tbuckley/cabot-search huggingface dataset:
GDC-0941, a Novel Class I Selective PI3K Inhibitor, Enhances the Efficacy of Docetaxel in Human Breast Cancer Models by Increasing Cell Death <i>In Vitro</i> and <i>In Vivo</i>
Authors: Jeffrey J. Wallin, Jane Guan, Wei Wei Prior, Leslie B. Lee, Leanne Berry, Lisa D. Belmont, Hartmut Koeppen, Marcia Belvin, Lori S. Friedman, Deepak Sampath
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Docetaxel is a front-line standard-of-care chemotherapeutic drug for the treatment of breast cancer. Phosphoinositide 3-kinases (PI3K) are lipid kinases that regulate breast tumor cell growth, migration, and survival. The current study was intended to determine whether GDC-0941, an orally bioavailable class I selective PI3K inhibitor, enhances the antitumor activity of docetaxel in human breast cancer models in vitro and in vivo. Experimental Design: A panel of 25 breast tumor cell lines representing HER2+, luminal, and basal subtypes were treated with GDC-0941, docetaxel, or the combination of both drugs and assayed for cellular viability, modulation of PI3K pathway markers, and apoptosis induction. Drug combination effects on cellular viability were also assessed in nontransformed MCF10A human mammary epithelial cells. Human xenografts of breast cancer cell lines and patient-derived tumors were used to assess efficacy of GDC-0941 and docetaxel in vivo. Results: Combination of GDC-0941 and docetaxel decreased the cellular viability of breast tumor cell lines in vitro but to variable degrees of drug synergy. Compared with nontransformed MCF10A cells, the addition of both drugs resulted in stronger synergistic effects in a subset of tumor cell lines that were not predicted by breast cancer subtype. In xenograft models, GDC-0941 enhanced the antitumor activity of docetaxel with maximum combination efficacy observed within 1 hour of administering both drugs. GDC-0941 increased the rate of apoptosis in cells arrested in mitosis upon cotreatment with docetaxel. Conclusion: GDC-0941 augments the efficacy of docetaxel by increasing drug-induced apoptosis in breast cancer models. Clin Cancer Res; 18(14); 3901–11. ©2012 AACR.
STREET RISK OF CARBON MONOXIDE POISONING
Authors: ELIZABETH D. WILSON
Journal: JAMA (1926)

Henderson and Haggard,<sup>1</sup>in 1923, reported the presence of carbon monoxide in recognizable concentrations in the air of New York and New Haven streets. Their discussion made physicians aware of the possibility of the existence of chronic or repeated carbon monoxide poisoning, to be looked for not only in the usual places, such as dwellings with leaky gas pipes, but also in streets where motor traffic was very dense. We decided to examine the blood of a number of subjects exposed in the most evident manner to the danger. It appeared advisable to investigate traffic patrolmen. It was recalled that during the past few years many of these men, on duty in the most congested mercantile districts of Philadelphia, have complained at the end of the day's work of symptoms that might be due to slight carbon monoxide anoxemia: headache, slight nausea and muscular weakness. These symptoms were noted
Metabolic Characterization of Hepatocellular Carcinoma Using Nontargeted Tissue Metabolomics
Authors: Qiang Huang, Yexiong Tan, Peiyuan Yin, Guozhu Ye, Peng Gao, Xin Lu, Hongyang Wang, Guowang Xu
Journal: Cancer Research (2013)

Abstract Hepatocellular carcinoma has a poor prognosis due to its rapid development and early metastasis. In this report, we characterized the metabolic features of hepatocellular carcinoma using a nontargeted metabolic profiling strategy based on liquid chromatography-mass spectrometry. Fifty pairs of liver cancer samples and matched normal tissues were collected from patients having hepatocellular carcinoma, including tumor tissues, adjacent noncancerous tissues, and distal noncancerous tissues, and 105 metabolites were filtered and identified from the tissue metabolome. The principal metabolic alternations in HCC tumors included elevated glycolysis, gluconeogenesis, and β-oxidation with reduced tricarboxylic acid cycle and Δ-12 desaturase. Furthermore, increased levels of glutathione and other antioxidative molecules, together with decreased levels of inflammatory-related polyunsaturated fatty acids and phospholipase A2, were observed. Differential metabolite levels in tissues were tested in 298 serum specimens from patients with chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Betaine and propionylcarnitine were confirmed to confer good diagnostic potential to distinguish hepatocellular carcinoma from chronic hepatitis and cirrhosis. External validation of cirrhosis and hepatocellular carcinoma serum specimens further showed that this combination biomarker is useful for diagnosis of hepatocellular carcinoma with a supplementary role to α-fetoprotein. Cancer Res; 73(16); 4992–5002. ©2013 AACR.
Early Alterations in Neutrophil Activation Are Associated with Outcome in Acute Lung Injury
Authors: Kuang-Yao Yang, John J. Arcaroli, Edward Abraham
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Persistent elevations of proinflammatory cytokines in the lungs are associated with increased mortality from acute lung injury (ALI), suggesting that the degree of pulmonary inflammation is an important determinant of clinical course in ALI. The transcriptional regulatory factor nuclear factor-kappaB (NF-kappaB) is involved in modulating the expression of many cytokines and other proinflammatory mediators implicated in the development and progression of ALI. Because neutrophils appear to play a major role in the development of ALI, we examined the relationships between clinical outcome and activation of NF-kappaB in peripheral neutrophils from patients (n = 30) with sepsis-induced ALI. We found that nuclear translocation of NF-kappaB in this setting was dependent on the activation of p38 and Akt kinases. Diminished activation of NF-kappaB or Akt, but not p38, in the early postintubation period was associated with less time on the ventilator and improved survival in critically ill patients with ALI. These results suggest that early alterations in neutrophil activation patterns, particularly involving the ability to accumulate NF-kappaB to the nucleus after relevant stimuli, contribute to subsequent clinical course in ALI.
Rearrangement and expression of T cell receptor genes in cloned murine natural suppressor cell lines
Authors: B Hertel-Wulff, T Lindsten, R Schwadron, DM Gilbert, MM Davis, S Strober
Journal: The Journal of Experimental Medicine (1987)

Naturally occurring suppressor cells of the in vitro mixed leukocyte culture reaction and of in vivo graft-vs.-host disease have been identified in the spleens of neonatal mice (1) and of adult mice recovering from total lymphoid irradiation (2), whole-body irradiation (3), and syngeneic marrow transplantation (4), or cyclophosphamide therapy (5). Using both positive and negative selection procedures, the suppressors were reported to be null lymphocytes that did not express mature macrophage surface markers, nor differentiate into mature macrophages in vitro, nor demonstrate natural killer (NK) activity (1). Subsequently, cloned lines of these natural suppressor (NS) cells were derived from either adult mice given total lymphoid irradiation (TLI) (2) or from neonates (6). The cloned NS cell lines expressed a surface phenotype (2, 6) similar to that reported previously for cloned NK cells (Thy-1(+), asialo-GM1(+), Ig(-), Lyt-1(-), Lyt-2(-), Ia(-), MAC-1(-)) (7-9). However, the NS cells did not show NK activity in the standard assay with YAC-1 target cells. The cloned NS lines suppressed the proliferation of responder cells and the generation of cytolytic cells in the mixed leukocyte reaction (MLR), and suppressed lethal graft-vs.-host disease in vivo (10, 11). In view of the unusual function and surface phenotype of the cells, the lineage of these cells remained unclear. To determine the lineage of the cloned NS cells, we searched for expression and rearrangement of the alpha and beta chain genes of the T cell antigen receptor, as well as that of the gamma chain gene. Studies of the phenotypically similar NK cell yielded conflicting results. Thus, cloned lines of murine NK cells were reported to have rearrangements of the beta chain genes, and to express mRNA for all three chains (12). In contrast, freshly purified rat or human large granular lymphocytes (LGL) were shown to express only the 1.0 kb mRNA species of the beta chain gene (13), indicative of D-J joining (14). Thus, some but not all cells with NK function express the T cell receptor and are members of the T cell lineage. The current report shows that the NS lines express full-length mRNA transcripts for the a and beta chain of the T cell receptor, as well as the gamma chain gene.
Targeting PI3K-p110α Suppresses Influenza Virus Infection in Chronic Obstructive Pulmonary Disease
Authors: Alan Chen-Yu Hsu, Malcolm R. Starkey, Irwan Hanish, Kristy Parsons, Tatt Jhong Haw, Linda J. Howland, Ian Barr, James B. Mahony, Paul S. Foster, Darryl A. Knight, Peter A. Wark, Philip M. Hansbro
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Chronic obstructive pulmonary disease (COPD) and influenza virus infections are major global health issues. Patients with COPD are more susceptible to infection, which exacerbates their condition and increases morbidity and mortality. The mechanisms of increased susceptibility remain poorly understood, and current preventions and treatments have substantial limitations.To characterize the mechanisms of increased susceptibility to influenza virus infection in COPD and the potential for therapeutic targeting.We used a combination of primary bronchial epithelial cells (pBECs) from COPD and healthy control subjects, a mouse model of cigarette smoke-induced experimental COPD, and influenza infection. The role of the phosphoinositide-3-kinase (PI3K) pathway was characterized using molecular methods, and its potential for targeting assessed using inhibitors.COPD pBECs were susceptible to increased viral entry and replication. Infected mice with experimental COPD also had more severe infection (increased viral titer and pulmonary inflammation, and compromised lung function). These processes were associated with impaired antiviral immunity, reduced retinoic acid-inducible gene-I, and IFN/cytokine and chemokine responses. Increased PI3K-p110α levels and activity in COPD pBECs and/or mice were responsible for increased infection and reduced antiviral responses. Global PI3K, specific therapeutic p110α inhibitors, or exogenous IFN-β restored protective antiviral responses, suppressed infection, and improved lung function.The increased susceptibility of individuals with COPD to influenza likely results from impaired antiviral responses, which are mediated by increased PI3K-p110α activity. This pathway may be targeted therapeutically in COPD, or in healthy individuals, during seasonal or pandemic outbreaks to prevent and/or treat influenza.
Can a Biological Force Contribute to Gender Identity?
Authors: HOWARD J. BAKER, ROBERT J. STOLLER
Journal: American Journal of Psychiatry (1968)

The authors describe six persons who were raised as members of their assigned sex but who felt that they belonged to the opposite sex. At puberty all developed some sort of cross-sex change, in effect confirming their earliest gender wishes. A possible explanation is that a biological force—a hidden hormonal or CNS aberration—exerted an effect upon gender identity development.
The humoral immune response to influenza vaccination in lung transplant patients
Authors: P.J. Mazzone, S.B. Mossad, S.D. Mawhorter, A.C. Mehta, R.J. Schilz, J.R. Maurer
Journal: European Respiratory Journal (2001)

The purpose of this study was to evaluate the humoral immune response to influenza vaccination in lung transplant recipients. Antibody levels to the three viral antigens included in the 1999–2000 trivalent influenza vaccine (A/Sydney/5/97-like (H3N2), A/Beijing262/95-like (H1N1), and B/Yamanashi/16/98) were measured before and 4 weeks postvaccination in 43 lung transplant recipients and 21 healthy adult controls. The ability to develop protective antibody levels, a serological response, and the magnitude of change in levels were assessed. The humoral immune response to influenza vaccination was significantly lower in the transplant group for all three viral antigens. To A/Sydney, 95% of the control group and 40% of the transplant group developed protective levels (p=0.0009); to A/Beijing, 71% of the control group and 30% of the transplant group developed protective levels (p=0.004); and to B/Yamanashi, 48% of the control group and 19% of the transplant group developed protective levels (p=0.02). Those receiving cyclosporine had lower antibody responses when compared to those receiving tacrolimus (r=−0.3056, p=0.0463). The humoral immune response to influenza vaccination in lung transplant recipients is poor. Lung transplant recipients receiving cyclosporine may have a lower antibody response than those receiving tacrolimus. Alternative prevention strategies may be needed.
Copper Transporter 2 Regulates the Cellular Accumulation and Cytotoxicity of Cisplatin and Carboplatin
Authors: Brian G. Blair, Christopher A. Larson, Roohangiz Safaei, Stephen B. Howell
Journal: Clinical Cancer Research (2009)

Copper transporter 2 (CTR2) is known to mediate the uptake of Cu(+1) by mammalian cells. Several other Cu transporters, including the influx transporter CTR1 and the two efflux transporters ATP7A and ATP7B, also regulate sensitivity to the platinum-containing drugs. We sought to determine the effect of CTR2 on influx, intracellular trafficking, and efflux of cisplatin and carboplatin.
Patient Income Level and Cancer Clinical Trial Participation
Authors: Joseph M. Unger, Julie R. Gralow, Kathy S. Albain, Scott D. Ramsey, Dawn L. Hershman
Journal: JAMA Oncology (2015)

ing to follow-up biopsies.Outcomes measured include changes in clinical management and incidence of false-positive findings defined as biopsy-evaluated PET/CT findings nondiagnostic for melanoma.Fisher exact tests were used to compare clinical factors with PET/CT use.The University of Michigan institutional review board approved this study.Results | Of the 46 patients who underwent a preoperative PET/CT, 15 (33%) had intense uptake distant from the primary tumor and local lymph node basin.Nine of those 15 patients (60%) had abnormalities biopsied prior to LND.Three of the 9 biopsies yielded metastatic melanoma, a falsepositive rate of 67% for PET/CT in identifying distant metastases in asymptomatic patients.Of the 46 patients staged with PET/CT, 3 (7%) had PET/CT findings that ultimately identified metastatic melanoma and precluded LND (Table 2).There was not a statistically significant association between T stage (P = .12)and N stage (P = .85)and whether or not patients underwent PET/CT imaging.There was a statistically significant association between undergoing PET/CT and tumor ulceration (P = .004).No patients undergoing computed tomography with brain magnetic resonance imaging had findings requiring further evaluation prior to treatment.Discussion | Staging patients for the detection of clinically occult metastatic melanoma is critical because its presence may preclude morbid interventions aimed at locoregional control (eg, a completion LND).It also informs prognosis.In our retrospective review, however, we found that PET/CT has a high false-positive rate and a minimal effect on patient management in this setting, and is best reserved in its established role evaluating treatment response and recurrence.These data also suggest that a significant majority of asymptomatic patients with newly discovered microscopic SLNpositive melanoma do not have synchronous metastases detectable by PET/CT.Our review also identified the potential for treatment delays, increased exposure to risk from additional procedures, and increased health care resource usage that patients incur following detection of asymptomatic abnormalities by preoperative PET/CT.We recommend that PET/CT staging be reevaluated as a category 2B recommendation by the NCCN and its use further evaluated prospectively in a clinical trial.
Quantitation of Minimal Residual Disease in Acute Myeloid Leukemia by Tryptase Monitoring Identifies a Group of Patients with a High Risk of Relapse
Authors: Wolfgang R. Sperr, Margit Mitterbauer, Gerlinde Mitterbauer, Michael Kundi, Ulrich Jäger, Klaus Lechner, Peter Valent
Journal: Clinical Cancer Research (2005)

Recent data suggest that tryptase is produced by blast cells in a group of patients with acute myeloid leukemia (AML). In these patients, serum tryptase levels are elevated at diagnosis and decrease to normal (<15 ng/mL) or near normal values in those achieving complete hematologic remission (CR) after chemotherapy.In this study, we examined the value of tryptase as a marker of minimal residual AML. In 61 patients with de novo AML exhibiting elevated serum tryptase (>15 ng/mL) at diagnosis, tryptase levels were measured serially during and after chemotherapy by a fluoroenzyme immunoassay.Of the 61 patients, 42 (68.9%) entered hematologic CR in response to induction chemotherapy. Twenty-nine of these 42 patients also entered biochemical remission (BR) defined by a decrease of tryptase levels to normal (<15 ng/mL). The remaining 13 patients exhibited elevated enzyme levels despite of hematologic CR. As assessed by multivariate analysis, the elevated tryptase in CR was found to be an independent prognostic variable concerning disease-free survival. Thus, AML relapses occurred in 15 of 29 patients with CR + BR (52%) and in 12 of 13 patients with CR without BR (92%), resulting in a significantly reduced probability of continuous CR for patients with CR without BR (P < 0.05). In all patients with continuous hematologic CR, tryptase levels remained constantly normal, whereas a recurrent elevation of tryptase in CR was invariably followed by a hematologic relapse.A persistently elevated tryptase level in AML in CR is indicative of minimal residual AML and associated with a high risk of relapse.
Is Intravenous Arsenic Trioxide a Useful Therapy in Myelodysplastic Syndromes?
Authors: Richard M. Stone
Journal: Journal of Clinical Oncology (2006)

How do we know when a new agent represents a therapeutic advance for patients with myelodysplastic syndromes (MDS)? The disease is heterogeneous in the extreme. First, from a clinical standpoint, prognosis can range from many years for patients with normal chromosomes, no excess myeloblasts in the bone marrow specimen, and minimal derangements of the blood counts to less than 1 year for patients with pantocytopenia, an excess number of marrow myeloblasts, and/or chromosomal abnormalities. The aforementioned features are indeed the three critical components of the widely accepted International Prognostic Scoring System. 1 The ability to discern prognosis among MDS patients using a model not solely based on histologywasamajoradvance.Unfortunately,theInternational Prognostic Scoring System is only tangentially responsive to the realprobleminclinicaldevelopmentinMDS.Thebiologicbasis for the vast majority of patients who have this disease is unknown, except for those relatively rare patients with chronic myelomonocytic leukemia whose blasts contain an activating rearrangement of the platelet derived growth factor receptor gene on chromosome 5 for whom imatinib represents excellent therapy. 2 Though patients whose bone marrow blasts contain an abnormality of the long arm of chromosome 5 with or without additional abnormalities respond well to lenalidomide, 3 we have no clear understanding of the mechanism.
Cross talk between Wnt/β-catenin and <i>Irf8</i> in leukemia progression and drug resistance
Authors: Marina Scheller, Jörg Schönheit, Karin Zimmermann, Ulf Leser, Frank Rosenbauer, Achim Leutz
Journal: The Journal of Experimental Medicine (2013)

Progression and disease relapse of chronic myeloid leukemia (CML) depends on leukemia-initiating cells (LIC) that resist treatment. Using mouse genetics and a BCR-ABL model of CML, we observed cross talk between Wnt/β-catenin signaling and the interferon-regulatory factor 8 (Irf8). In normal hematopoiesis, activation of β-catenin results in up-regulation of Irf8, which in turn limits oncogenic β-catenin functions. Self-renewal and myeloproliferation become dependent on β-catenin in Irf8-deficient animals that develop a CML-like disease. Combined Irf8 deletion and constitutive β-catenin activation result in progression of CML into fatal blast crisis, elevated leukemic potential of BCR-ABL–induced LICs, and Imatinib resistance. Interestingly, activated β-catenin enhances a preexisting Irf8-deficient gene signature, identifying β-catenin as an amplifier of progression-specific gene regulation in the shift of CML to blast crisis. Collectively, our data uncover Irf8 as a roadblock for β-catenin–driven leukemia and imply both factors as targets in combinatorial therapy.
MK-1775, a Novel Wee1 Kinase Inhibitor, Radiosensitizes p53-Defective Human Tumor Cells
Authors: Kathleen A. Bridges, Hiroshi Hirai, Carolyn A. Buser, Colin Brooks, Huifeng Liu, Thomas A. Buchholz, Jessica M. Molkentine, Kathryn A. Mason, Raymond E. Meyn
Journal: Clinical Cancer Research (2011)

Radiotherapy is commonly used to treat a variety of solid tumors. However, improvements in the therapeutic ratio for several disease sites are sorely needed, leading us to assess molecularly targeted therapeutics as radiosensitizers. The aim of this study was to assess the wee1 kinase inhibitor, MK-1775, for its ability to radiosensitize human tumor cells.Human tumor cells derived from lung, breast, and prostate cancers were tested for radiosensitization by MK-1775 using clonogenic survival assays. Both p53 wild-type and p53-defective lines were included. The ability of MK-1775 to abrogate the radiation-induced G₂ block, thereby allowing cells harboring DNA lesions to prematurely progress into mitosis, was determined using flow cytometry and detection of γ-H2AX foci. The in vivo efficacy of the combination of MK-1775 and radiation was assessed by tumor growth delay experiments using a human lung cancer cell line growing as a xenograft tumor in nude mice.Clonogenic survival analyses indicated that nanomolar concentrations of MK-1775 radiosensitized p53-defective human lung, breast, and prostate cancer cells but not similar lines with wild-type p53. Consistent with its ability to radiosensitize, MK-1775 abrogated the radiation-induced G₂ block in p53-defective cells but not in p53 wild-type lines. MK-1775 also significantly enhanced the antitumor efficacy of radiation in vivo as shown in tumor growth delay studies, again for p53-defective tumors.These results indicate that p53-defective human tumor cells are significantly radiosensitized by the potent and selective wee1 kinase inhibitor, MK-1775, in both the in vitro and in vivo settings. Taken together, our findings strongly support the clinical evaluation of MK-1775 in combination with radiation.