tbuckley/cabot-search huggingface dataset:
Mutations of the Epidermal Growth Factor Receptor Gene Predict Prolonged Survival After Gefitinib Treatment in Patients With Non–Small-Cell Lung Cancer With Postoperative Recurrence
Authors: Tetsuya Mitsudomi, Takayuki Kosaka, Hideki Endoh, Yoshitsugu Horio, Toyoaki Hida, Shoichi Mori, Shunzo Hatooka, Masayuki Shinoda, Takashi Takahashi, Yasushi Yatabe
Journal: Journal of Clinical Oncology (2005)

Purpose To evaluate the relationship between mutations of the epidermal growth factor receptor (EGFR) gene and the effectiveness of gefitinib treatment in patients with recurrent lung cancer after pulmonary resection. Patients and Methods We sequenced exons 18-21 of the EGFR gene using total RNA extracted from 59 patients with lung cancer who were treated with gefitinib for recurrent lung cancer. Gefitinib effectiveness was evaluated by both imaging studies and change in serum carcinoembryonic antigen (CEA) levels. Results EGFR mutations were found in 33 patients (56%). Of these mutations, 17 were deletions around codons 746-750 and 15 were point mutations (12 at codon 858, three at other codons), and one was an insertion. EGFR mutations were significantly more prevalent in females, adenocarcinoma, and never-smokers. Gefitinib treatment resulted in tumor shrinkage and/or CEA decrease to less than half of the baseline level in 26 patients, tumor growth and/or CEA elevation in 24 patients, and gefitinib effect was not assessable in nine patients. Female, never-smoking patients with adenocarcinoma tended to respond better to gefitinib treatment. Gefitinib was effective in 24 of 29 patients with EGFR mutations, compared with two of 21 patients without mutations (P &lt; .0001). Of note, del746-750 might be superior to L858R mutations for prediction of gefitinib response. Patients with EGFR mutations survived for a longer period than those without the mutations after initiation of gefitinib treatment (P = .0053). Conclusion EGFR mutations were a good predictor of clinical benefit of gefitinib in this setting.
Expression of the p53 homologue p63alpha and DeltaNp63alpha in the neoplastic sequence of Barrett's oesophagus: correlation with morphology and p53 protein
Authors: P A Hall
Journal: Gut (2001)

<h3>BACKGROUND</h3> While loss of p53 function is a key oncogenic step in human tumorigenesis, mutations of p53 are generally viewed as late events in the metaplasia-dysplasia-adenocarcinoma sequence of Barrett9s oesophagus. Recent reports of a series of genes (p63, p73, and others) exhibiting close homology to p53 raise the possibility that abnormalities of these p53 family members may exert their influence earlier in the sequence. <h3>AIM</h3> Following recent characterisation of expression of p63 and a major isoform ΔNp63 by generation of an antiserum that recognises p63 isoforms, but not p53, our aim was a comparative study of expression of p63 protein and p53 protein in a morphologically well defined biopsy series representative of all stages of the metaplasia-dysplasia-carcinoma sequence in Barrett9s oesophagus. <h3>METHODS</h3> A series of 60 biopsy cases representing normal oesophagus through to invasive adenocarcinoma were stained, using immunohistochemistry, with antibodies to p63 and p53. All biopsies derived from patients with endoscopic and histopathological substantiation of a diagnosis of traditional/classical Barrett9s oesophagus. <h3>RESULTS</h3> There was exact concordance in p53 and p63 expression in more advanced forms of neoplasia, high grade dysplasia, and invasive adenocarcinoma, while p63, but not p53, was detected in the proliferative compartment of some non-neoplastic oesophageal tissue, in both squamous mucosa and in the non-neoplastic metaplastic glandular epithelium. <h3>CONCLUSIONS</h3> In neoplastic Barrett9s oesophagus there is upregulation of both p63 and p53 while p63 isoforms may well have an important role in epithelial biology in both non-metaplastic and metaplastic mucosa of the oesophagus. While abnormalities of p53 function represent an indisputable and critical element of neoplastic transformation, other closely linked genes and their proteins have a role in both the physiology and pathophysiology of the oesophageal mucosa.
WHO multicentre randomised trial of misoprostol in the management of the third stage of labour
Authors: A Metin Gülmezoglu, José Villar, Nguyen Thi Nhu Ngoc, Gilda Piaggio, Guillermo Carroli, Lekan Adetoro, Hany Abdel-Aleem, Linan Cheng, G Justus Hofmeyr, Pisake Lumbiganon, Christian Unger, Walter Prendiville, Alain Pinol, Diana Elbourne, Hazem El-Refaey, Kenneth F Schulz
Journal: The Lancet (2001)
High Environmental Tobacco Smoke Exposure and Presence of IL4 Polymorphism (C-589T) Increases Risk of Infant Wheezing: the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS)
Authors: A.M. Smith, D.I. Bernstein, G.K. LeMasters, N.L. Huey, G.K. Khurana Hershey
Journal: Journal of Allergy and Clinical Immunology (2007)
Convection-Enhanced Delivery of Topotecan into a PDGF-Driven Model of Glioblastoma Prolongs Survival and Ablates Both Tumor-Initiating Cells and Recruited Glial Progenitors
Authors: Kim A. Lopez, Aaron M. Tannenbaum, Marcela C. Assanah, Katy Linskey, Jonathan Yun, Alayar Kangarlu, Orlando D. Gil, Peter Canoll, Jeffrey N. Bruce
Journal: Cancer Research (2011)

The contribution of microenvironment to tumor growth has important implications for optimizing chemotherapeutic response and understanding the biology of recurrent tumors. In this study, we tested the effects of locally administered topotecan on a rat model of glioblastoma that is induced by intracerebral injection of PDGF (platelet-derived growth factor)-IRES (internal ribosome entry site)-GFP (green fluorescent protein)-expressing retrovirus, treated the tumors by convection-enhanced delivery (CED) of topotecan (136 μmol/L) for 1, 4, or 7 days, and then characterized the effects on both the retrovirus-transformed tumor cells (GFP(+) cells) as well as the uninfected glial progenitor cells (GFP(-) cells) that are recruited to the tumor. Topotecan treatment reduced GFP(+) cells about 10-fold and recruited progenitors by about 80-fold while providing a significant survival advantage that improved with greater treatment duration. Regions of glial progenitor ablation occurred corresponding to the anatomic distribution of topotecan as predicted by MRI of a surrogate tracer. Histopathologic changes in recurrent tumors point to a decrease in recruitment, most likely due to the chemotherapeutic ablation of the recruitable progenitor pool.
Blocked Autophagy Using Lysosomotropic Agents Sensitizes Resistant Prostate Tumor Cells to the Novel Akt Inhibitor AZD5363
Authors: Francois Lamoureux, Christian Thomas, Claire Crafter, Masafumi Kumano, Fan Zhang, Barry R. Davies, Martin E. Gleave, Amina Zoubeidi
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Prostate cancer development is often associated with deletion or silencing of tumor suppressor phosphatase and tensin homolog (PTEN), a negative regulator of the phosphoinositide 3 kinase (PI3K)–Akt pathway, leading to resistance to various therapies in both the preclinical and clinical setting. Therefore, the PI3K–Akt pathway plays a central role in various cellular processes promoting survival signaling that can contribute to the malignant phenotype, and, consequently, is an attractive pharmacologic target. However, as single agents, the efficacy of AKT inhibitors may be limited by resistance mechanisms that result in minimal cell death in tumor cells. Experimental Design: We investigated the effects of the Akt inhibitor AZD5363 on cell proliferation, cell cycle, apoptosis, and Akt downstream pathway proteins. Survival mechanisms induced by AZD5363 were investigated. We then examined the impacts of inhibition of autophagy in combination with AZD5363 on cell proliferation and apoptosis. Furthermore, the anticancer activity of combination treatment of the lysosomotropic inhibitor of autophagy (chloroquine) with the Akt inhibitor AZD5363 was evaluated in PC-3 prostate cancer xenografts. Results: Here, we show that the Akt inhibitor AZD5363 affected the Akt downstream pathway by reducing p-mTOR, p-P70S6K, and p-S6K. While AZD5363 monotherapy induced G2 growth arrest and autophagy, it failed to induce significant apoptosis in PC-3 and DU145 prostate cancer cell lines. Blocking autophagy using pharmacologic inhibitors (3-methyladenine, chloroquine, and bafilomycin A) or genetic inhibitors (siRNA targeting Atg3 and Atg7) enhanced cell death induced by Akt inhibitor AZD5363 in these tumor prostate cell lines. Importantly, the combination of AZD5363 with chloroquine significantly reduced tumor volume by 84.9% compared with the control group and by 77.5% compared with either drug alone in PC3 xenografts. Conclusion: Taken together, these data show that the Akt inhibitor AZD5363 synergizes with the lysosomotropic inhibitor of autophagy chloroquine to induce apoptosis and delay tumor progression in prostate cancer models that are resistant to monotherapy AZD5363, providing a new therapeutic approach potentially translatable to patients. Clin Cancer Res; 19(4); 833–44. ©2012 AACR.
Detectable Subclinical Myocardial Necrosis Is Associated With Cardiovascular Risk in Stable Patients With Diabetes
Authors: W.H. Wilson Tang, Yuping Wu, Earl B. Britt, Naveed Iqbal, Stanley L. Hazen
Journal: Diabetes Care (2013)

To investigate the relationship between different degrees of subclinical myocardial necrosis, glycemic control, and long-term adverse clinical outcomes within a stable patient population with diabetes mellitus.We examined 1,275 stable patients with diabetes mellitus undergoing elective diagnostic coronary angiography with cardiac troponin I (cTnI) levels below the diagnostic cut-off for defining myocardial infarction (MI) (<0.03 ng/mL). The relationship of subclinical myocardial necrosis (cTnI 0.009-0.029 ng/mL) with incident major adverse cardiovascular events (MACE; defined as any death, MI, or stroke) over 3 years of follow-up was examined.Subclinical myocardial necrosis was observed in 22% of patients. A strong association was observed between the magnitude of subclinical myocardial necrosis and risk of 3-year incident MACE (hazard ratio, 1.98; 95% confidence interval, 1.48-2.65; P < 0.001) and remained statistically significant even after adjustment for traditional risk factors, high-sensitivity C-reactive protein, and creatinine clearance. Only a weak correlation was observed between the presence of subclinical myocardial necrosis and either glycemic control (r = 0.06; P = 0.044 for hemoglobin A1c versus cTnI) or insulin resistance (r = 0.04; P = 0.094 for glucose-to-insulin ratio versus cTnI).The presence of detectable subclinical myocardial necrosis in stable patients with diabetes mellitus is associated with heightened long-term risk for MACE, independent of traditional risk factors and glycemic control.
Volume Status in Severe Malaria: No Evidence Provided for the Degree of Filling of the Intravascular Compartment
Authors: Kathryn Maitland, Charles Newton, Kevin Marsh, Mike Levin
Journal: PLoS Medicine (2005)

The study by Planche et al. [1] provides important new information addressing intracellular volume depletion in children with severe childhood malaria, but does not address the question of whether intravascular volume depletion (hypovolemic shock) is present.Using sophisticated methodology to determine total body water and extracellular water, they demonstrate a 6.7% defi cit in total body water and an 11.7% defi cit of intracellular water, providing an important indication of the volumes of fl uid that may be required to optimize hydration.The data, however, do not address the degree of fi lling of the intravascular compartment, nor should they be used to answer the question about the state of tissue and organ perfusion.Indeed, we believe that these new data present no confl ict with our previously reported fi ndings.Using methods to study critical illness physiology that are widely employed within pediatric intensive care units for interpretation of circulatory status, we have demonstrated evidence for hypovolemia in 53 Kenyan children with severe malaria complicated by metabolic acidosis [2].Our children were younger, had longer capillary refi lling times (>3 s), lower central venous pressures (mean 2.9 cm H 2 O) and higher creatinines (>80 µmol/l): all features of compensated hypovolemic shock.Furthermore, hypotension (systolic BP < 80 mm Hg) was present in 44% of children with severe acidosis (base defi cit >15).These fi ndings also indicate important baseline differences in two cohorts of children studied.We agree that reconsideration of guidelines for acute fl uid management is warranted, particularly when current recommendations await an adequate evidence base.Nevertheless, confl icting opinions on the question of volume status in children with severe malaria can be satisfactorily resolved only through prospective randomized trials that include both fl uid resuscitation and control groups.While the design and conduct of such trials will involve considerable challenges, optimal fl uid management will never be resolved on the basis of theoretical consideration alone.
A nomogram for predicting distant brain failure in patients treated with gamma knife stereotactic radiosurgery without whole brain radiotherapy
Authors: D. N. Ayala-Peacock, A. M. Peiffer, J. T. Lucas, S. Isom, J. G. Kuremsky, J. J. Urbanic, J. D. Bourland, A. W. Laxton, S. B. Tatter, E. G. Shaw, M. D. Chan
Journal: Neuro-Oncology (2014)

We review our single institution experience to determine predictive factors for early and delayed distant brain failure (DBF) after radiosurgery without whole brain radiotherapy (WBRT) for brain metastases.Between January 2000 and December 2010, a total of 464 patients were treated with Gamma Knife stereotactic radiosurgery (SRS) without WBRT for primary management of newly diagnosed brain metastases. Histology, systemic disease, RPA class, and number of metastases were evaluated as possible predictors of DBF rate. DBF rates were determined by serial MRI. Kaplan-Meier method was used to estimate rate of DBF. Multivariate analysis was performed using Cox Proportional Hazard regression.Median number of lesions treated was 1 (range 1-13). Median time to DBF was 4.9 months. Twenty-seven percent of patients ultimately required WBRT with median time to WBRT of 5.6 months. Progressive systemic disease (χ(2)= 16.748, P < .001), number of metastases at SRS (χ(2) = 27.216, P < .001), discovery of new metastases at time of SRS (χ(2) = 9.197, P < .01), and histology (χ(2) = 12.819, P < .07) were factors that predicted for earlier time to distant failure. High risk histologic subtypes (melanoma, her2 negative breast, χ(2) = 11.020, P < .001) and low risk subtypes (her2 + breast, χ(2) = 11.343, P < .001) were identified. Progressive systemic disease (χ(2) = 9.549, P < .01), number of brain metastases (χ(2) = 16.953, P < .001), minimum SRS dose (χ(2) = 21.609, P < .001), and widespread metastatic disease (χ(2) = 29.396, P < .001) were predictive of shorter time to WBRT.Systemic disease, number of metastases, and histology are factors that predict distant failure rate after primary radiosurgical management of brain metastases.
Molecular Biology of Somatostatin Receptors*
Authors: TERRY REISINE, GRAEME I. BELL
Journal: Endocrine Reviews (1995)

SOMATOSTATIN [somatotropin release-inhibiting factor (SRIF)] is a 14-amino acid polypeptide that is widely distributed throughout the central nervous system and peripheral tissues (Ref. 1; reviewed in Refs. 2–4). It potently inhibits basal and stimulated secretion from a wide variety of endocrine and exocrine cells and functions as a neurotransmitter/neuromodulator in the central nervous system with effects on locomotor activity and cognitive functions (1–12). Somatostatin also has antiproliferative effects and may be an important hormonal regulator of cell proliferation and differentiation (Refs. 13–15 and reviewed in Ref. 16). The first evidence for somatostatin-like activity came from studies of Krulich et al. (17), reported in 1968, who while looking for GHRF described a factor in hypothalamic extracts that inhibited GH secretion from anterior pituitaries in culture. Based on the identification of this inhibitory activity, Krulich et al. (17) proposed that the secretion of GH was regulated by stimulatory (GHRF) and inhibitory (somatostatin) factors. Hellman and Lernmark (18) independently found a similar activity in extracts of pigeon pancreatic islets that inhibited insulin secretion in vitro. Although seemingly unrelated, we now know that both groups had identified somatostatin, the sequence of which was reported by Brazeau et al. (1) in 1972.
Molecular and Functional Evolution of Class I Chitinases for Plant Carnivory in the Caryophyllales
Authors: T. Renner, C. D. Specht
Journal: Molecular Biology and Evolution (2012)

Proteins produced by the large and diverse chitinase gene family are involved in the hydrolyzation of glycosidic bonds in chitin, a polymer of N-acetylglucosamines. In flowering plants, class I chitinases are important pathogenesis-related proteins, functioning in the determent of herbivory and pathogen attack by acting on insect exoskeletons and fungal cell walls. Within the carnivorous plants, two subclasses of class I chitinases have been identified to play a role in the digestion of prey. Members of these two subclasses, depending on the presence or absence of a C-terminal extension, can be secreted from specialized digestive glands found within the morphologically diverse traps that develop from carnivorous plant leaves. The degree of homology among carnivorous plant class I chitinases and the method by which these enzymes have been adapted for the carnivorous habit has yet to be elucidated. This study focuses on understanding the evolution of carnivory and chitinase genes in one of the major groups of plants that has evolved the carnivorous habit: the Caryophyllales. We recover novel class I chitinase homologs from species of genera Ancistrocladus, Dionaea, Drosera, Nepenthes, and Triphyophyllum, while also confirming the presence of two subclasses of class I chitinases based upon sequence homology and phylogenetic affinity to class I chitinases available from sequenced angiosperm genomes. We further detect residues under positive selection and reveal substitutions specific to carnivorous plant class I chitinases. These substitutions may confer functional differences as indicated by protein structure homology modeling.
A dedicated microarray for in-depth analysis of pre-mRNA splicing events: application to the study of genes involved in the response to targeted anticancer therapies
Authors: Marine Pesson, Béatrice Eymin, Pierre De La Grange, Brigitte Simon, Laurent Corcos
Journal: Molecular Cancer (2014)

Abstract Alternative pre-mRNA splicing (AS) widely expands proteome diversity through the combinatorial assembly of exons. The analysis of AS on a large scale, by using splice-sensitive microarrays, is a highly efficient method to detect the majority of known and predicted alternative transcripts for a given gene. The response to targeted anticancer therapies cannot easily be anticipated without prior knowledge of the expression, by the tumor, of target proteins or genes. To analyze, in depth, transcript structure and levels for genes involved in these responses, including AKT1-3 , HER1-4 , HIF1A , PIK3CA , PIK3R1-2 , VEGFA-D and PIR , we engineered a dedicated gene chip with coverage of an average 185 probes per gene and, especially, exon-exon junction probes. As a proof of concept, we demonstrated the ability of such a chip to detect the effects of over-expressed SRSF2 RNA binding protein on the structure and abundance of mRNA products in H358 lung cancer cells conditionally over-expressing SRSF2. Major splicing changes were observed, including in HER1/EGFR pre-mRNA, which were also seen in human lung cancer samples over-expressing the SRSF2 protein. In addition, we showed that variations in HER1/EGFR pre-mRNA splicing triggered by SRSF2 overexpression in H358 cells resulted in a drop in HER1/EGFR protein level, which correlated with increased sensitivity to gefitinib, an EGFR tyrosine kinase inhibitor. We propose, therefore, that this novel tool could be especially relevant for clinical applications, with the aim to predict the response before treatment.
p53-mediated apoptosis of CLL cells: evidence for a transcription-independent mechanism
Authors: Andrew J. Steele, Archibald G. Prentice, A. Victor Hoffbrand, Birunthini C. Yogashangary, Stephen M. Hart, Elisabeth P. Nacheva, Julie D. Howard-Reeves, Veronique M. Duke, Panagiotis D. Kottaridis, Kate Cwynarski, Lyubomir T. Vassilev, R. Gitendra Wickremasinghe
Journal: Blood (2008)
Short-term recombinant human DNase in bronchiectasis. Effect on clinical state and in vitro sputum transportability.
Authors: P J Wills, T Wodehouse, K Corkery, K Mallon, R Wilson, P J Cole
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

We report a double blind placebo-controlled phase II study of the efficacy and safety of nebulized recombinant human DNase (rhDNase) administered for 14 d to adults with bronchiectasis not caused by cystic fibrosis. All were in a stable clinical state at the commencement of the study, and they received (1) rhDNase 2.5 mg twice daily, (2) rhDNase once daily, or (3) placebo (excipient only) inhalation. The outcome measures were spirometry, subjective quality of life/dyspnea, and safety. We also measured the ciliary transportability of the sputum expectorated before and after the treatment period, using the mucus-depleted bovine trachea. The drug was well tolerated, but it produced no significant change in any of the outcome variables or in sputum transportability. When the drug was incubated with bronchiectatic sputum in vitro, a fall in transportability was observed. We discuss possible explanations for the lack of a measurable benefit from rhDNase in this study population, which appears to contrast with the improvements shown in cystic fibrosis using studies of similar design.
A Promoter Methylation Pattern in the <i>N</i>-Methyl-<scp>d</scp>-Aspartate Receptor 2B Gene Predicts Poor Prognosis in Esophageal Squamous Cell Carcinoma
Authors: Myoung Sook Kim, Keishi Yamashita, Young Kwang Chae, Yutaka Tokumaru, Xiaofei Chang, Marianna Zahurak, Motonobu Osada, Hannah Lui Park, Alice Chuang, Joseph A. Califano, David Sidransky
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To investigate whether the promoter methylation pattern in N-methyl-d-aspartate receptor 2B (NMDAR2B) is correlated with clinical features of human esophageal squamous cell carcinoma (ESCC), the methylation status of the gene was examined at three different sites (P1, P2, and P3) where two CpG islands reside within 1 kb upstream of the transcription start site. Experimental Design: Three independent modalities for methylation analysis (bisulfite sequencing, combined bisulfite restriction analysis, and TaqMan methylation-specific PCR) were done to analyze total 67 ESCC tissues that included 43 primary tumors with well-characterized clinicopathologic variables including patient outcome. Results: Using an optimized cutoff value based on quantitative methylation-specific PCR, we found that patients with higher NMDAR2B methylation ratio in the proximal region (P1) showed a worse 5-year disease-specific survival rate than those without NMDAR2B methylation (P &amp;lt; 0.006). A significant correlation was also seen between NMDAR2B promoter methylation and the presence of vascular permeation (P = 0.03). Conclusion: NMDAR2B promoter methylation could be a clinically applicable marker in ESCC.