tbuckley/cabot-search huggingface dataset:
New Lesions Detected by Single Nucleotide Polymorphism Array–Based Chromosomal Analysis Have Important Clinical Impact in Acute Myeloid Leukemia
Authors: Ramon V. Tiu, Lukasz P. Gondek, Christine L. O'Keefe, Jungwon Huh, Mikkael A. Sekeres, Paul Elson, Michael A. McDevitt, Xiao Fei Wang, Mark J. Levis, Judith E. Karp, Anjali S. Advani, Jaroslaw P. Maciejewski
Journal: Journal of Clinical Oncology (2009)

Cytogenetics is the primary outcome predictor in acute myeloid leukemia (AML). Metaphase cytogenetics (MC) detects an abnormal karyotype in only half of patients with AML, however. Single nucleotide polymorphism arrays (SNP-A) can detect acquired somatic uniparental disomy (UPD) and other cryptic defects, even in samples deemed normal by MC. We hypothesized that SNP-A will improve detection of chromosomal defects in AML and that this would enhance the prognostic value of MC.We performed 250K and 6.0 SNP-A analyses on 140 patients with primary (p) and secondary (s) AML and correlated the results with clinical outcomes and Flt-3/nucleophosmin (NPM-1) status.SNP-A is more sensitive than MC in detecting unbalanced lesions (pAML, 65% v 39%, P = .002; and sAML, 78% v 51%, P = .003). Acquired somatic UPD, not detectable by MC, was common in our AML cohort (29% in pAML and 35% in sAML). Patients with SNP-A lesions including acquired somatic UPD exhibited worse overall survival (OS) and event-free survival (EFS) in pAML with normal MC and in pAML/sAML with abnormal MC. SNP-A improved the predictive value of Flt-3 internal tandem duplication/NPM-1 status, with inferior survival seen in patients with additional SNP-A defects. Multivariate analyses confirmed the independent predictive value of SNP-A defects for OS (hazard ratio [HR] = 2.52; 95% CI, 1.29 to 5.22; P = .006) and EFS (HR = 1.72; 95% CI, 1.12 to 3.48; P = .04).SNP-A analysis allows enhanced detection of chromosomal abnormalities and provides important prognostic impact in AML.
Abstract 1734: <i>In vitro</i> characterization of EGF816, a third-generation mutant-selective EGFR inhibitor
Authors: Yong Jia, Jose Juarez, Mari Manuia, Gerald Lelais, Shailaja Kasibhatla, Oliver Long, Matthew McNeill, Michael DiDonato, Badry Bursulaya, Debbie Liao, Eric Murphy, Robert Epple, Thomas Marsilje, Nuzhat Pathan, Pierre-Yves Michellys, Steven Bender, Jennifer Harris
Journal: Cancer Research (2014)

Abstract EGFR is a major oncogene in NSCLC. Patients with the oncogenic mutations L858R and Ex19Del are responsive to the first generation pan-EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. The associated dose-limiting toxicities (DLTs) are severe rash and GI tolerability due to WT EGFR inhibition. However, therapy is universally limited by the development of acquired drug resistance where EGFR gatekeeper mutation T790M accounts for 50% of incidence. Second generation irreversible pan-EGFR TKI afatinib was developed to overcome T790M resistance. Though effective in animal models, the efficacy of afatinib on T790M patients is largely limited by its DLTs due to potent inhibition of WT EGFR. A strong medical need still exists for better tolerated therapy to treat NSCLC patients harboring EGFR mutations. Here we report the discovery and development of a potent third generation, irreversible mutant-selective EGFR TKI that is expected to improve/maintain efficacy on oncogenic EGFR mutant patients while demonstrating reduced side effects. EGF816 potently inhibits both activating (L858R and Ex19Del) and T790M resistant mutations in various cellular assays; it is selective against a large panel of kinases in both Ambit and BaF3 profiling, and more importantly is selective against WT EGFR. EGF816 is efficacious in mutant EGFR-driven xenograft models, is well tolerated in IND-enabling toxicology studies, and is entering phase 1 trials. Citation Format: Yong Jia, Jose Juarez, Mari Manuia, Gerald Lelais, Shailaja Kasibhatla, Oliver Long, Matthew McNeill, Michael DiDonato, Badry Bursulaya, Debbie Liao, Eric Murphy, Robert Epple, Thomas Marsilje, Nuzhat Pathan, Pierre-Yves Michellys, Steven Bender, Jennifer Harris. In vitro characterization of EGF816, a third-generation mutant-selective EGFR inhibitor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1734. doi:10.1158/1538-7445.AM2014-1734
Severe hepatic injury and adulterated Chinese medicines
Authors: Vincent Lai, Amanda Smith, Douglas Thorburn, V S Raman
Journal: BMJ (2006)

EDITOR—The incidence of obesity in the United Kingdom is increasing in parallel with an increase in the use of slimming aids, including traditional Chinese medicines. The safety and quality of herbal medicines have been weakly regulated because of an exemption in the Medicines Act 1968 that allowed them to be marketed without going through stringent criteria required for licensing of …
CSL-TREX: A Novel Alternatively Spliced Isoform of CSL (RBPJ-K) Predominates Over the Full-Length Isoform in Many Patients with Acute Myeloid Leukaemia, Can Activate Notch Signalling and Is Associated with Improved Outcome.
Authors: Marc R Mansour, Rosemary Gale, Asim Khwaja, Martin Pule, Robert Hills, Alan K. Burnett, David Linch
Journal: Blood (2008)
Hemodynamic Effects of Tezosentan, an Intravenous Dual Endothelin Receptor Antagonist, in Patients With Class III to IV Congestive Heart Failure
Authors: Guillermo Torre-Amione, James B. Young, Jean-Bernard Durand, Bykem Bozkurt, Douglas L. Mann, Isaac Kobrin, Craig M. Pratt
Journal: Circulation (2001)

Background —Endothelin-1, a powerful mediator of vasoconstriction, is increased in patients with congestive heart failure and appears to be a prognostic marker that strongly is correlated with the severity of disease. However, little is known about the potential immediate beneficial effects of acute blockade of the endothelin system in patients with symptomatic left ventricular dysfunction. We assessed the hemodynamic effects and safety of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with moderate to severe heart failure. Methods and Results —This randomized placebo-controlled study evaluated the hemodynamic effects of 6-hour infusions of tezosentan at 5, 20, 50, and 100 mg/h compared with placebo in 61 patients with New York Heart Association class III to IV heart failure. Plasma endothelin-1 and tezosentan concentrations were also determined. Treatment with tezosentan caused a dose-dependent increase in cardiac index ranging from 24.4% to 49.9% versus 3.0% with placebo. Tezosentan also dose-dependently reduced pulmonary capillary wedge pressure and pulmonary and systemic vascular resistances, with no change in heart rate. No episodes of ventricular tachycardia or hypotension requiring drug termination were observed during tezosentan infusion. Tezosentan administration resulted in dose-related increased plasma endothelin-1 concentrations. Conclusions —The present study demonstrated that tezosentan can be safely administered to patients with moderate to severe heart failure and that by virtue of its ability to antagonize the effects of endothelin-1, it induced vasodilatory responses leading to a significant improvement in cardiac index. Further studies are under way to determine the clinical effects of tezosentan in the setting of acute heart failure.
Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma
Authors: Weiqing Jing, Jill A Gershan, James Weber, Dominique Tlomak, Laura McOlash, Catherine Sabatos-Peyton, Bryon D Johnson
Journal: Journal for ImmunoTherapy of Cancer (2015)

Multiple myeloma is characterized by the presence of transformed neoplastic plasma cells in the bone marrow and is generally considered to be an incurable disease. Successful treatments will likely require multi-faceted approaches incorporating conventional drug therapies, immunotherapy and other novel treatments. Our lab previously showed that a combination of transient lymphodepletion (sublethal whole body irradiation) and PD-1/PD-L1 blockade generated anti-myeloma T cell reactivity capable of eliminating established disease. We hypothesized that blocking a combination of checkpoint receptors in the context of low-dose, lymphodepleting whole body radiation would boost anti-tumor immunity.To test our central hypothesis, we utilized a 5T33 murine multiple myeloma model. Myeloma-bearing mice were treated with a low dose of whole body irradiation and combinations of blocking antibodies to PD-L1, LAG-3, TIM-3, CD48 (the ligand for 2B4) and CTLA4.Temporal phenotypic analysis of bone marrow from myeloma-bearing mice demonstrated that elevated percentages of PD-1, 2B4, LAG-3 and TIM-3 proteins were expressed on T cells. When PD-L1 blockade was combined with blocking antibodies to LAG-3, TIM-3 or CTLA4, synergistic or additive increases in survival were observed (survival rates improved from ~30% to >80%). The increased survival rates correlated with increased frequencies of tumor-reactive CD8 and CD4 T cells. When stimulated in vitro with myeloma cells, CD8 T cells from treated mice produced elevated levels proinflammatory cytokines. Cytokines were spontaneously released from CD4 T cells isolated from mice treated with PD-L1 plus CTLA4 blocking antibodies.These data indicate that blocking PD-1/PD-L1 interactions in conjunction with other immune checkpoint proteins provides synergistic anti-tumor efficacy following lymphodepletive doses of whole body irradiation. This strategy is a promising combination strategy for myeloma and other hematologic malignancies.
Activity of DMP 840, a New Bis-naphthalimide, on Primary Human Tumor Colony-Forming Units
Authors: P. W. Cobb, D. R. Degen, G. M. Clark, S.-F. Chen, J. G. Kuhn, J. L. Gross, M. R. Kirshenbaum, J.-H. Sun, H. A. Burris, D. D. Von Hoff
Journal: JNCI Journal of the National Cancer Institute (1994)

DMP 840 ((R,R)-2,2'-[1,2-ethanediylbis[imino(1-methyl-2,1-ethanediyl)]]- bis[5-nitro-1H-benz[de]-iso[quinoline-1,3(2H)-dione]dimethane- sulfonate; NSC-D640430) is one in a series of bis-naphthalimides that binds DNA with high affinity and has sequence specificity to multiple G and C bases. It is also a potent inhibitor of RNA synthesis. DMP 840 has been selected for clinical evaluation on the basis of a broad spectrum of activity (including cures) in human tumors in murine models.We evaluated DMP 840 in a human tumor clonogenic assay to estimate what plasma concentrations may be necessary for clinical cytotoxic activity and to determine what types of tumors potentially might be primary targets for initial phase II studies.A soft-agar cloning system assay was used to determine the in vitro effects of DMP 840 against cells from biopsy specimens of colorectal, breast, lung ovarian, renal cell, stomach, and bladder cancers and from other tumor types. A total of 260 human tumor specimens were exposed continuously during the assay to DMP 840; 103 were assessable (20 colonies or more on control plates and 30% or less survival for the positive control). An in vitro response was defined as at least a 50% decrease in tumor colony formation resulting from drug exposure compared with controls.In vitro responses were seen in 10% (one of 10), 54% (55 of 101), 80% (82 of 103), and 89% (82 of 92) of specimens tested at 0.01, 0.1, 1.0, and 10.0 micrograms/mL of DMP 840, respectively. At a concentration of 0.1 microgram/mL, specific activity was seen against melanoma (80%) and against renal cell (80%), ovarian (63%), breast (54%), non-small-cell lung (42%), and colorectal cancers (33%). DMP 840 demonstrated activity in tumor specimens resistant in vitro to methotrexate (88%), doxorubicin (58%), platinum (57%), cyclophosphamide (53%), vinblastine (53%), etoposide (53%), fluorouracil (37%), and paclitaxel (36%).At in vitro concentrations of 0.1 microgram/mL as a continuous exposure, DMP 840 has activity against a variety of human tumors, including a subgroup resistant in vitro to standard antineoplastic agents.Further clinical development of DMP 840 is warranted.
Tiotropium inhibits pulmonary inflammation and remodelling in a guinea pig model of COPD
Authors: T. Pera, A. Zuidhof, J. Valadas, M. Smit, R.G. Schoemaker, R. Gosens, H. Maarsingh, J. Zaagsma, H. Meurs
Journal: European Respiratory Journal (2011)

Airway remodelling and emphysema are major structural abnormalities in chronic obstructive pulmonary disease (COPD). In addition, pulmonary vascular remodelling may occur and contribute to pulmonary hypertension, a comorbidity of COPD. Increased cholinergic activity in COPD contributes to airflow limitation and, possibly, to inflammation and airway remodelling. This study aimed to investigate the role of acetylcholine in pulmonary inflammation and remodelling using an animal model of COPD. To this aim, guinea pigs were instilled intranasally with lipopolysaccharide (LPS) twice weekly for 12 weeks and were treated, by inhalation, with the long-acting muscarinic receptor antagonist tiotropium. Repeated LPS exposure induced airway and parenchymal neutrophilia, and increased goblet cell numbers, lung hydroxyproline content, airway wall collagen and airspace size. Furthermore, LPS increased the number of muscularised microvessels in the adventitia of cartilaginous airways. Tiotropium abrogated the LPS-induced increase in neutrophils, goblet cells, collagen deposition and muscularised microvessels, but had no effect on emphysema. In conclusion, tiotropium inhibits remodelling of the airways as well as pulmonary inflammation in a guinea pig model of COPD, suggesting that endogenous acetylcholine plays a major role in the pathogenesis of this disease.
Nitrate and nitrosative chemistry within Barrett's oesophagus during acid reflux
Authors: H Suzuki
Journal: Gut (2005)

<b>Background and aims:</b> When saliva, with its high nitrite content derived from the enterosalivary recirculation of dietary nitrate, meets acidic gastric juice, the nitrite is converted to nitrous acid, nitrosative species, and nitric oxide. In healthy volunteers this potentially mutagenic chemistry is focused at the gastric cardia. We have studied the location of this luminal chemistry in Barrett’s patients during acid reflux. <b>Methods:</b> Ten Barrett’s patients were studied before and after administration of 2 mmol nitrate. Using microdialysis probes we measured nitrite, ascorbic acid, total vitamin C, and thiocyanate concentrations and pH simultaneously in the proximal oesophagus, Barrett’s segment, hiatal sac, proximal stomach, and distal stomach. In a subgroup, real time nitric oxide concentrations were also measured. <b>Results:</b> During acid reflux, Barrett’s segment was the anatomical site with maximal potential for acid catalysed nitrosation, with its median concentration of nitrite exceeding that of ascorbic acid in two of 10 subjects before nitrate and in four of nine after nitrate. Thiocyanate, which catalyses acid nitrosation, was abundant at all anatomical sites. On entering the acidic Barrett’s segment, there was a substantial fall in nitrite and the lowest ascorbic acid to total vitamin C ratio, indicative of reduction of salivary nitrite to nitric oxide at this anatomical site. Episodes of acid reflux were observed to generate nitric oxide concentrations of up to 60 μM within the Barrett’s segment. <b>Conclusion:</b> The interaction between acidic gastric refluxate and nitrite rich saliva activates potentially mutagenic luminal nitrosative chemistry within Barrett’s oesophagus.
Pulmonary function in normal Jordanian children
Authors: N. A Sliman, B. M Dajani, K. S Shubair
Journal: Thorax (1982)

A sample of 204 male and 224 female healthy Jordanian children was selected to determine the normal ventilatory functions of this Arab population. Forced vital capacity (FVC), one-second forced expiratory volume (FEV<sub>1</sub>), and forced mid-expiratory flow rate (FMFR 25-75%) were determined with a dry bellows spirometer. Multiple linear regression formulae and correlation coefficients were computed for the group. Jordanian values for FVC and FEV<sub>1</sub> were similar to those of Caucasians living in the Western hemisphere.
Genetics and Expression of Mouse Ia Antigens
Authors: Laurel Mengle-Gaw, Hugh O. McDevitt
Journal: Annual Review of Immunology (1985)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
USP2a Activation of MYC in Prostate Cancer
Authors: William G. Nelson, Angelo M. De Marzo, Srinivasan Yegnasubramanian
Journal: Cancer Discovery (2012)

Abstract Ubiquitin-specific protease 2a, a deubiquitinating enzyme, elevates MYC levels in prostate cancer cells via its stabilization of MDM2, undermining p53 regulation of microRNAs that target MYC mRNA. Cancer Discovery; 2(3); 206–7. ©2012 AACR. Commentary on Benassi et al., p. 236.
Effect of N-acetyl cysteine on the concentrations of thiols in plasma, bronchoalveolar lavage fluid, and lung tissue.
Authors: M M Bridgeman, M Marsden, C Selby, D Morrison, W MacNee
Journal: Thorax (1994)

BACKGROUND--Oxidant/antioxidant imbalance may occur in the lungs of patients with chronic obstructive pulmonary disease (COPD). Glutathione is an important extracellular and intracellular thiol oxidant in the lungs. These studies were carried out to determine the effect of N-acetyl cysteine on thiol concentrations in plasma, bronchoalveolar lavage fluid, and lung tissue. METHODS--Studies were carried out on normal subjects, patients with COPD, and those undergoing lung resection. In the first study N-acetyl cysteine was given to three groups; healthy subjects (600 mg once daily by mouth) and two groups of patients with COPD. In the first group of patients with COPD the dose was 600 mg once daily and in the second 600 mg thrice daily, all for five days. The latter dosage regimen was also given to six patients before bronchoscopy and to 11 patients before lung resection. Lung glutathione (GSH) levels in bronchoalveolar lavage fluid or lung tissue were compared with the same numbers of patients who did not receive N-acetyl cysteine. RESULTS--N-acetyl cysteine was detected in plasma after a single 600 mg dose in normal subjects and patients with COPD up to 1.5 hours after the drug was given. Plasma cysteine concentrations increased in normal subjects on both days 1 and 5, and in patients with COPD on day 5. Glutathione concentrations in plasma increased on day 1 in normal subjects but not in patients with COPD given 600 mg N-acetyl cysteine daily. With the higher dose of 600 mg thrice daily, however, there was a sustained elevation of GSH concentrations in plasma in patients with COPD. In patients undergoing routine diagnostic bronchoscopy and bronchoalveolar lavage those who were given N-acetyl cysteine (600 mg) thrice daily for five days had higher concentrations of cysteine in the plasma, but no significant differences in cysteine concentrations in bronchoalveolar lavage or epithelial lining fluid compared with a control group; nor were there any differences in reduced glutathione concentrations in plasma, bronchoalveolar lavage or epithelial lining fluids between the control and treated groups. Moreover, in patients undergoing lung resection those treated with N-acetyl cysteine (600 mg thrice daily for five days) had similar concentrations of cysteine and glutathione in both plasma and lung tissue when compared with a control untreated group. CONCLUSIONS--These data suggest that, even when given in high oral doses, N-acetyl cysteine does not produce a sustained increase in glutathione levels sufficient to increase the antioxidant capacity of the lungs.
Alveolar macrophages and CC chemokines are increased in children with cystic fibrosis
Authors: S. Brennan, P. D. Sly, C. L. Gangell, N. Sturges, K. Winfield, M. Wikstrom, S. Gard, J. W. Upham
Journal: European Respiratory Journal (2009)

Airway inflammation is an important component of cystic fibrosis (CF) lung disease. We sought to determine whether alveolar macrophages were involved in early CF lung disease. Children with CF (median age 3.1 yrs) participated in a surveillance programme that included annual bronchoalveolar lavage (BAL). Control samples were obtained from non-CF children (median age 3.1 yrs; n = 24) investigated for persistent respiratory symptoms. Pulmonary infection was detected in 31% (16 out of 51) and 38% (nine out of 24) of children from the CF and non-CF groups, respectively. Alveolar macrophages in BAL were increased in CF compared with non-CF in the absence of infection (223x10(3) versus 85x10(3) cells.mL(-1); p = 0.001) and were associated with elevations in the CC chemokines (macrophage inflammatory protein (MIP)-3alpha (chemokine (C-C motif) ligand (CCL)20; 355.8 versus 46.0 pg.mL(-1); p<0.001), monocyte chemotactic protein-1 (CCL2; 263.5 versus 25.3 pg.mL(-1); p<0.001), MIP-1alpha (CCL3; 38.2 versus 4.9 pg.mL(-1); p<0.001) and MIP-1beta (CCL4; 326.6 versus 27.5 pg.mL(-1); p<0.001)). Total cell counts and neutrophil numbers increased in the presence of infection; however, there was no additional effect of CF. Alveolar macrophages and CC chemokines are elevated in the lungs in young children with CF even in the absence of pulmonary infection. Longitudinal studies are required to determine the clinical relevance of these findings.
Family History of Suicide Among Suicide Victims
Authors: Bo Runeson, Marie Åsberg
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: The aim was to compare the rates of suicide in family members of suicide victims and comparison subjects who died of other causes. METHOD: The Swedish cause of death register identified all suicides in subjects born between 1949 and 1969 (N=8,396). The comparison group comprised persons of the same age who died of other causes (N=7,568). First-degree relatives of the suicide victims (N=33,173) and comparison subjects (N=28,945) were identified. RESULTS: Among families of the suicide victims there were 287 suicides, representing 9.4% of all deaths in family members. Among comparison families there were 120 suicides, 4.6% of all deaths. The difference was significant. Previous psychiatric care and suicide in a family member predicted suicide in the logistic regression model. CONCLUSIONS: The rate of suicide was twice as high in families of suicide victims as in comparison families. A family history of suicide predicted suicide independent of severe mental disorder.