gebhart/patrepeval huggingface dataset:
T47DCO cells, genetically unstable and containing estrogen receptor mutations, are a model for the progression of breast cancers to hormone resistance. (1990)

We postulate that one mechanism for the progression of breast cancers to hormone resistance involves the acquisition of mutant estrogen receptors (ER)4 by genetically unstable cell subpopulations. The T47D human breast cancer cell line may be a model for such progression, having sublines that are ER positive and estrogen responsive, ER positive and estrogen resistant, or ER negative. Also, T47D cells can be either hyperdiploid (HD) or hypertetraploid (HT) or persistently alternate between these states. T47DCO cells are a HD and ER-positive, but estrogen-resistant, subline of T47D cells that undergoes spontaneous tetraploidization. Such a stable variant, designated T47Dv, is 85% HT (Cancer Res., 49: 3943, 1989). We now show that single-cell clones derived from the mixed HD/HT T47Dv can be either HD or HT, and can be either estrogen responsive or estrogen resistant, for growth and for progesterone receptor regulation. To begin the study of ER in this model system of T47DCO and their derivatives, we have generated complementary DNA libraries from the parental HD T47DCO cells and have isolated three ER complementary DNA mutants. These include two frame-shift/termination mutants that would encode ERs truncated in the DNA-binding domain and in the hormone-binding domain and a third mutant with a large in-frame deletion spanning the hinge region and a part of the hormone-binding domain. If expressed, these mutant ERs would lack hormone-binding capacity and would be undetected by the anti-ER antibodies currently in clinical use. Genetic instability, when associated with mutant ERs in subpopulations of breast tumor cells, may provide the selective pressure leading to hormone resistance. T47DCO cells and their clonal derivatives provide a model for the systematic study of ER mutations and other mechanisms of hormone resistance in Stage IV breast cancer.
Clinical significance of epidermal growth factor (EGF), EGF receptor, and c-erbb-2 in human gastric cancer (1995)

The EGF stimulation system for growth regulation is implicated in normal and neoplastic cell proliferation. The role of EGF, the EGF receptor, and c-erbB-2 in human gastric cancer is reviewed on the basis of several reports, which have been mainly oriented toward their clinical significance. EGF has been shown immunohistochemically to be present in 26% of gastric cancers (n = 395). The presence of EGF in gastric cancer is correlated with the degree of gastric wall invasion and lymph node metastasis. The 5-year survival of patients with EGF-positive tumors is worse than that of patients with EGF-negative tumors. The presence of EGF in human gastric cancer may therefore represent a higher malignant potential. Fifteen percent of gastric cancers (n = 352) were also shown to be positive for both EGF and the EGF receptor immunohistochemically, and the simultaneous occurrence of EGF and the EGF receptor suggests that these tumors grow in an autocrine fashion. Tumors exhibiting EGF and the EGF receptor simultaneously show a greater degree of local invasion and lymph node metastasis. Increased expression of EGF receptor protein in gastric cancer appears to be related to biologic aggressiveness, although gene amplification has occurred only to a small extent. Twelve percent of gastric cancers (n = 486) were found to be positive for c-erbB-2. This type of tumor has a frequent metastasis, and patients with c-erbB-2-positive cancer have a poorer prognosis than those with c-erbB-2-negative tumors. Selective blockade of the EGF receptor and c-erbB-2 from their ligands with monoclonal antibodies (MoAbs) inhibits the growth of human gastric cancer xenografts. These MoAbs may therefore be effective antitumor agents against gastric cancer showing overexpression of EGF receptors or c-erbB-2.
Bruton's Tyrosine Kinase Is a Toll/Interleukin-1 Receptor Domain-binding Protein That Participates in Nuclear Factor κB Activation by Toll-like Receptor 4 (2003)

In this study we have identified members of the Toll-like receptor (TLR) family (namely, TLRs 4, 6, 8, and 9) as proteins to which the intracellular protein tyrosine kinase, Bruton's tyrosine kinase (Btk), binds. Detailed analysis of the interaction between Btk and TLR8 demonstrates that the presence of both Box 2 and 3 motifs in the Toll/interleukin-1 receptor domain was required for the interaction. Furthermore, co-immunoprecipitation experiments revealed that Btk can also interact with key proteins involved in TLR4 signal transduction, namely, MyD88, Mal (MyD88 adapter-like protein), and interleukin-1 receptor-associated kinase-1, but not TRAF-6. The ability of Btk to interact with TLR4 and Mal suggests a role for Btk in lipopolysaccharide (LPS) signal transduction. Stimulation of the human monocytic cell line THP-1 with LPS resulted in an increase in the level of tyrosine phosphorylation of Btk (indicative of activation). The autokinase activity of Btk was also stimulated after LPS stimulation. In addition, a dominant negative form of Btk inhibited TLR4-mediated activation of a nuclear factor kappaB (NFkappaB)-dependent reporter gene in HEK293 cells as well as LPS-induced activation of NFkappaB in the astrocytoma cell line U373 and the monocytic cell line RAW264.7. Further investigation revealed that the Btk-specific inhibitor, LFM-A13, inhibited the activation of NFkappaB by LPS in THP-1 cells. Our findings implicate Btk as a Toll/interleukin-1 receptor domain-binding protein that is important for NFkappaB activation by TLR4.
Platelet-rich plasma accelerated surgical angio-genesis in vascular-implanted necrotic bone: An experimental study in rabbits (2008)

A single injection of PRP accelerates surgical angiogenesis in vascular-implanted necrotic bone.
A Randomized, Double-Blind, Crossover Comparative Endoscopy Study on the Gastroduodenal Tolerability of a Highly Specific Cyclooxygenase-2 Inhibitor, Flosulide, and Naproxen (1997)

These results endorse the idea that highly selective Cox-2 inhibitors may be associated with lesser gastrointestinal side effects than conventional NSAIDs.
Use of Hammerstein models in identification of nonlinear systems (1991)

Abstract The utility of the Hammerstein model, which is composed of a static nonlinear element in series with a linear dynamic part, was investigated to represent the dynamics of nonlinear chemical processes. Different methods to identify the parameters of Hammerstein models were tested. The methods were applied to the identification of simulated distillation columns and to an experimental heat exchanger process. The results show that the dynamics of such processes can be better represented by Hammerstein‐type models than by linear models.
Anti-IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma (1998)

The tight-skin (Tsk/+) mutant mouse, a putative murine model of scleroderma, is characterized primarily by the excessive deposition of collagen and other extracellular matrix molecules in the dermis, and also by a developmentally acquired defect in pulmonary architecture. Passive transfer experiments have suggested an etiologic role for the immune system in Tsk/+ dermal pathology. In addition, CD4+ T lymphocytes have been shown to be required for the excessive accumulation of dermal collagen in these mice. As IL-4, a product of differentiated CD4+ T cells, is capable of regulating the synthesis of various matrix molecules (including type I collagen) by fibroblasts in vitro, we investigated the potential role of IL-4 in mediating Tsk/+ dermal fibrosis. Confirming that Tsk/+ cells are capable of responding to IL-4, we found receptors for this cytokine on Tsk/+ embryonic fibroblasts and a dermal fibroblast cell line derived from these mice. Furthermore, IL-4 receptors on Tsk/+ fibroblasts were functional since IL-4 stimulation in vitro increased type I collagen secretion from these cells. These results demonstrated the potential for IL-4 to be directly involved in the excessive deposition of dermal collagen in Tsk/+ mice. Critical insight into the role played by IL-4 in mediating the dermal phenotype, however, was obtained following the administration of neutralizing anti-lL-4 antibodies to Tsk/+ mice. This treatment prevented the development of dermal fibrosis, leading to normalization of dermal collagen content. Given the requirement for CD4+ T cells in Tsk/+ dermal fibrosis, our results suggest that Th2 cells and/or factors elaborated by this T cell subset may play a key role in regulating dermal collagen content in this strain.
Synthesis of a radiotracer for studying serotonin uptake sites with positron emission tomography: [11C]McN‐5652‐Z (1992)

Abstract The highly potent serotonin (5‐HT) uptake blocker, McN‐5652‐Z ( trans ‐1,2,3,5,6,10b ‐ hexahydro ‐ 6 ‐ [4 ‐ (methylthio)phenyl] pyrrolo ‐ [2,1‐a]‐isoquinoline) was labeled with 11 C for studying serotonin uptake sites using positron emission tomography (PET). [ 11 C]McN‐5652‐Z was synthesized by S‐methylation of the normethyl precursor with [ 11 C]iodomethane in DMF at 30 ‐ 35° C. The radiosyntheses including purification by HPLC and formulation for injection were completed in an average of 16 minutes following the end of bombardment (E.O.B.) with an overall radiochemical yield of 12%. The average specific activity determined at the end of synthesis (E.O.S.) was approximately 4250 mCi/μmole; this corresponds to approximately 7350 mCi/μmole at E.O.B. [ 11 C]McN‐5655‐Z, a less potent blocker, was also prepared by the same procedure.
Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer's disease. (1996)

In Alzheimer's disease (AD), affected neurons accumulate beta amyloid protein, components of which can induce mouse microglia to express the high-output isoform of nitric oxide synthase (NOS2) in vitro. Products of NOS2 can be neurotoxic. In mice, NOS2 is normally suppressed by transforming growth factor beta 1 (TGF-beta 1). Expression of TGF-beta 1 is decreased in brains from AD patients, a situation that might be permissive for accumulation of NOS2. Accordingly, we investigated the expression of NOS2 in patients with AD, using three monospecific antibodies: a previously described polyclonal and two new monoclonal antibodies. Neurofibrillary tangle-bearing neurons and neuropil threads contained NOS2 in brains from each of 11 AD patients ranging in age from 47 to 81 years. NOS2 was undetectable in brains from 6 control subjects aged 23-72 years, but was expressed in small amounts in 3 control subjects aged 77-87 years. Thus, human neurons can express NOS2 in vivo. The high-output pathway of NO production may contribute to pathogenesis in AD.
The Use of Fingernails as a Means of Assessing Bone Health: A Pilot Study (2005)

Bone collagen and nail keratin are two distinct structural proteins, and both require protein sulfation and disulfide bond formation, via cysteine, for structural integrity. A disorder of either process may lead to disordered collagen and keratin synthesis. This is reflected in the structural abnormalities seen in clinical syndromes in which there is either protein deficiency, disorders of sulfur metabolism, or cystathione beta-synthase deficiency. The relationship between nail and bone may exist in a measurable way. This pilot study should lead to further work to explore this relationship. Could nail prove to be a valuable adjunct to diagnosis or provide a means of more rapid follow-up after commencement of therapy?
One millisecond face alignment with an ensemble of regression trees (2014)

This paper addresses the problem of Face Alignment for a single image. We show how an ensemble of regression trees can be used to estimate the face's landmark positions directly from a sparse subset of pixel intensities, achieving super-realtime performance with high quality predictions. We present a general framework based on gradient boosting for learning an ensemble of regression trees that optimizes the sum of square error loss and naturally handles missing or partially labelled data. We show how using appropriate priors exploiting the structure of image data helps with efficient feature selection. Different regularization strategies and its importance to combat overfitting are also investigated. In addition, we analyse the effect of the quantity of training data on the accuracy of the predictions and explore the effect of data augmentation using synthesized data.
Cloning and sequence of the cDNA corresponding to the variable region of immunoglobulin heavy chain MPC11 (1980)

Poly(A)-containing mRNA from mouse myeloma MPC11 was transcribed into cDNA which was cloned in the PstI site of the plasmid pBR322. The transformants were screened by hybridization with a cDNA fragment, derived from plasmid p gamma(11)7, corresponding to the 5' portion of the constant region of MPC11 heavy chain. Several positive transformants were found to contain various lengths of the variable region of the heavy chain. We describe the structure and sequence of one of these clones, pV(11)2, which contains cDNA corresponding to the entire variable region of MPC11 heavy chain and extends to codon 248 in the constant region. The protein sequence deduced from the DNA sequence indicates that the variable region of MPC11 heavy chain contains 121 amino acids and belongs to subgroup II of mouse heavy chains. Comparison of this sequence with other heavy chain sequences suggests a J (joining) segment of 16 residues which overlaps five residues of the third hypervariable region. The cDNA sequence shows that there is no discontinuity between the end of the variable region and the beginning of the constant region.
Next-Generation Systemic Acquired Resistance (2011)

Systemic acquired resistance (SAR) is a plant immune response to pathogen attack. Recent evidence suggests that plant immunity involves regulation by chromatin remodeling and DNA methylation. We investigated whether SAR can be inherited epigenetically following disease pressure by Pseudomonas syringae pv tomato DC3000 (PstDC3000). Compared to progeny from control-treated Arabidopsis (Arabidopsis thaliana; C(1)), progeny from PstDC3000-inoculated Arabidopsis (P(1)) were primed to activate salicylic acid (SA)-inducible defense genes and were more resistant to the (hemi)biotrophic pathogens Hyaloperonospora arabidopsidis and PstDC3000. This transgenerational SAR was sustained over one stress-free generation, indicating an epigenetic basis of the phenomenon. Furthermore, P(1) progeny displayed reduced responsiveness of jasmonic acid (JA)-inducible genes and enhanced susceptibility to the necrotrophic fungus Alternaria brassicicola. This shift in SA- and JA-dependent gene responsiveness was not associated with changes in corresponding hormone levels. Instead, chromatin immunoprecipitation analyses revealed that SA-inducible promoters of PATHOGENESIS-RELATED GENE1, WRKY6, and WRKY53 in P(1) plants are enriched with acetylated histone H3 at lysine 9, a chromatin mark associated with a permissive state of transcription. Conversely, the JA-inducible promoter of PLANT DEFENSIN1.2 showed increased H3 triple methylation at lysine 27, a mark related to repressed gene transcription. P(1) progeny from the defense regulatory mutant non expressor of PR1 (npr1)-1 failed to develop transgenerational defense phenotypes, demonstrating a critical role for NPR1 in expression of transgenerational SAR. Furthermore, the drm1drm2cmt3 mutant that is affected in non-CpG DNA methylation mimicked the transgenerational SAR phenotype. Since PstDC3000 induces DNA hypomethylation in Arabidopsis, our results suggest that transgenerational SAR is transmitted by hypomethylated genes that direct priming of SA-dependent defenses in the following generations.
Vesicle Permeabilization by Protofibrillar α-Synuclein Is Sensitive to Parkinson's Disease-Linked Mutations and Occurs by a Pore-like Mechanism (2002)

Two mutations in the protein alpha-synuclein (A30P and A53T) are linked to an autosomal dominant form of Parkinson's disease. Both mutations accelerate the formation of prefibrillar oligomers (protofibrils) in vitro, but the mechanism by which they promote toxicity is unknown. Protofibrils of wild-type alpha-synuclein bind and permeabilize acidic phospholipid vesicles. This study examines the relative membrane permeabilizing activities of the wild type, mutant, and mouse variants of protofibrillar alpha-synuclein and the mechanism of membrane permeabilization. Protofibrillar A30P, A53T, and mouse variants were each found to have greater permeabilizing activities per mole than the wild-type protein. The leakage of vesicular contents induced by protofibrillar alpha-synuclein exhibits a strong preference for low-molecular mass molecules, suggesting a pore-like mechanism for permeabilization. Under conditions in which the vesicular membrane is less stable (lack of calcium as a phospholipid counterion), protofibril permeabilization is less size-selective and monomeric alpha-synuclein can permeabilize via a detergent-like mechanism. We conclude that the pathogenesis of Parkinson's disease may involve membrane permeabilization by protofibrillar alpha-synuclein, the extent of which will be strongly dependent on the in vivo conditions.
Simple and Inexpensive Fluorescence-Based Technique for High-Throughput Antimalarial Drug Screening (2004)

Radioisotopic assays involve expense, multistep protocols, equipment, and radioactivity safety requirements which are problematic in high-throughput drug testing. This study reports an alternative, simple, robust, inexpensive, one-step fluorescence assay for use in antimalarial drug screening. Parasite growth is determined by using SYBR Green I, a dye with marked fluorescence enhancement upon contact with Plasmodium DNA. A side-by-side comparison of this fluorescence assay and a standard radioisotopic method was performed by testing known antimalarial agents against Plasmodium falciparum strain D6. Both assay methods were used to determine the effective concentration of drug that resulted in a 50% reduction in the observed counts (EC(50)) after 48 h of parasite growth in the presence of each drug. The EC(50)s of chloroquine, quinine, mefloquine, artemisinin, and 3,6-bis-epsilon-(N,N-diethylamino)-amyloxyxanthone were similar or identical by both techniques. The results obtained with this new fluorescence assay suggest that it may be an ideal method for high-throughput antimalarial drug screening.
Quantifying selection in immune receptor repertoires (2014)

The efficient recognition of pathogens by the adaptive immune system relies on the diversity of receptors displayed at the surface of immune cells. T-cell receptor diversity results from an initial random DNA editing process, called VDJ recombination, followed by functional selection of cells according to the interaction of their surface receptors with self and foreign antigenic peptides. Using high-throughput sequence data from the β-chain of human T-cell receptors, we infer factors that quantify the overall effect of selection on the elements of receptor sequence composition: the V and J gene choice and the length and amino acid composition of the variable region. We find a significant correlation between biases induced by VDJ recombination and our inferred selection factors together with a reduction of diversity during selection. Both effects suggest that natural selection acting on the recombination process has anticipated the selection pressures experienced during somatic evolution. The inferred selection factors differ little between donors or between naive and memory repertoires. The number of sequences shared between donors is well-predicted by our model, indicating a stochastic origin of such public sequences. Our approach is based on a probabilistic maximum likelihood method, which is necessary to disentangle the effects of selection from biases inherent in the recombination process.
Associations of Cadmium and Lead Exposure With Leukocyte Telomere Length: Findings From National Health and Nutrition Examination Survey, 1999–2002 (2014)

Cadmium and lead are ubiquitous environmental contaminants that might increase risks of cardiovascular disease and other aging-related diseases, but their relationships with leukocyte telomere length (LTL), a marker of cellular aging, are poorly understood. In experimental studies, they have been shown to induce telomere shortening, but no epidemiologic study to date has examined their associations with LTL in the general population. We examined associations of blood lead and cadmium (n = 6,796) and urine cadmium (n = 2,093) levels with LTL among a nationally representative sample of US adults from the National Health and Nutrition Examination Survey (1999-2002). The study population geometric mean concentrations were 1.67 µg/dL (95% confidence interval (CI): 1.63, 1.70) for blood lead, 0.44 µg/L (95% CI: 0.42, 0.47) for blood cadmium, and 0.28 µg/L (95% CI: 0.27, 0.30) for urine cadmium. After adjustment for potential confounders, the highest (versus lowest) quartiles of blood and urine cadmium were associated with -5.54% (95% CI: -8.70, -2.37) and -4.50% (95% CI: -8.79, -0.20) shorter LTLs, respectively, with evidence of dose-response relationship (P for trend < 0.05). There was no association between blood lead concentration and LTL. These findings provide further evidence of physiological impacts of cadmium at environmental levels and might provide insight into biological pathways underlying cadmium toxicity and chronic disease risks.
Design Of Statistically Optimal Morphological Operators (2000)

Publication in the conference proceedings of EUSIPCO, Tampere, Finland, 2000
Safety and immunogenicity of TA-HPV, a recombinant vaccinia virus expressing modified human papillomavirus (HPV)-16 and HPV-18 E6 and E7 genes, in women with progressive cervical cancer. (2002)

This study confirmed the safety and immunogenicity of the vaccine in a proportion of those patients vaccinated. Additional clinical studies using TA-HPV in combination with an additional experimental vaccine for HPV-16 are currently under way.
The Rapamycin-Binding Domain Governs Substrate Selectivity by the Mammalian Target of Rapamycin (2002)

The mammalian target of rapamycin (mTOR) is a Ser/Thr (S/T) protein kinase, which controls mRNA translation initiation by modulating phosphorylation of the translational regulators PHAS-I and p70(S6K). Here we show that in vitro mTOR is able to phosphorylate these two regulators at comparable rates. Both (S/T)P sites, such as Thr36, Thr45, and Thr69 in PHAS-I and the h(S/T)h site (where h is a hydrophobic amino acid) Thr389 in p70(S6K), were phosphorylated. Rapamycin-FKBP12 inhibited mTOR activity. Surprisingly, the extent of inhibition depended on the substrate. Moreover, mutating Ser2035 in the rapamycin-binding domain (FRB) not only decreased rapamycin sensitivity as expected but also dramatically affected the sites phosphorylated by mTOR. The results demonstrate that mutations in Ser2035 are not silent with respect to mTOR activity and implicate the FRB in substrate recognition. The findings also impose new limitations on interpreting results from experiments in which rapamycin and/or rapamycin-resistant forms of mTOR are used to investigate mTOR function in cells.