gebhart/patrepeval huggingface dataset:
Sulfated proteoglycan synthesis by confluent cultures of rabbit costal chondrocytes grown in the presence of fibroblast growth factor. (1985)

We examined the effect of fibroblast growth factor (FGF) on proteoglycan synthesis by rabbit costal chondrocyte cultures maintained on plastic tissue culture dishes. Low density rabbit costal chondrocyte cultures grown in the absence of FGF gave rise at confluency to a heterogeneous cell population composed of fibroblastic cells and poorly differentiated chondrocytes. When similar cultures were grown in the presence of FGF, the confluent cultures organized into a homogenous cartilage-like tissue composed of rounded cells surrounded by a refractile matrix. The cell ultrastructure and that of the pericellular matrix were similar to those seen in vivo. The expression of the cartilage phenotype in confluent chondrocyte cultures grown from the sparse stage in the presence vs. absence of FGF was reflected by a fivefold increase in the rate of incorporation of [35S]sulfate into proteoglycans. These FGF effects were only observed when FGF was present during the cell logarithmic growth phase, but not when it was added after chondrocyte cultures became confluent. High molecular weight, chondroitin sulfate proteoglycans synthesized by confluent chondrocyte cultures grown in the presence of FGF were slightly larger in size than that produced by confluent cultures grown in the absence of FGF. The major sulfated glycosaminoglycans associated with low molecular weight proteoglycan in FGF-exposed cultures were chondroitin sulfate, while in cultures not exposed to FGF they were chondroitin sulfate and dermatan sulfate. Regardless of whether or not cells were grown in the presence or absence of FGF, the 6S/4S disaccharide ratio of chondroitin sulfate chains associated with high and low molecular weight proteoglycans synthesized by confluent cultures was the same. These results provide evidence that when low density chondrocyte cultures maintained on plastic tissue culture dishes are grown in the presence of FGF, it results in a stimulation of the expression and stabilization of the chondrocyte phenotype once cultures become confluent.
Determination of the Complete Amino-Acid Sequence of Subtilisin DY and its Comparison with the Primary Structures of the Subtilisins BPN’, Carlsberg and Amylosacchariticus (1985)

The complete amino-acid sequence of subtilisin DY, an extracellular alkaline proteinase produced by Bacillus subtilis strain DY was determined. This included automated sequence analysis of the whole molecule and its large fragments such as tryptic peptides obtained from the inactivated enzyme, peptides generated by cyanogen bromide, by o-iodosobenzoic acid and by hydroxylamine. The peptides were isolated by gel filtration and by reversed-phase high performance liquid chromatography. The amino-acid sequence of subtilisin DY was determined by overlapping the isolated peptides. It consists of 274 amino-acid residues, like that of subtilisin Carlsberg. By comparison with the structures of the subtilisins Carlsberg, amylosacchariticus and BPN' 32, 80 and 82 amino-acid substitutions were found, which are caused by 37, 102 and 106 nucleotide mutations, respectively. It was found also that 62.5% of the amino-acid residues in the molecules of these four subtilisins are identical with respect to kind and position of the residue, which suggests that these molecules have had a common ancestral precursor. The amino-acid replacement analysis of the four subtilisins leads to the conclusion that they have evolved almost independently.
Contrast echocardiography for assessing left ventricular vortex strength in heart failure: a prospective cohort study (2013)

Our preliminary data suggest that the persistence of vortex from late diastole into IC is a haemodynamic measure of coupling between diastole and systole. The change in VS is correlated with LV mechanical performance and shows association with adverse clinical outcomes seen in HF patients.
Chronic Rapid Atrial Pacing to Maintain Atrial Fibrillation: Use to Permit Control of Ventricular Rate in Order to Treat Tachycardia Induced Cardiomyopathy (1989)

LR was a patient, followed over a 16-year period, who presented with an atrial tachycardia which was initially intermittent, but became incessant. Neither the atrial tachycardia nor the associated rapid ventricular response rate could be treated successfully with available drug therapy, resulting in a dilated cardiomyopathy and New York Heart Association (NYHA) class III-IV congestive heart failure. Acute induction of atrial fibrillation with rapid atrial pacing demonstrated that the associated ventricular rate could be satisfactorily slowed with digitalis therapy. Initially, short bursts from an implanted, radiofrequency controlled, patient activated pacemaker programmed to a rate of 600 bpm and connected to a permanent endocardial atrial J lead successfully interrupted the tachycardia and precipitated atrial fibrillation. Over a period of 3 months, this therapy changed the patient's heart failure to NYHA class II status. Subsequently, precipitation of atrial fibrillation with this technique failed, resulting in return to NYHA class III-IV congestive heart failure. Therefore, a custom-designed, high rate, rate-programmable pacemaker was implanted to pace the atria rapidly and continuously to maintain atrial fibrillation. A pacing rate of 375 bpm plus digoxin slowed the ventricular rate to 70-80 bpm, with stabilization of the congestive heart failure to NYHA class II. The pacemaker generator was replaced 6 months later, and after another 5 months, pacing was discontinued. The patient's subsequent rhythm remained stable atrial fibrillation with clinically successful control of both the ventricular rate and heart failure (NYHA class II) until the patient's death 72 months later. This unique case demonstrates another form of chronic therapy which, in selected cases, can be used for the long term control of rapid ventricular response rates to supraventricular arrhythmia.
Micro–RNA-126 Reduces the Blood Thrombogenicity in Diabetes Mellitus via Targeting of Tissue Factor (2016)

Circulating miR-126 exhibits antithrombotic properties via regulating post-transcriptional TF expression, thereby impacting the hemostatic balance of the vasculature in diabetes mellitus.
Immunotherapy of Minimal Residual Disease by Immunocompetent Lymphocytes and Their Activation by Cytokines (1992)

A murine model of minimal residual disease (MRD) was established utilizing the murine B-cell leukemia (BCL1). BALB/c mice inoculated with up to 10(4) BCL1 were cured (greater than 1 year disease-free survival) following administration of intraperitoneal injections of recombinant human IL-2 (10(5) Cetus units x 3/day intraperitoneally x 5 days). Lethally irradiated BALB/c or (BALB/c x C57BL/6)F1 recipients were reconstituted with syngeneic bone marrow cells or T-cell-depleted C57BL/6 bone marrow cells contaminated with 10(4), 10(5), or 10(6) BCL1 to simulate quantitative MRD. Untreated mice died of typical leukemia without exception, whereas a substantial anti-leukemia effect was noted in mice treated by allogeneic spleen cells, IL-2, or particularly a combination of allogeneic spleen cells and IL-2 given concomitantly. Increments of donor-type spleen cells (10(6), 10(7), and 5 x 10(7)) or IL-2 (10(4) U x 2/day x 3 days) were given alone or in combination on days +1, +5, and +9 following Thy 1.2-depleted allogeneic BMT. All adoptive recipients of 10(5) spleen cells obtained from mice inoculated with 10(4) and 10(5) BCL1 treated by a combination of allogeneic spleen cells and IL-2 showed no evidence of disease greater than 100 days. The antitumor effects of allogeneic spleen cells alone and IL-2 alone were also highly significant, although not totally curative in all mice. Allogeneic spleen cells seemed more effective as compared with low dose IL-2 (3 courses of 2 x 10(4) U x 2/day x 3 days). None of the recipients of 10(6) BCL1 could be completely cured under the experimental conditions described without additional chemotherapy, although significant antitumor effects could again be documented following concomitant administration of allogeneic spleen cells and IL-2. Using an experimental model of autologous BMT, recipients of 10(3) tumor cells could also be cured following transplantation of syngeneic spleen cells by high-dose IL-2 (10(5) U x 3/day x 5 days) given at the time lymphocytes were present, optimally at 3 weeks following BMT. Based on encouraging results from experiments using our animal model of MRD, in conjunction with autologous and allogeneic BMT, pilot clinical trials are currently underway, investigating the effect of cytokine-mediated immunotherapy (CMI) in MRD following conventional and high-dose cytoreductive anticancer therapy in conjunction with ABMT. In addition, we are attempting induction of cell-mediated cytokine-activated immunotherapy (CCI) in conjunction with autologous and allogeneic BMT. Prospective randomized clinical trials and longer observation periods are required to assess the full efficacy of these new therapeutic modalities.
An Inducible Pathway for Degradation of FLIP Protein Sensitizes Tumor Cells to TRAIL-induced Apoptosis (2002)

TRAIL (Apo2 ligand) is a member of the tumor necrosis factor (TNF) family of cytokines that induces apoptosis. Because TRAIL preferentially kills tumor cells, sparing normal tissues, interest has emerged in applying this biological factor for cancer therapy in humans. However, not all tumors respond to TRAIL, raising questions about resistance mechanisms. We demonstrate here that a variety of natural and synthetic ligands of peroxisome proliferator-activated receptor-gamma (PPAR gamma) sensitize tumor but not normal cells to apoptosis induction by TRAIL. PPAR gamma ligands selectively reduce levels of FLIP, an apoptosis-suppressing protein that blocks early events in TRAIL/TNF family death receptor signaling. Both PPAR gamma agonists and antagonists displayed these effects, regardless of the levels of PPAR gamma expression and even in the presence of a PPAR gamma dominant-negative mutant, indicating a PPAR gamma-independent mechanism. Reductions in FLIP and sensitization to TRAIL-induced apoptosis were also not correlated with NF-kappa B, further suggesting a novel mechanism. PPAR gamma modulators induced ubiquitination and proteasome-dependent degradation of FLIP, without concomitant reductions in FLIP mRNA. The findings suggest the existence of a pharmacologically regulated novel target of this class of drugs that controls FLIP protein turnover, and raise the possibility of combining PPAR gamma modulators with TRAIL for more efficacious elimination of tumor cells through apoptosis.
Texture Synthesis Using Shallow Convolutional Networks with Random Filters (2016)

Here we demonstrate that the feature space of random shallow convolutional neural networks (CNNs) can serve as a surprisingly good model of natural textures. Patches from the same texture are consistently classified as being more similar then patches from different textures. Samples synthesized from the model capture spatial correlations on scales much larger then the receptive field size, and sometimes even rival or surpass the perceptual quality of state of the art texture models (but show less variability). The current state of the art in parametric texture synthesis relies on the multi-layer feature space of deep CNNs that were trained on natural images. Our finding suggests that such optimized multi-layer feature spaces are not imperative for texture modeling. Instead, much simpler shallow and convolutional networks can serve as the basis for novel texture synthesis algorithms.
RECOVERY OF ANTIGENIC SPECIFICITY AFTER DENATURATION AND COMPLETE REDUCTION OF DISULFIDES IN A PAPAIN FRAGMENT OF ANTIBODY (1964)

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans the biological, physical, and social sciences.
Repetitive coronary artery occlusions induce release of growth factors into the myocardial interstitium (1998)

Our objective was to delineate the temporal sequence of mitogenic activity in myocardial interstitial fluid (IF) during enhancement of collateral growth. Collateral development in chronically instrumented dogs was induced by eight 2-min coronary occlusions/day for 21 days. Collateralization was assessed by measurement of blood flow in the region distal to a total coronary occlusion. Myocardial IF was obtained periodically from an intramyocardial catheter, and mitogenic activity was assessed by proliferative response of cultured endothelial cells (EC) and vascular smooth muscle cells (VSMC) to the IF. Three experiments were conducted to test that the mitogenic activity is induced by protein growth factors: 1) protein digestion of the myocardial IF with Pronase-coupled latex beads; 2) heat inactivation (boiling) of the IF; and 3) neutralization of the mitogenic activity with antibodies for basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). Blood flow was reconstituted to baseline levels during occlusion after 3 wk of repetitive coronary occlusions. After initiation of occlusion the mitogenic activity of the myocardial IF on VSMC and EC increased up to days 12-14 and was reduced on days 19-23. Pronase treatment and heat inactivation blocked the mitogenic effect. Treatment with antibodies for bFGF and VEGF neutralized the proliferative response to the myocardial IF at specific times. bFGF antibody inhibited the mitogenic effect significantly on days 12-14. VEGF antibody neutralized the mitogenicity of the myocardial IF on day 7, days 12 and 13, and days 19 and 20 significantly. We conclude that myocardial IF harvested from ischemic myocardium is highly mitogenic up to 2 wk after initiation of repetitive coronary occlusions. After 3 wk of ischemia, the degree of mitogenic activity for VSMC and EC was decreased from peak levels. The antibodies could not neutralize the mitogenic effect of the myocardial IF during this time period. These results suggest that mitogens are expressed during various stages of collateral development in a time-dependent manner, that the mitogens are proteinaceous in nature, and that bFGF and VEGF are released into the myocardial IF.
Cells of the Monocyte-Macrophage Lineage and Pathogenesis of HIV-1 Infection (1999)

It is thought that monocyte-macrophages and probably dendritic cells play a central role in HIV-1 primary infection, as well as in its evolution, given that they are among the first cells infected and later function as important reservoirs for the virus. These cells may participate in the selection of certain viral strains instead of others. Levels of CCR5 coreceptor expression on the surface of monocytes and macrophages determine their susceptibility to infection by HIV-1 strains using this coreceptor and may explain, in part, the differences in the infectivity of these cells through the maturation process. However, selection for certain strains is not only determined by the level of coreceptor expression, but by the biochemical properties of the different coreceptors and their relationship with other surface molecules and the chemokine and cytokine networks, which also influence the selective viral infection and replication in these cells. Any current or newly designed therapies need to be evaluated, including careful analysis of the levels of HIV-1 infection of the cells of the monocyte-macrophage lineage, because these cells are both significant viral reservoirs and a center of virus production at all stages of the disease.
Vascular endothelial growth factor expression in early stage ovarian carcinoma (1997)

In this analysis, patients with early stage ovarian carcinoma with increased VEGF expression had a poorer prognosis. Further study of VEGF may ultimately lead to identification of patients with high risk lesions whose tumor biology portends a worse prognosis and who therefore may benefit from aggressive adjuvant therapy.
Characterization of a protein from normal human polymorphonuclear leukocytes with bactericidal activity against Pseudomonas aeruginosa (1986)

Purification of a bactericidal protein (BP) from the cytoplasmic granules of normal human polymorphonuclear leukocytes (PMN) with activity against Pseudomonas aeruginosa is described. Bactericidal activity from acid extracts of a mixed granule population was purified 175-fold by a two-step chromatographic procedure. The first step, dye-ligand affinity chromatography with Matrex-Gel Orange A, was followed by cation-exchange chromatography with Bio-Rex 70 resin, and this combination routinely gave a yield near 80%. Only one peak of bactericidal activity against P. aeruginosa type I was found after each chromatographic step. Characterization of BP showed a single band with an apparent molecular weight of 55,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Purified BP was most active against the six strains of P. aeruginosa tested and against Escherichia coli B (a deep rough mutant). Purified BP killed 5 X 10(6) CFU of P. aeruginosa type I per ml at a concentration of 60 to 80 ng/ml. Proteus mirabilis and Staphylococcus aureus were both resistant to the bactericidal activity of BP. BP was shown to be glycosylated by periodic acid staining after gel electrophoresis and to have an isoelectric point near 7.5 by chromatofocusing. The amino acid composition of BP is presented.
Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice (2017)

See Mercado and Hetz (doi:10.1093/brain/awx107) for a scientific commentary on this article.Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer's disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss. Re-establishing translation rates by inhibition of eIF2α-P activity, genetically or pharmacologically, restores memory and prevents neurodegeneration and extends survival. However, the experimental compounds used preclinically are unsuitable for use in humans, due to associated toxicity or poor pharmacokinetic properties. To discover compounds that have anti-eIF2α-P activity suitable for clinical use, we performed phenotypic screens on a NINDS small molecule library of 1040 drugs. We identified two compounds, trazodone hydrochloride and dibenzoylmethane, which reversed eIF2α-P-mediated translational attenuation <i>in vitro</i> and <i>in vivo</i>. Both drugs were markedly neuroprotective in two mouse models of neurodegeneration, using clinically relevant doses over a prolonged period of time, without systemic toxicity. Thus, in prion-diseased mice, both trazodone and dibenzoylmethane treatment restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival. In tauopathy-frontotemporal dementia mice, both drugs were neuroprotective, rescued memory deficits and reduced hippocampal atrophy. Further, trazodone reduced p-tau burden. These compounds therefore represent potential new disease-modifying treatments for dementia. Trazodone in particular, a licensed drug, should now be tested in clinical trials in patients.
Morphology and intermediate filament composition of human mammary epithelial cells treated with stable butyrate derivative. (1993)

A new stable butyrate derivative monobut-3 was previously shown to inhibit proliferation and promote differentiation in human mammary established cell lines. The present study on monobut-3's effects on mammary epithelial cells cultured from human non-malignant and malignant breast tissues demonstrated pronounced morphological alterations suggestive of cellular differentiation. In addition, some degree of architectural differentiation was also evident in treated primary cultures. Monobut-3 did not affect the expression of vimentin and cytokeratin 18 when assessed in human breast cell lines expressing one or both types of intermediate filaments. However, it did induce expression of cytokeratin 19, characteristic of fully differentiated mammary cells, in one of the two cell lines devoid of this cytokeratin subtype. Furthermore, the network of intermediate filaments was often more largely extended in cells treated with monobut-3 than in untreated ones. These results indicate that monobut-3 can induce subtle changes in intermediate filaments which may contribute to its ability to promote differentiation in human mammary cells.
Phase I study of an antisense oligonucleotide to protein kinase C-alpha (ISIS 3521/CGP 64128A) in patients with cancer. (1999)

Protein kinase C (PKC) is an attractive target in cancer therapy. It is overexpressed in a variety of cancers, and nonspecific inhibitors of PKC have demonstrated antitumor activity. Antisense oligonucleotides targeted against PKC-alpha, which have high specificity, can inhibit mRNA and protein expression as well as the growth of tumors in vitro and in vivo. This Phase I study sought to characterize the safety profile and to determine the maximum tolerated dose of antisense to PKC-alpha when administered by continuous infusion in patients. Patients with incurable malignancies received ISIS 3521, a 20-length phosphorothioate oligodeoxynucleotide specific for PKC-alpha. Treatment was delivered over a period of 21 days by continuous i.v. infusion followed by a 7-day rest period. Doses were increased from 0.5 to 3.0 mg/kg/day. Patients continued on the study until evidence of disease progression or unacceptable toxicity was detected. Between August 1996 and September 1997, 21 patients were treated in five patient cohorts. The maximum tolerated dose was 2.0 mg/kg/day. The dose-limiting toxicities were thrombocytopenia and fatigue at a dose of 3.0 mg/kg/day. Pharmacokinetic measurements showed rapid plasma clearance and dose-dependent steady-state concentrations of ISIS 3521. Evidence of tumor response lasting up to 11 months was observed in three of four patients with ovarian cancer. The recommended dose of ISIS 3521 for Phase II studies is 2.0 mg/kg/day when given over a period of 21 days. Side effects are modest and consist of thrombocytopenia and fatigue. Evidence of antitumor activity provides the rationale for Phase II studies in ovarian cancer and other malignancies.
An efficient external-memory implementation of region query with application to area routing (2003)

We present the tile-cached kd-tree, an efficient external-memory (disk) implementation of two-dimensional region query for use in a detailed area router. Most researchers have heretofore focused on in-memory algorithms. However as the need to tackle very large problems increases, conventional in-memory algorithms suffer from unpredictable caching and paging behavior and their performance may degrade considerably. In addition, since the region-query data structure is only part of the overall system, its consumption of large memory resources affects other parts of the system as well. Our implementation takes advantage of spatial locality in the detailed-routing process. We partition the routing space into tiles, each storing the data of objects (rectangles) that lie strictly within it. Objects that cross tile boundaries are separately stored. The data within a tile are then written out to disk, and a configurable cache is used to hold in memory the most recently visited tiles. Experimental results on large real-life routing problems show that this scheme significantly reduces memory usage with tolerable performance penalty.