tbuckley/cabot-search huggingface dataset:
An arginine to histidine mutation in codon 311 of the C-erbA beta gene results in a mutant thyroid hormone receptor that does not mediate a dominant negative phenotype.
Authors: M E Geffner, F Su, N S Ross, J M Hershman, C Van Dop, J B Menke, E Hao, R K Stanzak, T Eaton, H H Samuels
Journal: Journal of Clinical Investigation (1993)

We have examined the c-erbA beta thyroid hormone receptor gene in a kindred, G.H., with a member, patient G.H., who had a severe form of selective pituitary resistance to thyroid hormones (PRTH). This patient manifested inappropriately normal thyrotropin-stimulating hormone, markedly elevated serum free thyroxine (T4) and total triiodothyronine (T3), and clinical hyperthyroidism. The complete c-erbA beta 1 coding sequence was examined by a combination of genomic and cDNA cloning for patient G.H. and her unaffected father. A single mutation, a guanine to adenine transition at nucleotide 1,232, was found in one allele of both these members, altering codon 311 from arginine to histidine. In addition, a half-sister of patient G.H. also harbored this mutant allele and, like the father, was clinically normal. The G.H. receptor, synthesized with reticulocyte lysate, had significantly defective T3-binding activity with a Ka of approximately 5 x 10(8) M-1. RNA phenotyping using leukocytes and fibroblasts demonstrated an equal level of expression of wild-type and mutant alleles in patient G.H. and her unaffected father. Finally, the G.H. receptor had no detectable dominant negative activity in a transfection assay. Thus, in contrast to the many other beta-receptor mutants responsible for the generalized form of thyroid hormone resistance, the G.H. receptor appeared unable to antagonize normal receptor function. These results suggest that the arginine at codon 311 in c-erbA beta is crucial for the structural integrity required for dominant negative function. The ARG-311-HIS mutation may contribute to PRTH in patient G.H. by inactivating a beta-receptor allele, but it cannot be the sole cause of the disease.
B-Cell Lymphomas Differ in their Responsiveness to CpG Oligodeoxynucleotides
Authors: Bernd Jahrsdorfer, Lars Mühlenhoff, Sue E. Blackwell, Moritz Wagner, Hendrik Poeck, Evelyn Hartmann, Ralf Jox, Thomas Giese, Bertold Emmerich, Stefan Endres, George J. Weiner, Gunther Hartmann
Journal: Clinical Cancer Research (2005)

Human B cells detect CpG motifs within microbial DNA via TLR9. Synthetic CpG oligodeoxynucleotides are currently being tested in clinical trials for the therapy of different types of B cell non-Hodgkin's lymphoma. However, there is only limited information on the CpG oligodeoxynucleotide sensitivity of primary malignant B cells of different non-Hodgkin's lymphoma entities. Here we found that most B-cell malignancies except plasmacytoma respond to CpG oligodeoxynucleotides by up-regulating expression of costimulatory and antigen-presenting molecules, by increasing expression of CD20, and by proliferation. In an in vitro analysis of 41 individual patient-derived primary tumor samples, B-cell chronic lymphocytic leukemia (B-CLL) and marginal zone lymphoma showed the strongest activation upon stimulation with CpG oligodeoxynucleotides. Small lymphocytic lymphoma, follicular lymphoma, mantle cell lymphoma, and large cell lymphoma showed an intermediate response. Consistent with CpG oligodeoxynucleotides sensitivity, TLR9 mRNA was present in B-CLL but absent in plasmacytoma. Although CpG oligodeoxynucleotides induced proliferation in all CpG oligodeoxynucleotide-sensitive types of B-cell malignancies, proliferation was weaker than in normal B cells and at least for B-CLL was followed by increased apoptosis. In conclusion, B-cell malignancies show significant differences in their responsiveness to CpG oligodeoxynucleotides. Focusing clinical studies on patients with highly CpG oligodeoxynucleotide-sensitive B-cell malignancies may improve the clinical outcome of such trials.
Hb S/β°‐Thalassemia due to the ˜1.4‐kb deletion is associated with a relatively mild phenotype
Authors: John S. Waye, David H. K. Chui, Barry Eng, Shi‐Ping Cai, Mary B. Coleman, Junius G. Adams, Martin H. Steinberg
Journal: American Journal of Hematology (1991)

Abstract We report a relatively mild phenotype associated with two siblings who are compound heterozygotes for Hb S and a β°‐thalassemia mutation due to a ˜1.4‐kb deletion of the 5′ region of the β‐globin gene. Each is found to have unusually high levels of Hb A 2 and Hb F, accounting for more than 20% of the total hemoglobin. These may interfere with intracellular Hb 5 polymerization, thus leading to a mild clinical course.
Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1
Authors: Anna S. Lok, David F. Gardiner, Eric Lawitz, Claudia Martorell, Gregory T. Everson, Reem Ghalib, Robert Reindollar, Vinod Rustgi, Fiona McPhee, Megan Wind-Rotolo, Anna Persson, Kurt Zhu, Dessislava I. Dimitrova, Timothy Eley, Tong Guo, Dennis M. Grasela, Claudio Pasquinelli
Journal: New England Journal of Medicine (2012)

Patients with chronic hepatitis C virus (HCV) infection who have not had a response to therapy with peginterferon and ribavirin may benefit from the addition of multiple direct-acting antiviral agents to their treatment regimen.
The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease
Authors: J Threadgold
Journal: Gut (2002)

Background: Mutations in the PRSS1 gene explain most occurrences of hereditary pancreatitis (HP) but many HP families have no PRSS1 mutation. Recently, an association between the mutation N34S in the pancreatic secretory trypsin inhibitor (SPINK1 or PSTI) gene and idiopathic chronic pancreatitis (ICP) was reported. It is unclear whether the N34S mutation is a cause of pancreatitis per se, whether it modifies the disease, or whether it is a marker of the disease. Patients and methods: A total of 327 individuals from 217 families affected by pancreatitis were tested: 152 from families with HP, 108 from families with ICP, and 67 with alcohol related CP (ACP). Seven patients with ICP had a family history of pancreatitis but no evidence of autosomal dominant disease (f-ICP) compared with 87 patients with true ICP (t-ICP). Two hundred controls were also tested for the N34S mutation. The findings were related to clinical outcome. Results: The N34S mutation was carried by five controls (2.5%; allele frequency 1.25%), 11/87 (13%) t-ICP patients (p=0.0013 <i>v</i> controls), and 6/7 (86%) affected (p&lt;0.0001 <i>v</i> controls) and 1/9 (11%) unaffected f-ICP cases. N34S was found in 4/108 affected HP patients (p=0.724 <i>v</i> controls), in 3/27 (11%) with wild-type and in 1/81 (1%) with mutant PRSS1, and 4/67 ACP patients (all p&gt;0.05 <i>v</i> controls). The presence of the N34S mutation was not associated with early disease onset or disease severity. Conclusions: The prevalence of the N34S mutation was increased in patients with ICP and was greatest in f-ICP cases. Segregation of the N34S mutation in families with pancreatitis is unexplained and points to a complex association between N34S and another putative pancreatitis related gene.
Regulation of Protein Kinase B and 4E-BP1 by Oxidative Stress in Cardiac Myocytes
Authors: Fong H. Pham, Peter H. Sugden, Angela Clerk
Journal: Circulation Research (2000)

Abstract —Stimulation of phosphatidylinositol 3′-kinase (PI3K) and protein kinase B (PKB) is implicated in the regulation of protein synthesis in various cells. One mechanism involves PI3K/PKB-dependent phosphorylation of 4E-BP1, which dissociates from eIF4E, allowing initiation of translation from the 7-methylGTP cap of mRNAs. We examined the effects of insulin and H 2 O 2 on this pathway in neonatal cardiac myocytes. Cardiac myocyte protein synthesis was increased by insulin, but was inhibited by H 2 O 2 . PI3K inhibitors attenuated basal levels of protein synthesis and inhibited the insulin-induced increase in protein synthesis. Insulin or H 2 O 2 increased the phosphorylation (activation) of PKB through PI3K, but, whereas insulin induced a sustained response, the response to H 2 O 2 was transient. 4E-BP1 was phosphorylated in unstimulated cells, and 4E-BP1 phosphorylation was increased by insulin. H 2 O 2 stimulated dephosphorylation of 4E-BP1 by increasing protein phosphatase (PP1/PP2A) activity. This increased the association of 4E-BP1 with eIF4E, consistent with H 2 O 2 inhibition of protein synthesis. The effects of H 2 O 2 were sufficient to override the stimulation of protein synthesis and 4E-BP1 phosphorylation induced by insulin. These results indicate that PI3K and PKB are important regulators of protein synthesis in cardiac myocytes, but other factors, including phosphatase activity, modulate the overall response.
Selective Apoptotic Killing of Malignant Hemopoietic Cells by Antibody-Targeted Delivery of an Amphipathic Peptide
Authors: Alexandra J. Marks, Margaret S. Cooper, Robert J. Anderson, Kim H. Orchard, Geoffrey Hale, Janet M. North, Kanagasabai Ganeshaguru, Andrew J. Steele, Atul B. Mehta, Mark W. Lowdell, R. Gitendra Wickremasinghe
Journal: Cancer Research (2005)

The alpha-helical amphipathic peptide D-(KLAKLAK)2 is toxic to eukaryotic cells if internalized by a suitable targeting mechanism. We have targeted this peptide to malignant hemopoietic cells via conjugation to monoclonal antibodies, which recognize lineage-specific cell surface molecules. An anti-CD19/peptide conjugate efficiently killed 3/3 B lymphoid lines. However, an anti-CD33/peptide conjugate was cytotoxic to only one of three CD33-positive myeloid leukemia lines. The IC50 towards susceptible lines were in the low nanomolar range. Conjugates were highly selective and did not kill cells that did not express the appropriate cell surface cognate of the antibody moiety. Anti-CD19/peptide conjugates efficiently killed cells from patients with chronic lymphocytic leukemia but anti-CD33/peptide reagents were less effective against fresh acute myeloid leukemia cells. We therefore suggest that amphipathic peptides may be of value as targeted therapeutic agents for the treatment of a subset of hematologic malignancies.
Differential regulation of mast cell degranulation versus cytokine secretion by the actin regulatory proteins Coronin1a and Coronin1b
Authors: Niko Föger, André Jenckel, Zane Orinska, Kyeong-Hee Lee, Andrew C. Chan, Silvia Bulfone-Paus
Journal: The Journal of Experimental Medicine (2011)

Mast cell (MC) activation via aggregation of the high affinity IgE receptor (FcεRI) causes degranulation and release of proinflammatory mediators in a process that involves the reorganization of the actin cytoskeleton. However, the regulatory pathways and the molecular links between cytoskeletal changes and MC function are incompletely understood. In this study, we provide genetic evidence for a critical role of the actin-regulatory proteins Coronin1a (Coro1a) and Coro1b on exocytic pathways in MCs: Coro1a−/− bone marrow–derived MCs exhibit increased FcεRI-mediated degranulation of secretory lysosomes but significantly reduced secretion of cytokines. Hyperdegranulation of Coro1a−/− MCs is further augmented by the additional loss of Coro1b. In vivo, Coro1a−/−Coro1b−/− mice displayed enhanced passive cutaneous anaphylaxis. Functional reconstitution assays revealed that the inhibitory effect of Coro1a on MC degranulation strictly correlates with cortical localization of Coro1a, requires its filamentous actin–binding activity, and is regulated by phosphorylation of Ser2 of Coro1a. Thus, coronin proteins, and in turn the actin cytoskeleton, exhibit a functional dichotomy as differential regulators of degranulation versus cytokine secretion in MC biology.
Reducing short acting beta agonist overuse in the asthma population*1
Authors: C.A. Lamb, J. Hoban, L. Glaves, K. Jahn, C. Martin, C. Tacinas, S. Hay, J. Dotts, D. Flynn, M. Kleerup, J. Williams, J. McGaw
Journal: Journal of Allergy and Clinical Immunology (2004)
Efficacy and safety of tanezumab added on to diclofenac sustained release in patients with knee or hip osteoarthritis: a double-blind, placebo-controlled, parallel-group, multicentre phase III randomised clinical trial
Authors: Andra Rodica Balanescu, Eugen Feist, Gernot Wolfram, Isabelle Davignon, Michael D Smith, Mark T Brown, Christine R West
Journal: Annals of the Rheumatic Diseases (2013)

Tanezumab, a monoclonal antibody, inhibits nerve growth factor and reduces chronic pain. This randomised, double-blind, controlled multicentre study was conducted to evaluate the efficacy and safety of tanezumab added to oral diclofenac sustained release (DSR) in patients with hip or knee osteoarthritis (OA) pain.Patients (N=604) with moderate to severe knee or hip OA tolerating stable DSR were randomised and treated with DSR 75 mg twice daily combined with intravenous tanezumab 10, 5 or 2.5 mg or placebo at weeks 0, 8 and 16. Co-primary efficacy endpoints (Western Ontario and McMaster Universities OA Index (WOMAC) Pain and Physical Function subscales and patient's global assessment of OA) were assessed at week 16.All co-primary endpoints were significantly improved for all tanezumab+DSR groups versus placebo+DSR (p≤0.039). The incidence of adverse events of abnormal peripheral sensation was lower than in previous tanezumab trials. No new safety signals emerged. Overall incidence of adverse events was higher with tanezumab+DSR (45.2%-49.7%) than with placebo+DSR (34.9%); serious adverse event rates were similar across treatments (5.3%-7.6%). Osteonecrosis was reported in six of 452 patients with tanezumab+DSR (1.3%), but an external adjudication committee did not confirm osteonecrosis in any patient.Addition of tanezumab to DSR resulted in significant improvements in pain, function and global assessments in patients with OA. Although no new safety signals were observed, the higher incidence of adverse events in the tanezumab+diclofenac group suggests that combination therapy is unfavourable. Further investigations of tanezumab monotherapy for OA pain treatment are required.NCT00864097.
Clinical Implications of Fibroblast Activation Protein in Patients with Colon Cancer
Authors: Leonard R. Henry, Hyung-Ok Lee, John S. Lee, Andres Klein-Szanto, Perry Watts, Eric A. Ross, Wen-Tien Chen, Jonathan D. Cheng
Journal: Clinical Cancer Research (2007)

Human fibroblast activation protein (FAP)/seprase is a 97-kDa surface glycoprotein expressed on tumor associated fibroblasts in the majority of epithelial cancers including colon adenocarcinomas. FAP overexpression in human tumor cells has been shown to promote tumor growth in animal models, and clinical trials targeting FAP enzymatic activity have been initiated. The primary objective of this study was to evaluate the clinical significance of stromal FAP in human colon cancers by immunohistochemisty.Sections of paraffin-embedded resected primary human colon cancer specimens from 1996 through 2001 within the Fox Chase Cancer Center tumor bank were stained with D8 antibody directed against FAP/seprase. Xenotransplanted human colorectal tumors in mice were examined similarly for stromal FAP in tumors of different sizes. Overall percentage of stromal FAP staining of the primary tumor was assessed semiquantitatively (0, 1+, 2+, 3+) and staining intensity was also graded (none, weak, intermediate, strong). Survival time and time to recurrence data were analyzed using Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models.One hundred thirty-eight patients with resected specimens were available for study (mean follow-up, 1,050 days) with 6 (4%) stage I, 52 (38%) stage II, 43 (31%) stage III, and 37 (27%) stage IV patients. FAP was detected in >93% of specimens. Semiquantitative staining was scored as 1+ in 28 (20%), 2+ in 52 (38%), and 3+ in 49 (35%). FAP staining intensity was graded as weak in 45 (33%), intermediate in 48 (35%), and dark in 36 (26%). Stromal FAP was found to correlate inversely with tumor stage (semiquantitative, P = 0.01; intensity, P = 0.009) and with tumor size of the tumor xenograft model (correlation coefficient, -0.61; P = 0.047), suggesting that stromal FAP may have a greater role in the early development of tumors. Furthermore, greater stromal FAP for patients with known metastatic disease was associated with a decreased survival.Our data indicate that patients whose colon tumors have high levels of stromal FAP are more likely to have aggressive disease progression and potential development of metastases or recurrence. This study affirms the rationale for ongoing clinical investigations using FAP as a therapeutic target to disrupt FAP-driven tumor progression in patients with metastatic disease. It also suggests that the effects of FAP inhibition should be investigated in earlier-stage tumors, given its high levels and potential effect earlier in the course of the disease.
Self-assembling PEG-p(CL-co-TMC) copolymers for oral delivery of poorly water-soluble drugs: a case study with risperidone
Authors: Louisa Ould-Ouali, Marc Noppe, Xavier Langlois, Bart Willems, Paula Te Riele, Philip Timmerman, Marcus E. Brewster, Albertina Ariën, Véronique Préat
Journal: Journal of Controlled Release (2004)
TGFβ/TNFα-Mediated Epithelial–Mesenchymal Transition Generates Breast Cancer Stem Cells with a Claudin-Low Phenotype
Authors: Michael K. Asiedu, James N. Ingle, Marshall D. Behrens, Derek C. Radisky, Keith L. Knutson
Journal: Cancer Research (2011)

Abstract Breast cancer recurrence is believed to be caused by a subpopulation of cancer cells that possess the stem cell attribute of treatment resistance. Recently, we and others have reported the generation of breast cancer stem cells (BCSC) by epithelial–mesenchymal transition (EMT), although the physiologic process by which these cells may arise in vivo remains unclear. We show here that exposure of tumor cells to TGFβ and TNFα induces EMT and, more importantly, generates cells with a stable BCSC phenotype which is shown by increased self-renewing capacity, greatly increased tumorigenicity, and increased resistance to oxaliplatin, etoposide, and paclitaxel. Furthermore, gene expression analyses found that the TGFβ/TNFα-derived BCSCs showed downregulated expression of genes encoding claudin 3, 4, and 7 and the luminal marker, cytokeratin 18. These changes indicate a shift to the claudin-low molecular subtype, a recently identified breast cancer subtype characterized by the expression of mesenchymal and stem cell-associated markers and correlated with a poor prognosis. Taken together, the data show that cytokine exposure can be used to generate stable BCSCs ex vivo, and suggest that these cells may provide a valuable tool in the identification of stem cell-directed biomarkers and therapies in breast cancer. Cancer Res; 71(13); 4707–19. ©2011 AACR.
Background Mutational Features of the Radiation-Resistant Bacterium<i>Deinococcus radiodurans</i>
Authors: Hongan Long, Sibel Kucukyildirim, Way Sung, Emily Williams, Heewook Lee, Matthew Ackerman, Thomas G. Doak, Haixu Tang, Michael Lynch
Journal: Molecular Biology and Evolution (2015)

Deinococcus bacteria are extremely resistant to radiation, oxidation, and desiccation. Resilience to these factors has been suggested to be due to enhanced damage prevention and repair mechanisms, as well as highly efficient antioxidant protection systems. Here, using mutation-accumulation experiments, we find that the GC-rich Deinococcus radiodurans has an overall background genomic mutation rate similar to that of E. coli, but differs in mutation spectrum, with the A/T to G/C mutation rate (based on a total count of 88 A:T→G:C transitions and 82 A:T→C:G transversions) per site per generation higher than that in the other direction (based on a total count of 157 G:C→A:T transitions and 33 G:C→T:A transversions). We propose that this unique spectrum is shaped mainly by the abundant uracil DNA glycosylases reducing G:C→A:T transitions, adenine methylation elevating A:T→C:G transversions, and absence of cytosine methylation decreasing G:C→A:T transitions. As opposed to the greater than 100× elevation of the mutation rate in MMR− (DNA Mismatch Repair deficient) strains of most other organisms, MMR−D. radiodurans only exhibits a 4-fold elevation, raising the possibility that other DNA repair mechanisms compensate for a relatively low-efficiency DNA MMR pathway. As D. radiodurans has plentiful insertion sequence (IS) elements in the genome and the activities of IS elements are rarely directly explored, we also estimated the insertion (transposition) rate of the IS elements to be 2.50 × 10−3 per genome per generation in the wild-type strain; knocking out MMR did not elevate the IS element insertion rate in this organism.
Ligand-Independent EGFR Signaling
Authors: Gao Guo, Ke Gong, Bryan Wohlfeld, Kimmo J. Hatanpaa, Dawen Zhao, Amyn A. Habib
Journal: Cancer Research (2015)

Abstract Constitutive activation of the EGFR is common in cancer due to EGFR wild-type (EGFRwt) overexpression or the presence of mutant EGFR. Signaling by constitutively active NSCLC EGFR mutants or the EGFRvIII mutant in glioblastoma has been studied intensively and the downstream signals are known. Normally, the EGFRwt is activated when it is exposed to ligand, resulting in activation of canonical signals such as ERK and Akt. The EGFRwt also becomes tyrosine phosphorylated and constitutively activated without ligand when it is overexpressed, but downstream signals are unclear. Recent studies have identified a noncanonical form of signaling triggered by EGFRwt exclusively in the absence of ligand that does not involve ERK or Akt activation but, instead, results in activation of the transcription factor IRF3. The addition of ligand turns off IRF3-dependent transcription and activates ERK and Akt. Thus, the EGFR triggers distinct and mutually exclusive signaling networks, depending on the presence of ligand. Furthermore, noncanonical EGFRwt signaling may influence response to treatment in cancer. Also, there are reports of both synergistic and antagonistic interactions between ligand-dependent EGFRwt and EGFRvIII signaling. Here, we discuss ligand-independent EGFR signal transduction by oncogenic EGFR mutants and EGFRwt, and review the interplay between EGFRwt and EGFRvIII. Cancer Res; 75(17); 3436–41. ©2015 AACR.
Interpretation of negative results in fine needle aspiration of discrete pulmonary lesions.
Authors: A J Winning, J McIvor, W A Seed, O A Husain, N Metaxas
Journal: Thorax (1986)

A retrospective analysis was carried out on a consecutive series of 181 percutaneous fine needle aspiration biopsies of discrete pulmonary lesions, in which the outcome was established in 95%. In primary bronchial carcinoma the technique had a sensitivity of 86%. There was no relationship between the size, location, or radiological appearance of the lesion and the incidence of false negative results. The principal reason for failure to diagnose malignancy was inadequacy of the material provided for cytological examination. For metastatic neoplasms of non-bronchial origin the procedure had a sensitivity of 42% and a significantly greater false negative rate than for primary bronchial malignancy. For the entire series 72 (40%) of the procedures failed to produce a definite diagnosis, 29 (40%) of these cases subsequently proving to be malignant. A positive diagnosis was established in only 16% of patients with benign conditions. Review of published reports and consideration of the role of this and other biopsy techniques in the investigation of discrete pulmonary lesions lead to the conclusion that needle aspiration biopsy seems particularly appropriate in the investigation of inoperable patients with probable bronchial carcinoma in whom sputum cytology and bronchoscopy do not yield a diagnosis.