·g −1 resulted in an IS of 12.5±8.6% (n=10) of the area at risk. Also, in the presence of staurosporine, ischemic preconditioning by a cycle of 10 minutes of low-flow ischemia followed by 15 minutes reperfusion before the 90 minutes sustained ischemic period (ENDO, 0.05±0.03 mL·min −1 ·g −1 ) reduced IS to 3.3±3.4% (n=10, P &lt;.05). The protein kinase C inhibitor staurosporine does not prevent ischemic preconditioning in swine.
Breast Cancer Resistance Protein Impacts Clinical Outcome in Platinum-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer
Authors: Kiyotaka Yoh, Genichiro Ishii, Tomoyuki Yokose, Yuji Minegishi, Kohji Tsuta, Koichi Goto, Yutaka Nishiwaki, Tetsuro Kodama, Moritaka Suga, Atsushi Ochiai
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this study was to investigate the relationship between the level of expression of ATP-binding cassette (ABC) transporter proteins, and response to chemotherapy and prognosis in advanced non-small cell lung cancer (NSCLC). Experimental Design: Expression of ABC transporter proteins, including P-glycoprotein, multidrug resistance protein (MRP) 1, MRP2, MRP3, and breast cancer resistance protein (BCRP), was examined immunohistochemically in 72 formalin-fixed tumor samples from untreated stage IIIB or IV NSCLC patients. All of the patients received platinum-based chemotherapy. Response to chemotherapy, progression-free survival (PFS), and overall survival were compared in relation to expression of each of the ABC transporter proteins and clinicopathological factors. Results: Expression of P-glycoprotein, MRP1, and MRP3 was not significantly associated with response to chemotherapy or survival. MRP2 expression was associated with overall survival (P = 0.002) but not with response to chemotherapy and PFS. By contrast, the response rate to chemotherapy of patients with BCRP-negative tumors was 44%, as opposed to 24% in patients with BCRP-positive tumors. Response rate was lower in BCRP-positive tumors, although this difference was not statistically significant (P = 0.08). BCRP-positive patients had also shorter PFS (P = 0.0003) and overall survival (P = 0.004) than BCRP-negative patients. Multivariate analysis confirmed BCRP status as an independent variable related to PFS (P = 0.001). Conclusions: Positive immunostaining for BCRP appears to be a predictor of survival in patients with advanced NSCLC. These findings indicate that BCRP may serve as a molecular target for reducing drug resistance to chemotherapy in advanced NSCLC patients.