tbuckley/cabot-search huggingface dataset:
An Analysis of Determinants of Amino Acids Substitution Rates in Bacterial Proteins
Authors: Eduardo P. C. Rocha, Antoine Danchin
Journal: Molecular Biology and Evolution (2004)

The variation of amino acid substitution rates in proteins depends on several variables. Among these, the protein's expression level, functional category, essentiality, or metabolic costs of its amino acid residues may play an important role. However, the relative importance of each variable has not yet been evaluated in comparative analyses. To this aim, we made regression analyses combining data available on these variables and on evolutionary rates, in two well-documented model bacteria, Escherichia coli and Bacillus subtilis. In both bacteria, the level of expression of the protein in the cell was by far the most important driving force constraining the amino acids substitution rate. Subsequent inclusion in the analysis of the other variables added little further information. Furthermore, when the rates of synonymous substitutions were included in the analysis of the E. coli data, only the variable expression levels remained statistically significant. The rate of nonsynonymous substitution was shown to correlate with expression levels independently of the rate of synonymous substitution. These results suggest an important direct influence of expression levels, or at least codon usage bias for translation optimization, on the rates of nonsynonymous substitutions in bacteria. They also indicate that when a control for this variable is included, essentiality plays no significant role in the rate of protein evolution in bacteria, as is the case in eukaryotes.
Effect of Intensive Compared With Standard Glycemia Treatment Strategies on Mortality by Baseline Subgroup Characteristics
Authors: Jorge Calles-Escandón, Laura C. Lovato, Denise G. Simons-Morton, David M. Kendall, Rodica Pop-Busui, Robert M. Cohen, Denise E. Bonds, Vivian A. Fonseca, Faramarz Ismail-Beigi, Mary Ann Banerji, Alan Failor, Bruce Hamilton
Journal: Diabetes Care (2010)

OBJECTIVE To determine if baseline subgroups in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial can be identified for whom intensive compared with standard glycemia treatment had different effects on all-cause mortality. RESEARCH DESIGN AND METHODS Exploratory post hoc intention-to-treat comparisons were made between intensive and standard glycemia groups on all-cause mortality by subgroups defined by baseline characteristics. RESULTS There were few significant interactions between baseline characteristics and effects of intensive versus standard glycemia treatment on mortality: self-reported history of neuropathy (hazard ratio [HR] 1.95, 95% CI 1.41–2.69) versus no history of neuropathy (0.99, 0.79–1.26; P value for interaction 0.0008), higher A1C (A1C &amp;gt;8.5%: HR 1.64, 95% CI 1.22–2.22; A1C 7.5–8.4%: 1.00, 0.75–1.34; A1C &amp;lt;7.5%: 1.00, 0.67–1.50; P value for interaction 0.04), and aspirin use (HR 1.45, 95% CI 1.13–1.85, compared with 0.96, 0.72–1.27, in nonusers; P value for interaction 0.03). CONCLUSIONS We found a remarkable similarity of effect from intensive compared with standard glycemia treatment on mortality across most baseline subgroups. No differential effect was found in subgroups defined by variables anticipated to have an interaction: age, duration of diabetes, and previous history of cardiovascular disease. The three baseline characteristics that defined subgroups for which there was a differential effect on mortality may help identify patients with type 2 diabetes at higher risk of mortality from intensive regimens for glycemic control. Further research is warranted.
ras Oncogene p21 expression is increased in premalignant lesions and high grade bladder carcinoma.
Authors: M V Viola, F Fromowitz, S Oravez, S Deb, J Schlom
Journal: The Journal of Experimental Medicine (1985)

ras Oncogene p21 antigen is present in the most superficial cells of the normal bladder urothelium, as demonstrated by immunohistochemical staining. The pattern and intensity of p21 staining of cells in epithelial hyperplasia and low grade bladder carcinoma were similar to that seen in the normal urothelium. In contrast, epithelial cells in "premalignant" (dysplastic) lesions and high grade carcinomas exhibited an intense staining reaction for p21 antigen. ras p21 may be a useful marker for the malignant potential of both premalignant lesions and carcinomas of the bladder.
Evolution of the Insulin Receptor Family and Receptor Isoform Expression in Vertebrates
Authors: C. Hernandez-Sanchez, A. Mansilla, F. de Pablo, R. Zardoya
Journal: Molecular Biology and Evolution (2008)

The molecular phylogeny of the vertebrate insulin receptor (IR) family was reconstructed under maximum likelihood (ML) to establish homologous relationships among its members. A sister group relationship between the orphan insulin–related receptor (IRR) and the insulin-like growth factor 1 receptor (IGF1R) to the exclusion of the IR obtained maximal bootstrap support. Although both IR and IGF1R were identified in all vertebrates, IRR could not be found in any teleost fish. The ancestral character states at each position of the receptor molecule were inferred for IR, IRR + IGF1R, and all 3 paralogous groups based on the recovered phylogeny using ML in order to determine those residues that could be important for the specific function of IR. For 18 residues, ancestral character state of IR was significantly distinct (probability >0.95) with respect to the corresponding inferred ancestral character states both of IRR + IGF1R and of all 3 vertebrate paralogs. Most of these IR distinct (shared derived) residues were located on the extracellular portion of the receptor (because this portion is larger and the rate of generation of IR shared derived sites is uniform along the receptor), suggesting that functional diversification during the evolutionary history of the family was largely generated modifying ligand affinity rather than signal transduction at the tyrosine kinase domain. In addition, 2 residues at positions 436 and 1095 of the human IR sequence were identified as radical cluster-specific sites in IRR + IGF1R. Both Ir and Irr have an extra exon (namely exon 11) with respect to Igf1r. We used the molecular phylogeny to infer the evolution of this additional exon. The Irr exon 11 can be traced back to amphibians, whereas we show that presence and alternative splicing of Ir exon 11 seems to be restricted exclusively to mammals. The highly divergent sequence of both exons and the reconstructed phylogeny of the vertebrate IR family strongly indicate that both exons were acquired independently by each paralog.
The Oncogenic microRNA-27a Targets Genes That Regulate Specificity Protein Transcription Factors and the G2-M Checkpoint in MDA-MB-231 Breast Cancer Cells
Authors: Susanne U. Mertens-Talcott, Sudhakar Chintharlapalli, Xiangrong Li, Stephen Safe
Journal: Cancer Research (2007)

Abstract There is evidence that specificity proteins (Sp), such as Sp1, Sp3, and Sp4, are overexpressed in tumors and contribute to the proliferative and angiogenic phenotype associated with cancer cells. Sp1, Sp3, and Sp4 are expressed in a panel of estrogen receptor (ER)–positive and ER-negative breast cancer cell lines, and we hypothesized that regulation of their expression may be due to microRNA-27a (miR-27a), which is also expressed in these cell lines and has been reported to regulate the zinc finger ZBTB10 gene, a putative Sp repressor. Transfection of ER-negative MDA-MB-231 breast cancer cells with antisense miR-27a (as-miR-27a) resulted in increased expression of ZBTB10 mRNA and decreased expression of Sp1, Sp3, and Sp4 at the mRNA and protein levels and also decreased activity in cells transfected with constructs containing Sp1 and Sp3 promoter inserts. In addition, these responses were accompanied by decreased expression of Sp-dependent survival and angiogenic genes, including survivin, vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1). Moreover, similar results were observed in MDA-MB-231 cells transfected with ZBTB10 expression plasmid. Both as-miR-27a and ZBTB10 overexpression decreased the percentage of MDA-MB-231 cells in S phase of the cell cycle; however, ZBTB10 increased the percentage of cells in G0-G1, whereas as-miR-27a increased the percentage in G2-M. This latter response was associated with induction of Myt-1 (another miR-27a target gene), which inhibits G2-M through enhanced phosphorylation and inactivation of cdc2. Thus, the oncogenic activity of miR-27a in MDA-MB-231 cells is due, in part, to suppression of ZBTB10 and Myt-1. [Cancer Res 2007;67(22):11001–11]
RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement
Authors: Christina M. Lau, Courtney Broughton, Abigail S. Tabor, Shizuo Akira, Richard A. Flavell, Mark J. Mamula, Sean R. Christensen, Mark J. Shlomchik, Gregory A. Viglianti, Ian R. Rifkin, Ann Marshak-Rothstein
Journal: The Journal of Experimental Medicine (2005)

Previous studies (Leadbetter, E.A., I.R. Rifkin, A.H. Hohlbaum, B. Beaudette, M.J. Shlomchik, and A. Marshak-Rothstein. 2002. Nature. 416:603–607; Viglianti, G.A., C.M. Lau, T.M. Hanley, B.A. Miko, M.J. Shlomchik, and A. Marshak-Rothstein. 2003. Immunity. 19:837–847) established the unique capacity of DNA and DNA-associated autoantigens to activate autoreactive B cells via sequential engagement of the B cell antigen receptor (BCR) and Toll-like receptor (TLR) 9. We demonstrate that this two-receptor paradigm can be extended to the BCR/TLR7 activation of autoreactive B cells by RNA and RNA-associated autoantigens. These data implicate TLR recognition of endogenous ligands in the response to both DNA- and RNA-associated autoantigens. Importantly, the response to RNA-associated autoantigens was markedly enhanced by IFN-α, a cytokine strongly linked to disease progression in patients with systemic lupus erythematosus (SLE). As further evidence that TLRs play a key role in autoantibody responses in SLE, we found that autoimmune-prone mice, lacking the TLR adaptor protein MyD88, had markedly reduced chromatin, Sm, and rheumatoid factor autoantibody titers.
Predictive Factors for Outcome in a Phase II Study of Gefitinib in Second-Line Treatment of Advanced Esophageal Cancer Patients
Authors: Maarten L. Janmaat, Mariëlle I. Gallegos-Ruiz, José A. Rodriguez, Gerrit A. Meijer, Walter L. Vervenne, Dick J. Richel, Cees Van Groeningen, Giuseppe Giaccone
Journal: Journal of Clinical Oncology (2006)

Purpose The efficacy of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib was assessed in a phase II study in patients with advanced esophageal cancer. Several biologic features were investigated as potential markers of gefitinib activity. Patients and Methods Patients with advanced esophageal cancer, who had failed one line of prior chemotherapy, were administered gefitinib 500 mg/d. Response was evaluated every 8 weeks. Tumor material obtained before gefitinib treatment was investigated for gene mutations in EGFR, k-ras, and PIK3CA; protein expression levels of EGFR, p-Akt, and p-Erk; and EGFR gene amplification. Results Of the 36 enrolled patients, one (2.8%) achieved a partial response, 10 (27.8%) had stable disease, 17 (47.2%) experienced progression on treatment, and eight (22.2%) were not assessable for response. The progression-free survival time was 59 days, and the median overall survival time was 164 days. Although EGFR or PIK3CA mutations were absent, k-ras mutations were found in two patients with progressive disease. High EGFR gene copy number was identified in two patients experiencing partial response or progressive disease. A higher disease control rate (response plus stable disease) was observed in females (P = .038) and in patients with squamous cell carcinoma (SCC; P = .013) or high EGFR expression (P = .002). Conclusion Gefitinib has a modest activity in second-line treatment of advanced esophageal cancer. However, the patient outcome was significantly better in female patients and in patients demonstrating high EGFR expression or SCC histology. The selection of esophageal cancer patients for future studies with EGFR-TKIs based on the level of EGFR expression in their tumors or SCC histology should be considered.
A Cox-2 Promoter-Based Replication-Selective Adenoviral Vector to Target the Cox-2-Expressing Human Bladder Cancer Cells
Authors: Toshiro Shirakawa, Katsuyuki Hamada, Zhujun Zhang, Hiroshi Okada, Masatoshi Tagawa, Sadao Kamidono, Masato Kawabata, Akinobu Gotoh
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Cyclooxygenase-2 (Cox-2), an enzyme that catalyzes the synthesis of prostaglandins, is overexpressed in a variety of premalignant and malignant conditions, including urinary bladder cancer. In the present study, we examined the feasibility of using Cox-2 promoter-based replication-selective adenovirus for targeting bladder cancer cells that express Cox-2 transcriptional activity. Experimental Design: A series of human cancer cell lines, including three bladder cancer cell lines (KK47, T24, and 5637), were evaluated for their Cox-2 and CAR (the Coxsackievirus and adenovirus receptor) mRNA expression levels by quantitative real-time PCR. AdE3-cox2–327, a replication-selective adenovirus in which the expression of E1a is controlled by the Cox-2 promoter, was generated, and its tissue-specific activity was tested in vitro and in vivo. Results: Three bladder cancer cell lines express higher levels of Cox-2 mRNA than does the human prostate cancer cell line PC3, the primary cultured human benign prostatic fibroblast, PF cells, and the human colon cancer cell line Colo320. Relatively higher expression of CAR mRNA was detected in the KK47, 5637, respectively, and Colo320 than in the T24, PC-3, and PF cells. In vitro assays revealed significant growth suppression of both Cox-2- and CAR-expressing bladder cancer cells KK47 and 5637 in comparison with the other cells that lack Cox-2 expression and/or CAR expression. Conclusions: The present study demonstrated both specificity and efficacy of AdE3-cox2–327, a selectively replicated adenovirus, toward the Cox-2-expressing bladder cancer cells in vitro and in vivo. We also found that CAR expression in the target cancer cells is an important factor for the efficacy of selectively replicated adenovirus-based gene therapy.
BRIEF STIMULUS THERAPY
Authors: W. T. LIBERSON
Journal: American Journal of Psychiatry (1948)

1. Brief stimulus therapy was administered to 80 patients, 46 of whom had no other type of shock. In the latter group, patients with affective disorders were recovered in about 80% of cases; the remaining patients were all improved. In 20 schizophrenic patients, 45% of remissions were procured (with only a brief follow-up) and 2 patients were not improved. Both unimproved patients showed predominant hebephrenic features. 2. The assets of BST are the avoidance of memory disorders and of pronounced EEG changes; shorter postconvulsive recovery; facilitation of psychotherapy; and lower incidence of vertebral compressions. 3. The pitfalls of BST are all associated with an increased fear of treatments in some patients. This fear seems to be related to "unobliterated" minor reactions and an occurrence of "dissociated shocks." Different procedures are suggested to decrease such fear. 4. Physiological mechanisms underlying BST, its assets and its pitfalls, are reviewed, particularly the physiological meaning of "dissociated shock." Further possibilities of the refinement of BST on the basis of physiological analysis of excitabilities involved are suggested.
Use of CA-125 to Assess Response to New Agents in Ovarian Cancer Trials
Authors: G. J.S. Rustin
Journal: Journal of Clinical Oncology (2003)

The purpose of this article is to demonstrate how CA-125 could be used in clinical trials to ascertain the efficacy of new drugs for ovarian cancer. Studies that have investigated the use of CA-125 in assessing response and progression of ovarian cancer are reviewed. A precise CA-125 response definition that requires either a 50% or 75% decrease in CA-125 levels has been shown in trials of both initial chemotherapy and in phase II trials to predict accurately the response in comparison with standard response criteria. A simpler response definition that is based on just a 50% decrease in CA-125 levels has been proposed by the Gynaecological Cancer Intergroup (GCIG) but requires further validation. Definitions for progression have also been proposed by the GCIG on the basis of a confirmed doubling of CA-125 levels from either the upper limit of normal or the nadir CA-125 level. These CA-125 definitions for progression falsely predict progression in fewer than 2% of patients and can be used to define the date of progression. Precise definitions for response and progression according to CA-125 should be incorporated into ovarian cancer clinical trial protocols. These definitions already have been shown to be valuable in assessing efficacy of new agents but require further prospective evaluation.
INCREASED ALDOSTERONE SECRETION IN DOGS WITH RIGHT-SIDED CONGESTIVE HEART FAILURE AND IN DOGS WITH THORACIC INFERIOR VENA CAVA CONSTRICTION
Authors: James O. Davis, Maurice M. Pechet, Wilmot C. Ball, M. Jay Goodkind, Alfred Casper
Journal: Journal of Clinical Investigation (1957)

Studies (1-5) of patients with congestive heart failure, decompensated hepatic cirrhosis and nephrosis have provided evidence of increased amounts of aldosterone or aldosterone-like substances in urine during edema or ascites formation. More recently, it has been demonstrated (6) that increased urinary excretion of aldosterone occurs in association with sodium retention in dogs with right heart failure and in dogs with ascites secondary to constriction of the thoracic inferior vena cava. The data in both man and dog imply that the blood level of aldosterone is elevated. Numerous attempts have been made to elucidate the mechanism regulating aldosterone secretion in clinical states associated with the formation of edema, but no data have been reported to show that increased circulating aldosterone results from increased secretion rather than from a decreased rate of inactivation. The purpose of this study was to determine the relative rates of secretion of aldosterone in 1) dogs with cardiac failure produced by stenosis of the pulmonary artery, 2) dogs with thoracic inferior vena cava constriction and ascites, and 3) normal dogs.
Cytomegalovirus Contributes to Glioblastoma in the Context of Tumor Suppressor Mutations
Authors: Richard L. Price, Jieun Song, Katherine Bingmer, Tae Hyong Kim, Ji-Yeun Yi, Michal O. Nowicki, Xiaokui Mo, Todd Hollon, Eric Murnan, Christopher Alvarez-Breckenridge, Soledad Fernandez, Balveen Kaur, Andreana Rivera, Michael Oglesbee, Charles Cook, E. Antonio Chiocca, Chang-Hyuk Kwon
Journal: Cancer Research (2013)

Abstract To study the controversial role of cytomegalovirus (CMV) in glioblastoma, we assessed the effects of murine CMV (MCMV) perinatal infection in a GFAP-cre; Nf1loxP/+; Trp53−/+ genetic mouse model of glioma (Mut3 mice). Early on after infection, MCMV antigen was predominantly localized in CD45+ lymphocytes in the brain with active viral replication and local areas of inflammation, but, by 7 weeks, there was a generalized loss of MCMV in brain, confirmed by bioluminescent imaging. MCMV-infected Mut3 mice exhibited a shorter survival time from their gliomas than control Mut3 mice perinatally infected with mock or with a different neurotropic virus. Animal survival was also significantly shortened when orthotopic gliomas were implanted in mice perinatally infected with MCMV versus controls. MCMV infection increased phosphorylated STAT3 (p-STAT3) levels in neural stem cells (NSC) harvested from Mut3 mice subventricular zone, and, in vivo, there was increased p-STAT3 in NSCs in MCMV-infected compared with control mice. Of relevance, human CMV (HCMV) also increased p-STAT3 and proliferation of patient-derived glioblastoma neurospheres, whereas a STAT3 inhibitor reversed this effect in vitro and in vivo. These findings thus associate CMV infection to a STAT3-dependent modulatory role in glioma formation/progression in the context of tumor suppressor mutations in mice and possibly in humans. Cancer Res; 73(11); 3441–50. ©2013 AACR.
Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells
Authors: Junfang Ji, Taro Yamashita, Anuradha Budhu, Marshonna Forgues, Hu‐Liang Jia, Cuiling Li, Chuxia Deng, Elaine Wauthier, Lola M. Reid, Qing‐Hai Ye, Lun‐Xiu Qin, Wen Yang, Hong‐Yang Wang, Zhao‐You Tang, Carlo M. Croce, Xin Wei Wang
Journal: Hepatology (2009)

MicroRNAs (miRNAs) are endogenous small noncoding RNAs that regulate gene expression with functional links to tumorigenesis. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and it is heterogeneous in clinical outcomes and biological activities. Recently, we have identified a subset of highly invasive epithelial cell adhesion molecule (EpCAM)+ HCC cells from alpha-fetoprotein (AFP)+ tumors with cancer stem/progenitor cell features, that is, the abilities to self-renew, differentiate, and initiate aggressive tumors in vivo. Here, using a global microarray-based miRNA profiling approach followed by validation with quantitative reverse transcription polymerase chain reaction, we have demonstrated that conserved miR-181 family members were up-regulated in EpCAM+AFP+ HCCs and in EpCAM+ HCC cells isolated from AFP+ tumors. Moreover, miR-181 family members were highly expressed in embryonic livers and in isolated hepatic stem cells. Importantly, inhibition of miR-181 led to a reduction in EpCAM+ HCC cell quantity and tumor initiating ability, whereas exogenous miR-181 expression in HCC cells resulted in an enrichment of EpCAM+ HCC cells. We have found that miR-181 could directly target hepatic transcriptional regulators of differentiation (for example, caudal type homeobox transcription factor 2 [CDX2] and GATA binding protein 6 [GATA6]) and an inhibitor of Wnt/β-catenin signaling (nemo-like kinase [NLK]). Taken together, our results define a novel regulatory link between miR-181s and human EpCAM+ liver cancer stem/progenitor cells and imply that molecular targeting of miR-181 may eradicate HCC. (HEPATOLOGY 2009.)
Large increase of Langerhans cells in human skin lymph derived from irritant contact dermatitis
Authors: C.U. BRAND, T. HUNZIKER, A. LIMAT, L.R. BRAATHEN
Journal: British Journal of Dermatology (1993)

Journal Article Large increase of Langerhans cells in human skin lymph derived from irritant contact dermatitis Get access C.U. BRAND, C.U. BRAND Dermatological Clink; University of Berne. Switzerland Dr Ch.U.Brand, Dermatological Clinic, Inselspital, 3010 Berne, Switzerland. Search for other works by this author on: Oxford Academic Google Scholar T. HUNZIKER, T. HUNZIKER Dermatological Clink; University of Berne. Switzerland Search for other works by this author on: Oxford Academic Google Scholar A. LIMAT, A. LIMAT Dermatological Clink; University of Berne. Switzerland Search for other works by this author on: Oxford Academic Google Scholar L.R. BRAATHEN L.R. BRAATHEN Dermatological Clink; University of Berne. Switzerland Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 128, Issue 2, 1 February 1993, Pages 184–188, https://doi.org/10.1111/j.1365-2133.1993.tb15149.x Published: 01 February 1993 Article history Accepted: 19 August 1992 Published: 01 February 1993