tbuckley/cabot-search huggingface dataset:
High-Throughput Time-Resolved FRET Reveals Akt/PKB Activation as a Poor Prognostic Marker in Breast Cancer
Authors: Selvaraju Veeriah, Pierre Leboucher, Julien de Naurois, Nirmal Jethwa, Emma Nye, Tamara Bunting, Richard Stone, Gordon Stamp, Véronique Calleja, Stefanie S. Jeffrey, Peter J. Parker, Banafshé Larijani
Journal: Cancer Research (2014)

Abstract Dysregulation of the Akt/PKB pathway has been associated with poor prognosis in several human carcinomas. Current approaches to assess Akt activation rely on intensity-based methods, which are limited by the subjectivity of manual scoring and poor specificity. Here, we report the development of a novel assay using amplified, time-resolved Förster resonance energy transfer (FRET), which is highly specific and sensitive and can be adapted to any protein. Using this approach to analyze primary breast tissue microarrays, we quantified levels of activated pAkt at a spatial resolution that revealed molecular heterogeneity within tumors. High pAkt status assessed by amplified FRET correlated with worse disease-free survival. Our findings support the use of amplified FRET to determine pAkt status in cancer tissues as candidate biomarker for the identification of high-risk patients. Cancer Res; 74(18); 4983–95. ©2014 AACR.
THE MANUFACTURE OF ASEPTIC HOSPITAL FURNITURE
Authors: J. L. Stretton
Journal: BMJ (1915)

ASEPTIC HOSPITAL FURNITURE. [OcT 30, 19i5 tlhat the mnental conditioni was dtue to shiock; and thiis view tippears to liave been corlect, I saw him tliree months after hxg jeft the hospital, and he appeared then quite well.
Progression-free survival as a surrogate endpoint for overall survival in glioblastoma: a literature-based meta-analysis from 91 trials
Authors: K. Han, M. Ren, W. Wick, L. Abrey, A. Das, J. Jin, D. A. Reardon
Journal: Neuro-Oncology (2013)

The aim of this study was to determine correlations between progression-free survival (PFS) and the objective response rate (ORR) with overall survival (OS) in glioblastoma and to evaluate their potential use as surrogates for OS. Published glioblastoma trials reporting OS and ORR and/or PFS with sufficient detail were included in correlative analyses using weighted linear regression. Of 274 published unique glioblastoma trials, 91 were included. PFS and OS hazard ratios were strongly correlated; R2 = 0.92 (95% confidence interval [CI], 0.71–0.99). Linear regression determined that a 10% PFS risk reduction would yield an 8.1% ± 0.8% OS risk reduction. R2 between median PFS and median OS was 0.70 (95% CI, 0.59–0.79), with a higher value in trials using Response Assessment in Neuro-Oncology (RANO; R2 = 0.96, n = 8) versus Macdonald criteria (R2 = 0.70; n = 83). No significant differences were demonstrated between temozolomide- and bevacizumab-containing regimens (P = .10) or between trials using RANO and Macdonald criteria (P = .49). The regression line slope between median PFS and OS was significantly higher in newly diagnosed versus recurrent disease (0.58 vs 0.35, P = .04). R2 for 6-month PFS with 1-year OS and median OS were 0.60 (95% CI, 0.37–0.77) and 0.64 (95% CI, 0.42–0.77), respectively. Objective response rate and OS were poorly correlated (R2 = 0.22). In glioblastoma, PFS and OS are strongly correlated, indicating that PFS may be an appropriate surrogate for OS. Compared with OS, PFS offers earlier assessment and higher statistical power at the time of analysis.
The Nuclear Factor of Activated T Cells (Nfat) Transcription Factor Nfatp (Nfatc2) Is a Repressor of Chondrogenesis
Authors: Ann M. Ranger, Louis C. Gerstenfeld, Jinxi Wang, Tamiyo Kon, Hyunsu Bae, Ellen M. Gravallese, Melvin J. Glimcher, Laurie H. Glimcher
Journal: The Journal of Experimental Medicine (2000)

Nuclear factor of activated T cells (NFAT) transcription factors regulate gene expression in lymphocytes and control cardiac valve formation. Here, we report that NFATp regulates chondrogenesis in the adult animal. In mice lacking NFATp, resident cells in the extraarticular connective tissues spontaneously differentiate to cartilage. These cartilage cells progressively differentiate and the tissue undergoes endochondral ossification, recapitulating the development of endochondral bone. Proliferation of already existing articular cartilage cells also occurs in some older animals. At both sites, neoplastic changes in the cartilage cells occur. Consistent with these data, NFATp expression is regulated in mesenchymal stem cells induced to differentiate along a chondrogenic pathway. Lack of NFATp in articular cartilage cells results in increased expression of cartilage markers, whereas overexpression of NFATp in cartilage cell lines extinguishes the cartilage phenotype. Thus, NFATp is a repressor of cartilage cell growth and differentiation and also has the properties of a tumor suppressor.
Efficient dissociation of the p88 chaperone from major histocompatibility complex class I molecules requires both beta 2-microglobulin and peptide.
Authors: E Degen, M F Cohen-Doyle, D B Williams
Journal: The Journal of Experimental Medicine (1992)

Previously, we showed that an 88-kD protein (p88) associates rapidly and quantitatively with newly synthesized murine major histocompatibility complex class I molecules within the endoplasmic reticulum (ER). This interaction is transient and dissociation of p88 appears to be rate limiting for transport of class I molecules from the ER to the Golgi apparatus. In this report, we examine the relationship between p88 interaction and assembly of the ternary complex of class I heavy chain beta 2-microglobulin (beta 2m), and peptide ligand. In both murine and human beta 2m-deficient cells, in which little or no transport of class I heavy chains is observed, p88 remained associated with intracellular heavy chains throughout their lifetime. In murine RMA-S cells, which are apparently defective in accumulating peptide ligands for class I within the ER, prolonged association of p88 with "empty" heavy chain-beta 2m heterodimers was also observed. However, p88 dissociated slowly in parallel with the slow rate of ER to Golgi transport of empty class I molecules in these cells. The close correlation between p88 association and impaired class I transport suggests that p88 functions to retain incompletely assembled class I molecules in the ER. We propose that conformational changes in class I heavy chains induced by the binding of both beta 2m and peptide are required for efficient p88 dissociation and subsequent class I transport.
Liver-Enriched Transcription Factors in Liver Function and Development. Part I: The Hepatocyte Nuclear Factor Network and Liver-Specific Gene Expression
Authors: H. Schrem
Journal: Pharmacological Reviews (2002)

Numerous studies have established the pivotal role of liver-enriched transcription factors in organ development and cellular function, and there is conclusive evidence for transcription factors to act in concert in liver-specific gene expression. During organ development and in progenitor cells the timely expression of certain transcription factors is necessary for cellular differentiation, and there is overwhelming evidence for hierarchical and cooperative principles in a networked environment of transcription factors. The search for molecular switches that control stem cell imprinting and liver-specific functions has lead to the discovery of many interactions between such different molecules as transcription factors, coactivators, corepressors, enzymes, DNA, and RNA. Many of these interactions either repress or activate liver-specific gene expression. It thus can be demonstrated that specific mutational changes in liver-enriched transcription factors lead to altered intermolecular interactions with the consequence of human disease. This review provides an overview of our current knowledge about liver-enriched transcription factors and their role in liver function and development. We review the basic principles of gene transcription, the role of liver-enriched transcription factors in liver gene regulation, and the classification of transcription factors by their DNA-binding domains.
UGT1A1*28 Genotype and Irinotecan-Induced Neutropenia: Dose Matters
Authors: J. M. Hoskins, R. M. Goldberg, P. Qu, J. G. Ibrahim, H. L. McLeod
Journal: JNCI Journal of the National Cancer Institute (2007)

The Food and Drug Administration and Pfizer changed the package insert for irinotecan to include a patient's UGT1A1*28 genotype as a risk factor for severe neutropenia on the basis of the findings of four pharmacogenetic studies, which found that irinotecan-treated patients who were homozygous for the UGT1A1*28 allele had a greater risk of hematologic toxic effects than patients who had one or two copies of the wild-type allele (UGT1A1*1). Findings of subsequent irinotecan pharmacogenetic studies have been inconsistent. In a meta-analysis, we reviewed data presented in nine studies that included a total of 10 sets of patients (for a total of 821 patients) and assessed the association of irinotecan dose with the risk of irinotecan-related hematologic toxicities (grade III–IV) for patients with a UGT1A1*28/*28 genotype. The risk of toxicity was higher among patients with a UGT1A1*28/*28 genotype than among those with a UGT1A1*1/*1 or UGT1A1*1/*28 genotype at both medium (odds ratio [OR] = 3.22, 95% confidence interval [CI] = 1.52 to 6.81; P = .008) and high (OR = 27.8, 95% CI = 4.0 to 195; P = .005) doses of irinotecan. However, risk was similar at lower doses (OR = 1.80, 95% CI = 0.37 to 8.84; P = .41). Low doses of irinotecan (100–125 mg/m 2 ) are in the commonly used therapeutic range. The risk of experiencing irinotecan-induced hematologic toxicity for patients with a UGT1A1*28/*28 genotype thus appears to be a function of the dose of irinotecan administered.
Relation between nodule size and 18F-FDG-PET SUV for malignant and benign pulmonary nodules.
Authors: Majid Khalaf, Hani Abdel-Nabi, John Baker, Yiping Shao, Dominick Lamonica, Jayakumari Gona
Journal: Journal of Hematology & Oncology (2008)

The most common semiquantitative method of evaluation of pulmonary lesions using 18F-FDG PET is FDG standardized uptake value (SUV). An SUV cutoff of 2.5 or greater has been used to differentiate between benign and malignant nodules. The goal of our study was to investigate the correlation between the size of pulmonary nodules and the SUV for benign as well as for malignant nodules. Retrospectively, 173 patients were selected from 420 referrals for evaluation of pulmonary lesions. All patients selected had a positive CT and PET scans and histopathology biopsy. A linear regression equation was fitted to a scatter plot of size and SUVmax for malignant and benign nodules together. A dot diagram was created to calculate the sensitivity, specificity, and accuracy using an SUVmax cutoff of 2.5. The linear regression equations and (R2)s as well as the trendlines for malignant and benign nodules demonstrated that the slope of the regression line is greater for malignant than for benign nodules. Twenty-eight nodules of group one (≤ 1.0 cm) are plotted in a dot diagram using an SUVmax cutoff of 2.5. The sensitivity, specificity, and accuracy were calculated to be 85%, 36% and 54% respectively. Similarly, sensitivity, specificity, and accuracy were calculated for an SUVmax cutoff of 2.5 and found to be 91%, 47%, and 79% respectively for group 2 (1.1–2.0 cm); 94%, 23%, and 76%, respectively for group 3 (2.1–3.0 cm); and 100%, 17%, and 82%,, respectively for group 4 (> 3.0 cm). The previous results of the dot diagram indicating that the sensitivity and the accuracy of the test using an SUVmax cutoff of 2.5 are increased with an increase in the diameter of pulmonary nodules. The slope of the regression line is greater for malignant than for benign nodules. Although, the SUVmax cutoff of 2.5 is a useful tool in the evaluation of large pulmonary nodules (> 1.0 cm), it has no or minimal value in the evaluation of small pulmonary nodules (≤ 1.0 cm).
Impairment of Glioma Stem Cell Survival and Growth by a Novel Inhibitor for Survivin–Ran Protein Complex
Authors: Hacer Guvenc, Marat S. Pavlyukov, Kaushal Joshi, Habibe Kurt, Yeshavanth K. Banasavadi-Siddegowda, Ping Mao, Christopher Hong, Ryosuke Yamada, Chang-Hyuk Kwon, Deepak Bhasin, Somsundaram Chettiar, Gaspar Kitange, In-Hee Park, Jann N. Sarkaria, Chenglong Li, Mihail I. Shakhparonov, Ichiro Nakano
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Glioblastoma multiforme (GBM) is a devastating disease. Recent studies suggest that the stem cell properties of GBM contribute to the development of therapy resistance. Experimental Design: The expression of Survivin and Ran was evaluated by immunohistochemistry with GBM tissues, and quantitative reverse transcriptase (qRT)-PCR and immunocytochemistry with patient-derived GBM sphere cultures. With a computational structure-based drug design, 11 small-molecule compounds were designed, synthesized, and evaluated as inhibitor candidates for the molecular interaction of Survivin protein. The molecular mechanism of the lead compound, LLP-3, was determined by Western blot, ELISA, in situ proximity ligation assay, and immunocytochemistry. The effects of LLP-3 treatment on GSCs were evaluated both in vitro and in vivo. Quantitative immunohistochemistry was carried out to compare Survivin expression in tissues from 44 newly diagnosed and 31 recurrent post-chemoradiation GBM patients. Lastly, the sensitivities of temozolomide-resistant GBM spheres to LLP-3 were evaluated in vitro. Results: Survivin and Ran were strongly expressed in GBM tissues, particularly in the perivasculature, and also in patient-derived GSC cultures. LLP-3 treatment disrupted the Survivin–Ran protein complex in cancer cells and abolished the growth of patient-derived GBM spheres in vitro and in vivo. This inhibition was dependent on caspase activity and associated with p53 status of cells. Immunohistochemistry showed that Survivin expression is significantly increased in recurrent GBM compared with newly diagnosed tumors, and temozolomide-resistant GBM spheres exhibited high sensitivities to LLP-3 treatment. Conclusions: Disruption of the Survivin–Ran complex by LLP-3 abolishes survival and growth of GSCs both in vitro and in vivo, indicating an attractive novel therapeutic approach for GBM. Clin Cancer Res; 19(3); 631–42. ©2012 AACR.
Relevance of medial and dorsal cortex function to the dorsalization hypothesis
Authors: Alice Schade Powers
Journal: Behavioral and Brain Sciences (2003)

The overall dorsalizing effect proposed by the authors may be consistent with behavioral evidence showing that the dorsal cortex of reptiles functions like the hippocampal formation of mammals. It is suggested that the dorsal cortex of reptiles expanded in this dorsalizing process to become both entorhinal/subicular cortex and sensory neocortex.
A Role for the Fas/FasL System in Modulating Genetic Susceptibility to T-Cell Lymphoblastic Lymphomas
Authors: María Villa-Morales, Javier Santos, Eduardo Pérez-Gómez, Miguel Quintanilla, José Fernández-Piqueras
Journal: Cancer Research (2007)

Abstract The Fas/FasL system mediates induced apoptosis of immature thymocytes and peripheral T lymphocytes, but little is known about its implication in genetic susceptibility to T-cell malignancies. In this article, we report that the expression of FasL increases early in all mice after γ-radiation treatments, maintaining such high levels for a long time in mice that resisted tumor induction. However, its expression is practically absent in T-cell lymphoblastic lymphomas. Interestingly, there exist significant differences in the level of expression between two mice strains exhibiting extremely distinct susceptibilities that can be attributed to promoter functional polymorphisms. In addition, several functional nucleotide changes in the coding sequences of both Fas and FasL genes significantly affect their biological activity. These results lead us to propose that germ-line functional polymorphisms affecting either the levels of expression or the biological activity of both Fas and FasL genes could be contributing to the genetic risk to develop T-cell lymphoblastic lymphomas and support the use of radiotherapy as an adequate procedure to choose in the treatment of T-cell malignancies. [Cancer Res 2007;67(11):5107–16]
GENETIC INFLUENCES AFFECTING THE OCCURRENCE OF A DIABETES MELLITUS-LIKE DISEASE IN MICE INFECTED WITH THE ENCEPHALOMYOCARDITIS VIRUS
Authors: John E. Craighead, Duncan A. Higgins
Journal: The Journal of Experimental Medicine (1974)

The M variant of encephalomyocarditis virus produces a diabetes mellitus-like disease in DBA/2 mice but not in animals of the C3H strain. Fewer than one-third of infected F1 (DBA/2 x C3H) progeny exhibit the disease, whereas the prevalence in backcrosses (F1 x DBA/2, F1 x C3H) is comparable to the parental inbred strain. Thus, the mode of inheritance of the diabetic predisposition appears to be polygenic. DBA/2 animals develop striking inflammatory and necrotizing lesions of the islets of Langerhans; in contrast, alterations of the insular tissue in the C3H mice are minimal. Although metabolic abnormalities appear to be consequent to lesions of beta cells, the factors influencing the severity of these insular changes are incompletely understood.
Chloroform in Midwifery, and as a Sedative of Uterine Pain Generally
Authors: J. H. Bennet
Journal: BMJ (1850)

published, in the Lancet, the result of my ex- perience respecting the administration of Chloroform in irregular and operative labour, in dysmenorrhcea, and in uterine pain generally; and on that occasion I stated that it had proved, in my hands, a most valu- able therapeutic agent.During the twro years which have since elapsed, I have been constantly in the habit of aministeg Chloroform in these varied conditions, and am able to confirm, in every respect, the statements which I then made; no single event having occurred in my practice, calculated to modify the opinion which I then expressed, re- specting its great practical value to the accoucheur and to the uterine pathologist Various fatal cases, however, have been since published, in which death was so evidently the result of the employment of Chloroform, that we cannot but admit its inhalation to be attended with a certin amount of risk.That this risk is very slight indeed, is proved by the very small number of fatal cases recorded, as compared with the innumerable instances in which it has been administered for surgical purposes; and by the fact that, in many large hospitals in London and Paris, it has been given, ever since its first introduction, in all cases of operation, to the full anmsthetic extent, without any unto- ward event having been observed.Such being the case, I do not think that the fatal -instances that have occurred, imply such an amount of danger as to induce us to forego the benefit of Chloroform, when it is likely to be therapeutically useful, or when its inhalation will save a patient from the pain of an operation; or even to refuse our sanction to its inhalation in a -slight operation, if the patient shrink from any pain, and is willing to incur the very trifling risk attached to its administration.The very greatest care, however, ought clearly to be shown, and I cannot too decidedly urge the precaution on wbich I laid so much stress two years ago,-viz, that of seeing that the Chloroform vapour is mixed with a sufficient quantity of atmospheric air for the purposes of respiration; so that, on the one hand, asphyxia may not be produced;and that, on the other, the sedative effect of the Chloroform on the nervous centres may take place grdually, so that the latter may not be instantaneously paralysed by the sudden presence of a large quantity of Chloroform in the system.It is for this reason that, like Dr. Simpson, I generally prefer, for inhaling, a thin cambric handkerchief, to the various inhalers now in use.The former appears to me to admit more easily of gradual, progressive chloroformization.Extreme caution in the first stage of inhalation is the more necessary, as, in most of the cases of death from Chloroform that have been recorded, it: seems to have taken place after a few inhalations only, and from a quantity of Chloro- forn, which appears incredibly small (half a drachm, or a drachm) to VOL.
Hepatocyte Growth Factor Induces Gefitinib Resistance of Lung Adenocarcinoma with Epidermal Growth Factor Receptor–Activating Mutations
Authors: Seiji Yano, Wei Wang, Qi Li, Kunio Matsumoto, Haruko Sakurama, Takahiro Nakamura, Hirokazu Ogino, Soji Kakiuchi, Masaki Hanibuchi, Yasuhiko Nishioka, Hisanori Uehara, Tetsuya Mitsudomi, Yasushi Yatabe, Toshikazu Nakamura, Saburo Sone
Journal: Cancer Research (2008)

Abstract Lung cancer with epidermal growth factor receptor (EGFR)–activating mutations responds favorably to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. However, 25% to 30% of patients with EGFR-activating mutations show intrinsic resistance, and the responders invariably acquire resistance to gefitinib. Here, we showed that hepatocyte growth factor (HGF), a ligand of MET oncoprotein, induces gefitinib resistance of lung adenocarcinoma cells with EGFR-activating mutations by restoring the phosphatidylinositol 3-kinase/Akt signaling pathway via phosphorylation of MET, but not EGFR or ErbB3. Strong immunoreactivity for HGF in cancer cells was detected in lung adenocarcinoma patients harboring EGFR-activating mutations, but no T790M mutation or MET amplification, who showed intrinsic or acquired resistance to gefitinib. The findings indicate that HGF-mediated MET activation is a novel mechanism of gefitinib resistance in lung adenocarcinoma with EGFR-activating mutations. Therefore, inhibition of HGF-MET signaling may be a considerable strategy for more successful treatment with gefitinib. [Cancer Res 2008;68(22):9479–87]