tbuckley/cabot-search huggingface dataset:
Multicolor fluorescence in situ hybridization reveals complex aberrations of chromosome 8 and cryptic translocations in Burkitt’s lymphoma cell lines
Authors: T. Zivković, P. Behrmann, K. Hinz, E. M. Murga Penas, D. K. Hossfeld, J. Dierlamm
Journal: Journal of Clinical Oncology (2005)

6643 Background: The genetic hallmark of Burkitt’s lymphomas (BL) and acute lymphoblastic leukemia, subtype L3, is a rearrangement of the CMYC gene on 8q24 by the chromosomal translocation t(8;14)(q24;q32) or its variants the t(2;8)(p12;q24) and the t(8;22)(q24;q11). Secondary chromosomal abnormalities occur in about 70% of BL, but their spectrum, incidence and prognostic relevance are not well known. The recent development of multicolor fluorescence in situ hybridization (M-FISH) allows the identification of each individual chromosome by its fluorescence pattern and hereby greatly enhances the resolution of conventional cytogenetic analysis, like the accuracy of characterization of marker chromosomes or complex chromosomal rearrangements. Materials: In order to better characterize primary and secondary chromosomal abnormalities and to screen for new aberrations, we applied M-FISH to 8 BL cell lines (BL-41, BL-70, Ca-46, DOHH-2, MN-60, Namalwa, Raji, Tanoue) and compared our results with the G-banded karyotypes obtained by conventional cytogenetic analysis. Results: All cell lines revealed the t(8;14) within a complex karyotype. In 5 cell lines, M-FISH could specify the results obtained by conventional cytogenetic analysis or add new data. Interestingly, 2 cases revealed cytogenetically unrecognized three-way-translocations involving 8q24/CMYC, 14q32/IgH and the regions 18q21 and 4q12, respectively (BL-41, DOHH-2). In addition, structural aberrations of 8p22 involving the der(8)t(8;14) were detected in 2 cell lines (Namalwa, Raji). Duplication of genetic material from the der(14)t(8;14)(q24;q32) was found at 22q13 in one case. The most frequent secondary abnormalities were duplications (4 cases) and structural abnormalities (2 cases) of 1q as well as trisomy 7 (4 cases) or duplication of 7q (1 case). Conclusion: M-FISH provides important information in the description of complex chromosomal rearrangements, cryptic translocations and cytogenetically unresolved changes, which are the basis for further molecular analyses in Burkitt’s lymphoma. No significant financial relationships to disclose.
A clonogenic study of arsenic trioxide (ATO) and temozolomide (TMZ) together and in combination with radiation therapy (RT) in a human glioma cell line
Authors: J. Portnow, S. Gaur, T. W. Synold
Journal: Journal of Clinical Oncology (2006)

11506 Background: ATO is effective in the treatment of acute promyelocytic leukemia, but its role in the management of solid tumors has yet to be defined. Post-operative therapy consisting of TMZ with and without RT is considered the standard of care for patients with newly-diagnosed glioblastoma multiforme (GBM). ATO has been shown to potentiate the effects of RT in preclinical models. Therefore, we investigated the cytotoxicity of ATO and TMZ both together and in combination with RT in the U251T human glioma cell line. Methods: U251T cells in log phase growth were treated with ATO (0.05–5 μM) and/or TMZ (0.05–5 μM) for 24 hours or sequentially according to the following schedules: ATO for 18 hours followed by TMZ for 6 hours or the reverse sequence. For RT experiments, cells were treated with 0–10 Gy of ionizing RT using a Cesium-137 source. Following drug and/or RT treatment, cells were replated onto 1.5 cm tissue culture dishes in triplicate and incubated at 37 o C for 8 to 10 days to form colonies. Colonies of more than 40 cells each were counted and the IC 50 values and combination indices (CI) were derived using Calcusyn software (Biosoft, Cambridge, UK). Each combination was repeated at least 3 times. Results: The mean single agent IC 50 for ATO, TMZ, and RT were 1.10 ± 0.28 μM, 1.88 ± 0.91 μM, and 2.62 ± 0.23 Gy, respectively. Simultaneous treatment with ATO and TMZ was slightly synergistic, while sequential treatment was either additive (TMZ→ATO) or synergistic (ATO→TMZ). Combinations of RT with ATO, TMZ or both were all synergistic, with the triple agent combination showing the greatest synergy. Conclusions: RT followed by ATO and TMZ given sequentially demonstrated striking synergy in U251T human glioma cells. A clinical trial of this combination therapy in patients with newly-diagnosed GBM is currently under development. [Table: see text] No significant financial relationships to disclose.
Abstract 14: Pim-1 Preserves Mitochondrial Morphology by Inhibiting Drp1 Translocation
Authors: Shabana Din, Matt Mason, Mirko Volkers, Bevan Johnson, Mathias Konstandin, Pearl Quijada, Jodi Nunnari, Mark A Sussman
Journal: Circulation Research (2012)

Rationale:  Mitochondrial morphological dynamics affect the outcome of ischemic heart damage. Mitochondrial fission protein Dynamin Related Protein 1 (Drp1) is a mediator of mitochondrial morphological changes and cell death during ischemic injury. Mitochondrial integrity is maintained by cardioprotective kinase Pim1, which enhances resistance to apoptotic challenge and ischemia reperfusion injury. In this study we examine the relationship between Pim1 activity and Drp1 regulation of mitochondrial morphology in cardiomyocytes challenged by ischemia.   Objective:  To demonstrate that Pim1 inhibits Drp1 translocation to the mitochondria in response to ischemic injury.   Methods and Results:  Simulated ischemia and simulated ischemia reperfusion (sI & sI/R) induced mitochondrial fragmentation and cell death in neonatal rat cardiac myocytes (NRCM), respectively. Mitochondrial fragmentation accompanied Drp1 translocation to the mitochondria in NRCM. Inhibition of Drp1 by mdivi1 preserved mitochondrial reticular morphology and inhibited apoptotic cell death. Mice subjected to sI/R injury displayed Drp1 mitochondrial localization, while exposure to mdivi1 led to reduced infarct size. Interestingly, transgenic hearts overexpressing Pim1 decreased total Drp1 levels, increased phosphorylation of Drp1 at serine 637, and inhibited Drp1 localization to mitochondria while preserving reticular morphology after sI. In contrast, Pim1 dominant negative (PDN) transgenic hearts and NRCM exhibit increased Drp1 translocation to mitochondria and fragmented mitochondria. PDN hearts exhibit decreased phosphorylation of serine 637 and upregulation of BH3 protein PUMA, inducing Drp1 accumulation at mitochondria and increased sensitivity to apoptotic stimuli. In PDN NRCMs, overexpression of Puma dominant negative (PumaDN) attenuated localization of Drp1 to mitochondria and inhibited cell death during sI.   Conclusion:  Pim1 activity prevents Drp1 compartmentalization to the mitochondria and preserves reticular mitochondrial morphology in response to simulated ischemia. Therefore, selective manipulation of Pim1 should be pursued as a therapeutic target to maintain mitochondrial morphology for cardioprotection.
Abstract P185: Cardiac Characterization of Phlpp1 Knockout Mice: A Novel Phosphatase to Terminate Akt Signaling
Authors: Nicole H Purcell, Katherine Huang, Xiaoxue Zhang, Natalie Gude, Mark Sussman, Asa B Gustafsson, Shigeki Miyamoto, Joan Heller Brown
Journal: Circulation Research (2011)

The serine/threonine kinase Akt, also known as protein kinase B (PKB), regulates a wide variety of cellular processes including metabolism, cell growth, survival, protein synthesis, and gene transcription. Akt is activated by upstream kinases through sequential phosphorylation on its activation loop (Thr308) followed by phosphorylation on the hydrophobic motif (Ser473). Studies using overexpression of Akt in vitro and in vivo have implicated the kinase in either attenuating or increasing cardiac hypertrophy, depending on signal intensity and localization of Akt in the cell. Recently the protein phosphatase PHLPP (PH domain leucine-rich repeat protein phosphatase) was shown to dephosphorylate Akt on its hydrophobic motif (Ser473), thereby decreasing kinase activity. We hypothesized that PHLPP could serve as an important regulator of Akt signaling in the heart and that loss of PHLPP would accentuate Akt activation under physiological conditions. We generated phlpp1 null mice to investigate the cardiac phenotype induced by modulating the kinetics of Akt activation in vivo . Myocytes were isolated from PHLPP1 knock-out and wild-type mice to demonstrate loss of PHLPP1 protein and increased Akt phosphorylation following stimulation with the cytokine LIF. Histological examination of hearts revealed that PHLPP1 KO mice have an increased capillary to myocyte ratio compared to age matched wild-type mice at baseline. Increased capillary networks were also detected in the PHLPP1 KO mice relative to wild-type mice using corrosion casting. To determine the role of PHLPP removal on cardiac hypertrophy, PHLPP1 null mice and wild-type mice were subjected to two weeks pressure overload by transverse aortic constriction (TAC). Cardiac hypertrophy was unexpectedly attenuated in PHLPP1 null mice (26% increase in HW/BW ratio vs. 48% in wild-type mice). In contrast, PHLPP1 null mice display an accentuated response to physiological hypertrophy induced by swimming compared to wild-type controls (46% vs. 38% respectively). Our data suggests that there is enhanced Akt activation following PHLPP removal and this attenuates pathological hypertrophy due to changes in capillary density.
Treatment of cancer with light-activated compounds.
Authors: T F DeLaney
Journal: Journal of Clinical Oncology (1987)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1987.5.11.1714 Journal of Clinical Oncology - published online before print September 22, 2016 PMID: 2960787 Treatment of cancer with light-activated compounds. T F DeLaneyxT F DeLaneySearch for articles by this author https://doi.org/10.1200/JCO.1987.5.11.1714 PDF "Treatment of cancer with light-activated compounds.." Journal of Clinical Oncology, 5(11), pp. 1714–1715© 1987 by American Society of Clinical Oncology
OP15 Early biliary complications after liver transplantation: incidence, risk factors and centre effect
Authors: M Dawwas, A Gimson
Journal: Gut (2010)

Introduction  Although biliary disease is one of the most common complications of liver transplantation, its incidence and risk factors have not been previously determined in a large risk-adjusted analysis.  Method  Using the United Kingdom and Ireland Liver Transplant Database, we sought to identify the incidence of and independent risk factors for early biliary complications (EBC, defined as the occurrence of a biliary tract leak, or stricture either of which required endoscopic, percutaneous or surgical intervention or culminated in graft loss within the first 3 months after transplantation) among 7044 adult, orthotopic, single-organ liver transplants between March 1994 and February 2007. Univariate and multivariable logistic regression models were fitted to examine the association between EBC and a wide range of recipient, donor and graft risk factors.  Results  The incidence of EBC in the cohort was 8.5%, of which 5.2% were strictures and 4.7% were bile leaks. Multivariable analysis identified the following independent risk factors for EBC: lower donor-recipient age difference (per year, OR 0.99 p  Conclusion  This multi-centre analysis, the largest reported to date, has identified several novel recipient, donor and graft risk factors that could be utilised to stratify the risk of EBC among patients undergoing liver transplantation. Significant variations exist among liver transplant centres in the risk of post-transplant biliary disease that cannot be accounted for by differences in recipient, donor or graft characteristics.
Requirement of leucine-rich repeats of glycoprotein (GP) Ibα for shear-dependent and static binding of von Willebrand factor to the platelet membrane GP Ib–IX-V complex
Authors: Yang Shen, Gabriel M. Romo, Jing-fei Dong, Alicia Schade, Larry V. McIntire, Dermot Kenny, James C. Whisstock, Michael C. Berndt, José A. López, Robert K. Andrews
Journal: Blood (2000)
Phase I trial of escalating doses of ABI-007 (nanoparticle albumin-bound paclitaxel) and gemcitabine in patients (pts) with thoracic malignancies
Authors: C. B. Lee, T. E. Stinchcombe, M. A. Socinski, D. N. Hayes, R. M. Goldberg, M. J. Hawkins, C. K. Obasaju, E. C. Dees
Journal: Journal of Clinical Oncology (2007)

18094 Background: ABI-007, nanoparticle albumin-bound paclitaxel, has a different toxicity profile than solvent-based paclitaxel including a lower rate of severe neutropenia. This trial was designed to determine the maximum tolerated dose (MTD) of ABI-007 in combination with gemcitabine (G) in patients with thoracic malignancies. Methods: Patients were required to have a performance status of 0–1, =3 cytotoxic chemotherapy regimens, and preserved renal, hepatic, and bone marrow function. Patients received G 1,000 mg/m 2 on days 1, 8 in all cohorts and ABI-007 on day 1 at doses of 260, 300, 340 mg/m 2 depending on the treatment cohort every 21 days (1 cycle = 21 days). Day 8 G dose modifications were: G held for ANC &lt; 500 x 10 9 /L or platelets (plts) &lt; 50,000 x 10 9 /L, and 75% of the G dose was given if the ANC 500–999 x 10 9 /L or plts 50,000–99,000 x 10 9 /L. Dose limiting toxicities (DLT) were assessed after the first cycle and were defined as: grade 3 non-hematologic toxicity, febrile neutropenia, grade 4 anemia or thrombocytopenia, ANC = 500 for = 7 days, 2-week delay in initiating the second cycle, or omission of the day 8 G. Doses were escalated in cohorts of 3–6 pts. Results: Thirteen patients were consented and 12 pts were treated (median age 62.5 years (range 35–75); median number of prior treatments 2.5 (range 1–4); tumor types: 6 non-small cell lung cancer (NSCLC), 5 small cell lung cancer (SCLC), and 1 esophageal. At an ABI-007 dose of 300 mg/m 2 , 1 of 6 pts experienced a DLT (omission of day 8 G due to ANC &lt; 500), and at an ABI-007 dose of 340 mg/m 2 2 of 3 patients experienced a DLT (1 pt grade 3 rash and pruritus; 1 pt grade 3 fatigue and anorexia). Additional grade 3 or 4 toxicities observed over all cycles were: neutropenia (n=2), sensory neuropathy (n=1), febrile neutropenia (n=1). G was given at full dose in 38 of the 39 cycles. Eight pts were evaluable for response by RECIST: 4 partial responses (SCLC, n=2; NSCLC, n=2), 4 stable disease (NSCLC, n=3; esophageal, n=1). Conclusions: The MTD of ABI-007 is 300 mg/m 2 day 1 in combination with G 1,000 mg/m 2 on days 1, 8 every 21 days. This combination was well tolerated and demonstrated activity in previously treated NSCLC and SCLC patients. No significant financial relationships to disclose.
The effect of long-term macrolides therapy for acute exacerbation of chronic obstructive pulmonary disease: A meta-analysis
Authors: Guoyan Yao, Moqin Zhang, Zhancheng Gao, Yanliang Ma
Journal: European Respiratory Journal (2012)

Introduction: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with frequent hospital admission reduction of lung function, and decreased quality of life. Macrolides have airway antiinflammatory actions and may reduce the frequency of COPD exacerbations.

Methods: we searched PubMed and Embase databases to identify randomized controlled trials (RCTs) that assessed the effect of long-term macrolides therapy for COPD. The primary outcome assessed was frequency of acute exacerbations during follow-up. Both the fixed and random-effects models were used to obtain the hazard ratio of exacerbations associated with the use of macrolides versus controls or placebo depending on the heterogeneity of effects among studies.

Results: Combining six studies (N=1485), use of macrolides showed can decrease relative risk of experiencing acute exacerbation of COPD [point estimate=0.592, 95%CI(0.423, 0.829), P <0.05], but the effect on number of patients with at least one exacerbation was not so sure (RR=0.58, 95%CI[0.33, 1.04], P=0.07). However, subgroup analysis found that prolonged treatment period to more than 6 months can decrease not only relative risk of experiencing acute exacerbation of COPD (with Point estimate=0.569, 95% CI [0.416, 0.778], P<0.05), but also number of patients with at least one exacerbation(RR=0.50, 95%CI (0.27, 0.90), P=0.02). Five studies reported adverse events, and adverse events were more frequent with macrolides (RR=1.35,95%CI(1.09,1.67),p=0.007).

Conclusions: Long-term macrolide therapy in patients with COPD can decrease exacerbations, but the safety is not sure.
Enhancement of Two-Stage Skin Carcinogenesis by Exposure of Distant Skin to UV Radiation&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN4"&gt;4&lt;/xref&gt;
Authors: P T Strickland, D Creasia, M L Kripke
Journal: JNCI Journal of the National Cancer Institute (1985)

Exposure of C3H/HeN mice to UV 280-320 nm (UVB) radiation induces a systemic, immunologic alteration that interferes with the rejection of highly antigenic UVB radiation-induced skin cancers. The effect of this systemic alteration, induced by ventral UVB irradiation of mice, was tested on the induction of dorsal skin tumors resulting from initiation with UVB radiation and promotion with 12-O-tetradecanoylphorbol 13-acetate (TPA). The systemic effect of UVB radiation markedly potentiated carcinogenesis at the distant site. More important, mice treated with TPA alone on the dorsal skin developed a significant number of dorsal tumors if the mice also had been exposed ventrally to UVB radiation. Treatment of dorsal skin with UVB radiation alone did not result in the development of cancers, regardless of whether the mice received ventral irradiation. These results suggest that the systemic effect of UVB radiation is exerted during the promotion phase of two-stage carcinogenesis. Furthermore, they imply that a systemic effect of UVB radiation interferes with a natural host control mechanism that ordinarily holds skin cancers in check.
Inflammatory markers, lipids and metabolic hormones in lung transplant recipients with obstructive sleep apnea
Authors: Frederike Kruse, Thomas Rabis, Bjoern E. Kleibrink, Yi Wang, Nina Langguth, Martina Broecker-Preuss, Andrea Jaeger, Gerhard Weinreich, Markus Kamler, Helmut Teschler, Urte Sommerwerck
Journal: European Respiratory Journal (2013)

Background  The prevalence of obstructive sleep apnea (OSA) is high in patients after lung transplantation (LTX). OSA is associated with i) systemic inflammation and ii) metabolic dysfunction as indicated by levels of leptin, adiponectin, ghrelin, HDL, LDL and triacylglyceride (TAG). The aim of our ongoing prospective study was to compare markers of systemic inflammation and metabolic dysfunction in LTX patients with and without OSA.  Methods  Full in-lab polysomnography was performed in 40 clinically stable LTX recipients (≥6 months after transplantation) according to AASM standards. We compared the non-OSA group (apnea-hypopnea index (AHI)  Results  The OSA group included 15 patients (12 male, age 58.6±6.1yrs, BMI 28.1±4.2kg/m², AHI 45.0±24.6/h), and the non-OSA group comprised of 13 patients (5 male, age 47.3±12.5yrs, BMI 23.4±4.3kg/m², AHI 2.2±1.5/h). There was no difference in markers of systemic inflammation such as hs-CRP, IL-6, VCAM-1 and ICAM-1. Metabolic markers such as LDL (p=0.001), TAG (p=0.02) and HDL (p=0.01) were significantly increased in the OSA group. Adiponectin (3253±975vs.4787±2537ng/ml, p=0.058) and ghrelin (400±334vs.779±514pg/ml, p=0.009) were lower in the OSA group.  Conclusion  OSA did not increase systemic inflammation in stable LTX recipients. There was a profound metabolic dysbalance associated with OSA. The unexpected decrease of ghrelin in the OSA group requires further investigation.
Serum-free circulating DNA as a biomarker of prostate cancer diagnosis.
Authors: E. Gordian, K. Ramachandran, I. M. Reis, M. Manoharan, M. S. Soloway, R. Singal
Journal: Journal of Clinical Oncology (2010)

4640 Background: The current prostate cancer screening methods include digital rectal examination (DRE) and quantitation of serum prostate specific antigen (PSA) levels. However, PSA screening alone results in a large number of false positives and there is a need for biomarkers that can improve the sensitivity and specificity of prostate cancer screening. Previous studies have shown that free circulating DNA (fcDNA) levels are elevated in cancer patients compared to healthy controls. Our study examined the use of serum fcDNA levels as a biomarker of prostate cancer. Methods: The patient cohort included 252 men, 18 years and older with PSA levels > 4 ng/mL and/or abnormal DRE. Blood samples were collected prior to patients undergoing prostate biopsy. The study included 89 prostate cancer (PCA), 59 prostatitis (PTIS), and 104 benign prostatic hyperplasia (BPH) patients. DNA was extracted from 1 mL of serum and fcDNA levels were quantitated by real- time polymerase chain reaction (PCR) amplification of the Glutathione Sulfotransferase, pi (GSTPi) gene. Logistic regression was used to examine the effect of fcDNA on risk of disease comparing PCA versus a combined reference group of patients with PTIS and BPH. Models were adjusted for age (years), race (black or white), and PSA. Results: In univariate analysis fcDNA level > 180 ng/mL vs. ≤ 180 ng/mL was associated with prostate cancer risk (odds ratio [OR]: 2.07, 95% confidence interval [CI]:1.21-3.56, p=0.008, model area under the curve [AUC]= 0.584). In multivariate analysis, with adjustment for age, race, and PSA (>8 vs. ≤8), fcDNA remained significantly associated with prostate cancer risk (OR = 2.32, 95% CI: 1.29-4.15, p = 0.005, model AUC = 0.714). Including the interaction between fcDNA and PSA (p=0.020) improved model fit and predictivity (AUC=0.726). Based on the new model, patients with PSA ≤ 8 with fcDNA≥180ng/ml were at 4.37-fold increased risk of PCA compared to those with fcDNA ≤180ng/ml (OR=4.37, 95%CI: 1.96 – 9.75, p<.001), while there was no significant effect of fcDNA among patients with PSA > 8 (OR=1.09, 95%CI: 0.46 – 2.56, p= 0.846). Conclusions: Our study suggests that serum fcDNA levels may be a useful biomarker for prostate cancer diagnosis. No significant financial relationships to disclose.
Normal values of exhaled nitric oxide at 50 mL/s – A revisit
Authors: Anna-Carin Olin, Björn Bake, Kjell Torén
Journal: European Respiratory Journal (2014)

Background: Airway inflammation is an important feature in asthma, and measurement of fractional exhaled nitric oxide (FENO) is used as a marker of eosinophil airway inflammation. For clinical use there is a lack of reference values for healthy adults.

Methods: FENO have been measured in a population based study (the Intergene-Adonix study), using a chemiluminescence analyser (NIOX™) according to ATS/ERS guidelines, in 6800 subjects. Of those 1,131 healthy subjects were non-atopic, never smokers and did not report asthma or asthma medication and were selected for calculation of reference values. The subjects exhaled against a resistance resulting in an oral pressure of 5 cm H2O at a flow rate of 50 mL/s. Blood samples were analysed for specific IgE using PhadiatopO.

Results: FENO (ppb) according to age class and gender are presented in the table below, median values and 95th percentiles are given.

View this table:

FENO (ppb) in females and males in relation to age





Conclusions: The interindividual variation of FENO is large in a healhty population. FENO is higher in men than women and increase with age. Whether the 95th percentile of if normal is an optimal cut off point in management of asthma has to be examined in a clinical material.