gebhart/patrepeval huggingface dataset:
Correlation between c-erbB-2 amplification and risk of recurrent disease in node-negative breast cancer. (1991)

Drawing upon the comprehensive population-based Northern Alberta Breast Cancer Registry containing 704 patients with histologically negative axillary lymph nodes who have been followed for 5-16 years, we have undertaken a retrospective case-control study to evaluate the utility of genomic amplification of specific protooncogenes [c-erbB-2 (nee HER-2/neu), c-erbA, c-myc, int-2, and hst-1] as predictive indicators of clinical outcome in node-negative disease. To this end, 115 women with node-negative breast cancer who had recurred at any time up to 16 years posttreatment (cases) were matched pairwise for appropriate clinicopathological variables (size of primary tumor, menopausal state, estrogen receptor status, anniversary year of treatment, and patient age) with a second group of 115 women (controls) selected from a cohort of 502 node-negative patients who had not relapsed during long-term follow-up. Tumor DNA extracted from archival formalin-fixed, paraffin-embedded tissue blocks were analyzed for protooncogene copy number by slot-blot hybridization. Taking a gene copy number of 3 as the cutoff, 27 of the 230 tumor samples examined contained from 3- to 22-fold elevation in c-erbB-2 genomic equivalents. Twenty-one of the 27 tumors amplified for c-erbB-2 were derived from cases and 6 from controls, signifying that 18% of the node-negative patients who had relapsed harbored excessive copies of the protooncogene in their malignant tissue compared to only 5% for the patients who had remained in remission. Accordingly, the occurrence of amplification of c-erbB-2 proved to be a statistically significant predictor of poor prognosis, especially disease-free interval (P = 0.006). Moreover, this genetic alteration appeared to be independent of and to have greater predictive power than most commonly used prognostic factors. Our findings also indicated that as a clinical test, measurement of c-erbB-2 amplification suffers from low sensitivity; however, when greater than 6 gene copies are present, the test has a positive predictive value for recurrence of 70%. Concurrent analysis of tumor DNA blots with probes for the other four protooncogenes examined revealed that their amplification, which others have reported to arise often, especially in node-positive disease, was seldom found even in our high-risk case group (2-3%). In short, our data strongly suggest that amplification of c-erbB-2 may contribute to the pathogenesis of some forms of node-negative breast cancer and thus may serve as a useful genetic marker to identify a subset of high-risk patients.
Low-Dose Naltrexone Therapy Improves Active Crohn's Disease (2007)

LDN therapy appears effective and safe in subjects with active Crohn's disease. Further studies are needed to explore the use of this compound.
Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. (1997)

Signal transducers and activators of transcription (STATs) were originally identified as key components of signaling pathways involved in mediating responses to IFNs. Previous studies showed that the Src oncoprotein constitutively activates one STAT family member, Stat3. In this study, we investigated STAT activation in a panel of rodent fibroblast cell lines stably transformed by diverse viral oncoproteins. Using a temperature-sensitive mutant of v-Src, we determined that Stat3 is activated within 15 min of shift from nonpermissive to permissive temperature for cell transformation. This finding indicates that v-Src tyrosine kinase activity is required for Stat3 activation and suggests that Stat3 is proximal to signaling initiated by Src. In addition, Stat3 activation is induced by another nonreceptor tyrosine kinase, v-Fps; by polyoma virus middle T antigen, which activates Src family kinases; and by v-Sis, which acts as a ligand for the platelet-derived growth factor receptor. In contrast SV40 large T antigen, which transforms cells through different mechanisms, and the v-Ras and v-Raf oncoproteins, which lie in signaling pathways downstream of tyrosine kinases, do not activate Stat3. We did not detect significant activation of Stat1, Stat5, or Stat6 in fibroblasts transformed by the viral oncoproteins investigated. Moreover, Stat3 is activated in response to epidermal growth factor (EGF) but not heregulins in immortalized normal human breast epithelial cells. Because constitutive activation of c-Src and EGF receptor kinases is associated with the progression of breast cancer, we examined activation of STATs in human cell lines derived from breast carcinomas. We detected constitutive activation of Stat3 in five of nine breast carcinoma cell lines but not in normal breast epithelial cells. Furthermore, experiments with an EGF receptor-specific inhibitor indicated that the constitutive activation of Stat3 in these breast carcinoma cell lines is not necessarily dependent on signaling through the EGF receptor, although EGF stimulation further increases Stat3 activation. Taken together, our results demonstrate that selective activation of Stat3 is a common event during oncogenic transformation that directly or indirectly involves activation of specific tyrosine kinase signaling pathways.
Microdomain Morphology of Thin ABC Triblock Copolymer Films (1999)

We combine scanning force microscopy experiments with ex-situ swelling in different solvent vapors to investigate the microdomain structure of a thin ABC triblock copolymer film (poly(styrene-b-2-vinylpyridine-b-tert-butyl methacrylate)). We demonstrate that short treatment in a selective vapor and subsequent drying lead to characteristic changes in the surface morphology. The use of different solvents then allows to unambiguously identify the different phases present at the surface. This approach is established studying polymer blend and diblock copolymer thin films of known morphology. It is then applied to the a priori unknown morphology of the ABC triblock copolymer thin film. The results indicate a laterally microphase-separated polymer surface in agreement with recent theoretical considerations. The conclusions are corroborated by XPS measurements monitoring the average surface composition of the copolymer films.
Managing advanced multiple sclerosis. (1993)

Multiple sclerosis is one of the most common neurologic conditions in Canada. Many individuals with MS eventually develop the progressive form of the disease. The neurologic and psychosocial manifestations of the later stages of MS are numerous. Family physicians ought to have some understanding of patients with advanced MS and some knowledge of how to manage them.
Isolation and characterization of a cDNA coding for human factor IX. (1982)

A cDNA library prepared from human liver has been screened for factor IX (Christmas factor), a clotting factor that participates in the middle phase of blood coagulation. The library was screened with a single-stranded DNA prepared from enriched mRNA for baboon factor IX and a synthetic oligonucleotide mixture. A plasmid was identified that contained a cDNA insert of 1,466 base pairs coding for human factor IX. The insert is flanked by G-C tails of 11 and 18 base pairs at the 5' and 3' ends, respectively. It also included 138 base pairs that code for an amino-terminal leader sequence, 1,248 base pairs that code for the mature protein, a stop codon, and 48 base pairs of noncoding sequence at the 3' end. The leader sequence contains 46 amino acid residues, and it is proposed that this sequence includes both a signal sequence and a pro sequence for the mature protein that circulates in plasma. The 1,248 base pairs code for a polypeptide chain composed of 416 amino acids. The amino-terminal region for this protein contains 12 glutamic acid residues that are converted to gamma-carboxyglutamic acid in the mature protein. These glutamic acid residues are coded for by both GAA and GAG. The arginyl peptide bonds that are cleaved in the conversion of human factor IX to factor IXa by factor XIa were identified as Arg145-Ala146 and Arg180-Val181. The cleavage of these two internal peptide bonds results in the formation of an activation peptide (35 amino acids) and factor IXa, a serine protease composed of a light chain (145 amino acids) and a heavy chain (236 amino acids), and these two chains are held together by a disulfide bond(s). The active site residues including histidine, aspartate, and serine are located in the heavy chain at positions 221, 270, and 366, respectively. These amino acids are homologous with His57, Asp102, and Ser195 in the active site of chymotrypsin. Two potential carbohydrate binding sites (Asn-X-Thr) were identified in the activation peptide, and these were located at Asn157 and Asn167. The homology in the amino acid sequence between human and bovine factor IX was found to be 83%.
Blind Separation of Independent Sources Using Gaussian Mixture Model (2007)

In this paper, two novel algorithms for blind separation of noiseless instantaneous linear mixture of independent sources are presented. The proposed algorithms exploit nonGaussianity of the independent sources by modeling their distribution using the Gaussian mixture model (GMM). The first proposed method is based on the maximum-likelihood (ML) estimator. According to this method, the sensors distribution parameters are estimated via the expectation-maximization (EM) algorithm for GMM parameter estimation and the separation matrix is estimated by applying nonorthogonal joint diagonalization of the estimated GMM covariance matrices. The second proposed method is also a ML-based approach. According to this method, the distribution parameters of the prewhitened sensors are estimated via the EM algorithm for GMM parameter estimation and a unitary separation matrix is estimated by applying orthogonal joint diagonalization of the estimated GMM covariance matrices. It is shown that estimation of the sensors distribution parameters amounts to obtaining a tight lower bound on the log-likelihood of the separation matrix, and that the joint diagonalization of the estimated GMM covariance matrices amounts to maximization of the obtained tight lower bound. Simulations demonstrate that the proposed methods outperform state-of-the-art blind source separation techniques in terms of interference-to-signal ratio.
The LAZ3(BCL-6) oncoprotein recruits a SMRT/mSIN3A/histone deacetylase containing complex to mediate transcriptional repression (1998)

Recent works demonstrated that some transcriptional repressors recruit histone deacetylases (HDACs) either through direct interaction, or as a member of a multisubunit repressing complex containing other components referred to as corepressors. For instance, the bHLH-Zip transcriptional repressors MAD/MXI recruit HDACs together with the mSIN3 corepressors, whereas unliganded nuclear receptors contact another corepressor, SMRT (or its relative N-CoR), which, in turn, associates with both mSIN3 and HDACs to form the repressor complex. Recently, we reported that SMRT also directly associates with LAZ3(BCL-6), a POZ/Zn finger transcriptional repressor involvedin the pathogenesis of non-Hodgkin lymphomas. However, whether LAZ3 recruits the HDACs-containing repression complex is currently unknown. We report here that LAZ3 associates with corepressor mSIN3A both in vivo and in vitro , and found that a central region, which harbours autonomous repression activity, is mainly responsible for this interaction. Conversely, the N-terminal half of mSIN3A is both necessary and sufficient to bind LAZ3. Moreover, we show that LAZ3 also interacts with an HDAC (HDAC-1) through its POZ domain in vitro while the immunoprecipitation of LAZ3 results in the coretention of an endogenous HDAC activity in vivo . Finally, inhibitors of HDACs significantly reduce the LAZ3-mediated repression. Taken together, we conclude that LAZ3 recruits a repressing complex containing SMRT, mSIN3A and a HDAC, and that its full repressing potential on transcription requires HDACs activity. Our results identify HDACs as molecular targets of LAZ3 oncogene and further strengthen the connection between aberrant chromatin acetylation and human cancers.
Effects of Oxidation Curing and Sintering Additives on the Formation of Polymer‐Derived Near‐Stoichiometric Silicon Carbide Fibers (2008)

The effects of oxygen pick‐up and sintering additives on the formation of silicon carbide (SiC) fibers from polyaluminocarbosilane are studied. It has been found that the strict control of oxygen pick up during the oxidation curing is essential to produce near‐stoichiometric SiC fibers. When the molar ratio of oxygen to excess carbon in the pyrolyzed fibers (SiC x O y ) is slightly over 1 (O/C Excess = y /( x −1)&gt;1), the excess carbon is eliminated during the subsequent sintering as CO and CO 2 as a result of the decomposition of SiC x O y ; the remaining oxygen is removed as SiO and CO vapor, leaving near‐stoichiometric SiC as the residue. However, with still increasing oxygen pick up, the final ceramic fibers become more porous and rich in silicon. The evolution of CO, CO 2 , and SiO generates high porosity in the absence of a sintering additive, leading to low fiber density. The inter‐connected and open porosity favors the formation of CO. In contrast, for the fibers containing aluminum (Al) or Al/B sintering additives, the pores are much smaller and essentially closed, favoring the formation of CO 2 . Therefore, after sintering at 1800°C, the fibers without sintering additives contain excess silicon, while those with sintering additives are near stoichiometric. Al is beneficial to the densification but it alone cannot produce fibers of high density. When B is added in addition to Al, the fibers can be sintered to nearly full density.
Towards defining the urinary proteome using liquid chromatography-tandem mass spectrometry II.Limitations of complex mixture analyses (2001)

With an emphasis on obtaining a multitude of high quality tandem mass spectrometry spectra for protein identification, instrumental parameters are described for the liquid chromatography-tandem mass spectrometry analysis of trypsin digested unfractionated urine using a hybrid quadrupole-time-of-flight (Q-TOF) mass spectrometer. Precursor acquisition rates of up to 20 distinct precursors/minute in a single analysis were obtained through the use of parallel precursor selection (four precursors/survey period) and variable collision induced dissociation integration time (1 to 6 periods summed). Maximal exploitation of the gas phase fractionated ions was obtained through the use of narrow survey scans and iterative data-dependent analyses incorporating dynamic exclusion. The impact on data fidelity as a product of data-dependent selection of precursor ions from a dynamically excluded field is discussed with regards to sample complexity, precursor selection rates, survey scan range and facile chemical modifications. Operational and post-analysis strategies are presented to restore data confidence and reconcile the greatest number of matched spectra.
Role of Regulatory Elements and the MAPK/ERK or p38 MAPK Pathways for Activation of Human Cytomegalovirus Gene Expression (2002)

A series of recombinant viruses with either site-specific mutations or various deletions of the early UL4 promoter of human cytomegalovirus were used to determine the roles of regulatory elements and the effects of the mitogen-activated protein kinase (MAPK) pathways. Viral gene expression was regulated by upstream cis-acting sites and by basic promoter elements that respond to the MAPK signal transduction pathways. Inhibitors of either the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway or the p38 MAPK pathway affected expression equally with either wild-type or mutant early UL4 promoters in the viral genome, indicating that the effects of the inhibitors are not exclusive for a single transcription factor. The minimal responsive element is the TATA box-containing early viral promoter.
Neural coding using telegraphic switching of magnetic tunnel junction (2015)

In this work, we present a synaptic transmission representing neural coding with spike trains by using a magnetic tunnel junction (MTJ). Telegraphic switching generates an artificial neural signal with both the applied magnetic field and the spin-transfer torque that act as conflicting inputs for modulating the number of spikes in spike trains. The spiking probability is observed to be weighted with modulation between 27.6% and 99.8% by varying the amplitude of the voltage input or the external magnetic field. With a combination of the reverse coding scheme and the synaptic characteristic of MTJ, an artificial function for the synaptic transmission is achieved.
Contact with cultured epithelial cells stimulates secretion of Salmonella typhimurium invasion protein InvJ (1995)

Contact of Salmonella typhimurium with cultured epithelial cells results in the assembly of surface appendages termed invasomes which are presumably required for the internalization of these organisms into host cells. The assembly of these structures requires the function of a dedicated protein secretion system encoded in the inv locus. We show in this report that contact of wild-type S. typhimurium with cultured Henle-407 cells stimulated the secretion of InvJ, a recently identified target of the inv-encoded type III protein secretion system. Stimulation of InvJ secretion also occurred upon bacterial contact with bovine calf serum-coated culture dishes but did not occur upon S. typhimurium contact with glutaraldehyde-fixed Henle-407 cells. The stimulation of InvJ secretion did not require de novo protein synthesis. Invasion-defective invC and invG mutants of S. typhimurium failed to secrete InvJ upon contact with live Henle-407 cells. In contrast, contact-dependent secretion of InvJ in S. typhimurium invE mutants occurred at levels equivalent to those of the wild type. These results indicate that the presence of Henle-407 cells and/or serum is capable of activating the type III secretion system encoded in the inv locus, further supporting the notion that Salmonella entry into cultured cells is the result of a biochemical cross-talk between the bacteria and the host cells.
Phthalazinone Pyrazoles as Potent, Selective, and Orally Bioavailable Inhibitors of Aurora-A Kinase (2010)

The inhibition of Aurora kinases in order to arrest mitosis and subsequently inhibit tumor growth via apoptosis of proliferating cells has generated significant discussion within the literature. We report a novel class of Aurora kinase inhibitors based upon a phthalazinone pyrazole scaffold. The development of the phthalazinone template resulted in a potent Aurora-A selective series of compounds (typically >1000-fold selectivity over Aurora-B) that display good pharmacological profiles with significantly improved oral bioavailability compared to the well studied Aurora inhibitor VX-680.
The Combined Effects of Tryptophan Starvation and Tryptophan Catabolites Down-Regulate T Cell Receptor ζ-Chain and Induce a Regulatory Phenotype in Naive T Cells (2006)

Tryptophan catabolism is a tolerogenic effector system in regulatory T cell function, yet the general mechanisms whereby tryptophan catabolism affects T cell responses remain unclear. We provide evidence that the short-term, combined effects of tryptophan deprivation and tryptophan catabolites result in GCN2 kinase-dependent down-regulation of the TCR zeta-chain in murine CD8+ T cells. TCR zeta down-regulation can be demonstrated in vivo and is associated with an impaired cytotoxic effector function in vitro. The longer-term effects of tryptophan catabolism include the emergence of a regulatory phenotype in naive CD4+CD25- T cells via TGF-beta induction of the forkhead transcription factor Foxp3. Such converted cells appear to be CD25+, CD69-, CD45RBlow, CD62L+, CTLA-4+, BTLAlow and GITR+, and are capable of effective control of diabetogenic T cells when transferred in vivo. Thus, both tryptophan starvation and tryptophan catabolites contribute to establishing a regulatory environment affecting CD8+ as well as CD4+ T cell function, and not only is tryptophan catabolism an effector mechanism of tolerance, but it also results in GCN2-dependent generation of autoimmune-preventive regulatory T cells.
Asp304 of Escherichia coli acid phosphatase is involved in leaving group protonation. (1993)

Site-directed mutagenesis was used to explore the role of potential proton donors in the mechanism of the Escherichia coli acid phosphatase that is encoded by the appA gene. Asp304 appeared to be the only carboxylic acid residue that is conserved in the protein sequences of the high molecular weight acid phosphatases. The mutations Asp304Ala and Asp304Glu were introduced into appA and the corresponding proteins were overexpressed in E. coli and purified to homogeneity. Only small decreases were observed for the Km values of the substrates p-nitrophenyl phosphate, fructose 1,6-diphosphate, and tripolyphosphate. However, Vmax was greatly decreased, and the magnitude of effect depended markedly on substrate. Both mutant proteins exhibited significantly lower Vmax values with fructose 1,6-diphosphate, which possesses a much poorer leaving group than do the other two substrates. The importance of the leaving group was further tested by using a number of phenyl and alkyl phosphate derivatives as substrates. A linear correlation was observed between log Vmax and the pKa of the substrate leaving group for catalysis by the Asp304Ala mutant enzyme. These results are consistent with partition experiments using ethylene glycol as an alternate nucleophile, which indicated that for the Asp304Ala protein, the formation of a phosphoenzyme intermediate is the rate-determining step, in contrast to the situation for the wild type enzyme and the His303Ala mutant. In the latter case, the rate-limiting step of the reaction is interpreted to be the breakdown of phosphoenzyme. It is concluded that Asp304, rather than His303, is involved in protonation of the substrate leaving group.
Comparative Analysis of USA300 Virulence Determinants in a Rabbit Model of Skin and Soft Tissue Infection (2011)

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections are frequently associated with strains harboring genes encoding Panton-Valentine leukocidin (PVL). The role of PVL in the success of the epidemic CA-MRSA strain USA300 remains unknown. Here we developed a skin and soft tissue infection model in rabbits to test the hypothesis that PVL contributes to USA300 pathogenesis and compare it with well-established virulence determinants: alpha-hemolysin (Hla), phenol-soluble modulin-alpha peptides (PSMα), and accessory gene regulator (Agr). The data indicate that Hla, PSMα, and Agr contribute to the pathogenesis of USA300 skin infections in rabbits, whereas a role for PVL could not be detected.