gebhart/patrepeval huggingface dataset:
Current progress of siRNA/shRNA therapeutics in clinical trials (2011)

Through a mechanism known as RNA interference (RNAi), small interfering RNA (siRNA) molecules can target complementary mRNA strands for degradation, thus specifically inhibiting gene expression. The ability of siRNAs to inhibit gene expression offers a mechanism that can be exploited for novel therapeutics. Indeed, over the past decade, at least 21 siRNA therapeutics have been developed for more than a dozen diseases, including various cancers, viruses, and genetic disorders. Like other biological drugs, RNAi-based therapeutics often require a delivery vehicle to transport them to the targeted cells. Thus, the clinical advancement of numerous siRNA drugs has relied on the development of siRNA carriers, including biodegradable nanoparticles, lipids, bacteria, and attenuated viruses. Most therapies permit systemic delivery of the siRNA drug, while others use ex vivo delivery by autologous cell therapy. Advancements in bioengineering and nanotechnology have led to improved control of delivery and release of some siRNA therapeutics. Likewise, progress in molecular biology has allowed for improved design of the siRNA molecules. Here, we provide an overview of siRNA therapeutics in clinical trials, including their clinical progress, the challenges they have encountered, and the future they hold in the treatment of human diseases.
Phenotype and function of human hematopoietic cells engrafting immune- deficient CB17-severe combined immunodeficiency mice and nonobese diabetic-severe combined immunodeficiency mice after transplantation of human cord blood mononuclear cells (1996)

In an attempt to understand better the regulation of stem cell function in chimeric immunodeficient mice transplanted with human cells, and the filiation between progenitor cells identified in vitro and in vivo, we assessed the different compartments of hematopoietic progenitors found in the marrow of CB17-severe combined immunodeficiency (SCID) mice (34 mice, 9 experiments) after intravenous injection of 2 to 3 x 10(7) cord blood mononuclear cells. On average 6.3 +/- 4 x 10(5) human cells were detected per four long bones 4 to 6 weeks after the transplant predominantly represented by granulomonocytic (CD11b+) and B lymphoid (CD19+) cells. Twenty five percent of these human cells expressed the CD34 antigen, of which 90% coexpressed the CD38 antigen and 50% the CD19 antigen. Functional assessment of progenitor cells (both clonogenic and long-term culture-initiating cells [LTC-IC]) was performed after human CD34+ cells and CD34+/CD38- cells have been sorted from chimeric CB17-SCID marrow 3 to 10 weeks after intravenous (IV) injection of human cells. The frequency of both colony-forming cells and LTC-IC was low (4% and 0.4%, respectively in the CD34+ fraction) when compared with the frequencies of cells with similar function in CD34+ cells from the starting cord blood mononuclear cells (26% +/- 7% and 7.2% +/- 5%, respectively). More surprisingly, the frequency of LTC-IC was also low in the human CD34+ CD38- fraction sorted from chimeric mice. This observation might be partly accounted for by the expansion of the CD34+ CD19+ B-cell precursor compartment. Despite their decreased frequency and absolute numbers, the differentiation capability of these LTC-IC, assessed by their clonogenic progeny output after 5 weeks in coculture with murine stromal cells was intact when compared with that of input LTC-IC. Furthermore the ratio between clonogenic progenitor cells and LTC-IC was similar in severe combined immunodeficiency (SCID) mice studied 4 weeks after transplant and in adult marrow or cord blood suspensions. Results generated in experiments where nonobese diabetic (NOD)-SCID mice were used as recipients indicate a higher level of engraftment but no change in the distribution of clonogenic cells or LTC-IC. These results suggest that the hierarchy of hematopoietic differentiation classically defined in human hematopoietic tissues can be reconstituted in immunodeficient SCID or NOD-SCID mice.
Plasma Levels of Insulin-Like Growth Factor-I and Lung Cancer Risk: a Case-Control Analysis (1999)

Plasma levels of IGF-I are higher and plasma levels of IGFBP-3 are lower in patients with lung cancer than in control subjects. If these findings can be confirmed in prospective studies, measuring levels of IGF-I and IGFBP-3 in blood may prove useful in assessing lung cancer risk.
Modeling Slump of Ready Mix Concrete Using Genetically Evolved Artificial Neural Networks (2014)

Artificial neural networks (ANNs) have been the preferred choice for modeling the complex and nonlinear material behavior where conventional mathematical approaches do not yield the desired accuracy and predictability. Despite their popularity as a universal function approximator and wide range of applications, no specific rules for deciding the architecture of neural networks catering to a specific modeling task have been formulated. The research paper presents a methodology for automated design of neural network architecture, replacing the conventional trial and error technique of finding the optimal neural network. The genetic algorithms (GA) stochastic search has been harnessed for evolving the optimum number of hidden layer neurons, transfer function, learning rate, and momentum coefficient for backpropagation ANN. The methodology has been applied for modeling slump of ready mix concrete based on its design mix constituents, namely, cement, fly ash, sand, coarse aggregates, admixture, and water-binder ratio. Six different statistical performance measures have been used for evaluating the performance of the trained neural networks. The study showed that, in comparison to conventional trial and error technique of deciding the neural network architecture and training parameters, the neural network architecture evolved through GA was of reduced complexity and provided better prediction performance.
Synthesis of Acyclic α,β-Unsaturated Ketones via Pd(II)-Catalyzed Intermolecular Reaction of Alkynamides and Alkenes (2007)

We report an intermolecular oxidative coupling of alkynamides and terminal alkenes to synthesize E-α,β-unsaturated ketones under very mild conditions using catalytic Pd(II) and an oxidant. An 17O isotope labeling experiment implicates a cyclic oxypalladation intermediate in this reaction.
Enterohemorrhagic Escherichia coli O157:H7 requires intimin to colonize the gnotobiotic pig intestine and to adhere to HEp-2 cells (1995)

In a previous study, enterohemorrhagic Escherichia coli (EHEC) O157:H7 with a deletion and insertion in the eaeA gene encoding intimin was used to establish that intimin is required for the organism to attach to and efface microvilli in the piglet intestine (M. S. Donnenberg, S. Tzipori, M. L. McKee, A. D. O'Brien, J. Alroy, and J. B. Kaper, J. Clin. Invest. 92:1418-1424, 1993). However, in the same investigation, a role for intimin in EHEC adherence to HEp-2 cells could not be definitively demonstrated. To analyze the basis for this discrepancy, we constructed an in-frame deletion of eaeA and compared the adherence capacity of this mutant with that of the wild-type strain in vitro and in vivo. We observed a direct correlation between the requisite for intimin in EHEC O157:H7 colonization of the gnotobiotic piglet intestine and adherence of the bacterium to HEp-2 cells. The in vitro-in vivo correlation lends credence to the use of the HEp-2 cell adherence model for further study of the intimin protein.
Symptoms associated with impaired gastric emptying of solids and liquids in functional dyspepsia (2003)

A subset of dyspeptic patients has delayed gastric emptying of solids or of liquids. Delayed gastric emptying of solids was constantly associated with postprandial fullness and with vomiting. Delayed emptying for liquids was also associated with postprandial fullness and with severe early satiety.
Serum neutralizing antibody response to the vacuolating cytotoxin of Helicobacter pylori. (1992)

Approximately 50% of Helicobacter pylori isolates produce a cytotoxin in vitro that induces vacuolation of eukaryotic cells. To determine the in vivo relevance of this phenomenon, we sought to detect cytotoxin-neutralizing antibodies in sera from H. pylori-infected persons. As a group, sera from 29 H. pylori-infected patients neutralized the activity of the purified cytotoxin to a significantly greater extent than sera from 24 uninfected persons (P = 0.007). The cytotoxin neutralizing activity in sera from H. pylori-infected persons was mediated predominantly by the purified IgG fraction. Sera from H. pylori-infected persons neutralized the cytotoxins produced by multiple H. pylori strains, but failed to neutralize trimethylamine-induced cell vacuolation. Neutralization of cytotoxin activity by human or immune rabbit sera was associated with immunoblot IgG recognition of an 87-kD H. pylori protein. Similarly, neutralization of the toxin by sera was associated with IgG recognition of the purified cytotoxin in an enzyme-linked immunosorbent assay (P less than 0.0001). The presence of cytotoxin-neutralizing antibodies in sera from H. pylori-infected persons indicates that the cytotoxin is synthesized in vivo.
Concentration-dependent antioxidant activity of probucol in low density lipoproteins in vitro: probucol degradation precedes lipoprotein oxidation. (1989)

The ability of probucol, a lipid-lowering drug with antioxidant properties, to prevent the Cu2+-induced oxidation of human plasma low density lipoproteins (LDL) was examined as a function of the concentration of probucol in LDL. In the absence of probucol, 3 microM Cu2+ induced half-maximal LDL lipid oxidation, as determined by the formation of thiobarbituric acid reactive substances (TBARS). Oxidation was associated with a loss of apolipoprotein B-100 and the appearance of higher molecular weight forms of the protein. In the presence of 0.6 mol% probucol (relative to phospholipid) and with 3 microM Cu2+, the time required to obtain half-maximal LDL lipid oxidation increased from 130 to 270 min and was explained by an increase in the lag time prior to LDL lipid oxidation. Once rapid oxidation of LDL had begun, the rate of TBARS formation was similar to that for LDL containing no probucol. At a probucol concentration of 4.2 mol%, the antioxidant prevented the oxidation of LDL-lipids. The delay in Cu2+-induced LDL oxidation with probucol corresponded to the time required for free radical-mediated processes to convert probucol to a spiroquinone and a diphenoquinone. These in vitro findings suggest that the potent antioxidant property of probucol is directly related to the amount of drug in the LDL particle and may have relevance to its antiatherosclerotic effects observed in vivo.
Immunologic Evidence of Reinfection with Varicella-Zoster Virus (1983)

Resistance to reinfection with varicella-zoster virus (VZV) was evaluated in immune adults who had household exposure to varicella. Sixty-four percent of 25 adults exposed to varicella had a fourfold or greater rise in IgG antibody to VZV or had a high initial IgG antibody titer to VZV that declined by fourfold. IgM antibody was detected in only 12% of 25 VZV-immune subjects. Seventy percent of 23 subjects exposed to varicella had IgA antibody to VZV compared with 13% of 23 subjects with antibody to VZV who had no recent exposure (P less than 0.001, chi 2 test). Enhanced cellular immunity was documented by an increase in lymphocyte transformation to VZV antigen from a mean +/- SE index of 7.8 +/- 1.30 to 15.3 +/- 2.56 (P = 0.01, paired t-test). The increase in immunity to VZV in many immune subjects exposed to VZV suggests the occurrence of subclinical reinfection.
Expression and regulation of human neutrophil-derived macrophage inflammatory protein 1 alpha. (1993)

Neutrophil (polymorphonuclear leukocyte [PMN]) sequestration is one of the histologic hallmarks of an acute inflammatory response. During the natural evolution of an inflammatory response, PMNs are often replaced by mononuclear cells. This shift in the elicitation of specific leukocyte populations usually occurs as the inflammatory lesion enters either the repair/resolution stage or progresses to a chronic inflammation. To elucidate a potential mechanism for the temporal change from predominantly PMN recruitment to the presence of monocytes, we postulated that PMNs could be a rich source of monocyte chemotactic factors. In our studies, we have identified a dose-dependent induction of monocyte chemotactic activity by PMNs treated with lipopolysaccharide (LPS; 1-100 ng/ml). Interestingly, this monocyte chemotactic activity was significantly attenuated in the presence of neutralizing anti-human macrophage inflammatory protein 1 alpha (MIP-1 alpha) antibodies. Moreover, immunolocalization studies demonstrated the expression of MIP-1 alpha by stimulated PMNs. These findings showed that a significant amount of PMN-derived monocyte chemotactic activity was attributable to MIP-1 alpha. Subsequent characterization of MIP-1 alpha steady-state mRNA and antigen expression demonstrated both a dose- and time-dependent production by LPS-treated PMNs. Granulocyte/macrophage colony-stimulating factor (GM-CSF), a potent PMN activator, failed to induce the expression of MIP-1 alpha over a wide range of concentrations. However, PMNs stimulated in the presence of both LPS and GM-CSF resulted in a synergistic expression pattern for MIP-1 alpha. PMNs stimulated in the presence of both GM-CSF and LPS demonstrated an enhanced and prolonged expression for both MIP-1 alpha mRNA and antigen, as compared with LPS alone. Messenger RNA stabilization analyses demonstrated that MIP-1 alpha mRNA isolated from PMNs stimulated in the presence of GM-CSF and LPS had a prolonged mRNA t1/2, as compared with LPS alone. These findings support the notion that PMNs are capable of producing MIP-1 alpha in the presence of LPS, and that GM-CSF can influence this production through prolongation of MIP-1 alpha mRNA t1/2. The production of PMN-derived MIP-1 alpha, in association with the expression of appropriate adhesion molecules at a site of inflammation, may be one of the central events that contributes to the temporal shift from predominantly PMNs to monocytes during the evolution of inflammation.
Local Anesthetic Infusion Pumps Improve Postoperative Pain after Inguinal Hernia Repair: A Randomized Trial (2004)

Pain after an open inguinal hernia repair may be significant. In fact, some surgeons feel that the pain after open repair justifies a laparoscopic approach. The purpose of this study was to determine if the use of local anesthetic infusion pumps would reduce postoperative pain after open inguinal hernia repair. We performed a prospective, double-blind randomized study of 45 open plug and patch inguinal hernia repairs. Patients were randomized to receive either 0.25 per cent bupivicaine or saline solution via an elastomeric infusion pump (ON-Q) for 48 hours, at 2 cc/h. The catheters were placed in the subcutaneous tissue and removed on postoperative day 3. Both groups were prescribed hydrocodone to use in the postoperative period at the prescribed dosage as needed for pain. Interviews were conducted on postoperative days 3 and 7, and patient's questionnaires, including pain scores, amount of pain medicine used, and any complications, were collected accordingly. During the first 5 postoperative days, postoperative pain was assessed using a visual analog scale. Twenty-three repairs were randomized to the bupivicaine group and 22 repairs randomized to the placebo group. In the bupivicaine group, there was a significant decrease in postoperative pain on postoperative days 2 through 5 with P values <0.05. This significant difference continued through postoperative day 5, 2 days after the infusion pumps were removed. Patients who had bupivicaine instilled in their infusion pump had statistically significant lower subjective pain scores on postoperative days 2 through 5. This significant difference continued even after the infusion pumps were removed. Local anesthetic infusion pumps significantly decreased the amount of early postoperative pain. Pain relief persisted for 2 days after catheter and pump removal.
CD21 and CD62L shedding are both inducible via P2X7Rs (2006)

Neutrophils and lymphocytes are recruited to sites of inflammation and require the adhesion molecule L-selectin (CD62L) for adherence to endothelial cells. Nucleotides released from activated or dying cells at sites of inflammation can mediate signaling through purinergic receptor family II, resulting in CD62L shedding. Activation of B lymphocytes requires the complement receptor type II (CD21) and at the same time leads to shedding of CD21. Both CD62L and CD21 shedding possibly depends on the same families of proteases. In the present study, we characterized peripheral blood naive and memory cells and neutrophils for CD62L surface expression and analyzed benzoyl-benzoyl triphosphate (BzATP)-induced shedding. BzATP is able to induce CD62L shedding in naive and memory lymphocytes, but not in neutrophils. CD21 shedding can be induced through activation of the B cell receptor (BCR) or with mitogens. Here we show that CD21 is also susceptible to BzATP-induced shedding on peripheral B cells. In addition, using receptor inhibitiors, we show that shedding of CD21 and CD62L is mediated via the P2X7R. P2X7R-mediated CD62L and CD21 shedding could occur as a result of extracellular accumulated ATP and may have an influence on leukocyte migrational behavior and BCR-mediated signaling.
Conformation-Specific Blockade of the Integrin GPIIb/IIIa (2006)

Platelet activation causes conformational changes of integrin GPIIb/IIIa (alpha(IIb)beta3), resulting in the exposure of its ligand-binding pocket. This provides the unique possibility to design agents that specifically block activated platelets only. We used phage display of single-chain antibody (scFv) libraries in combination with several rounds of depletion/selection to obtain human scFvs that bind specifically to the activated conformation of GPIIb/IIIa. Functional evaluation of these scFv clones revealed that fibrinogen binding to human platelets and platelet aggregation can be effectively inhibited by activation-specific scFvs. In contrast to clinically used GPIIb/IIIa blockers, which are all conformation unspecific, activation-specific GPIIb/IIIa blockers do not induce conformational changes in GPIIb/IIIa or outside-in signaling, as evaluated by ligand-induced binding-site (LIBS) exposure in flow cytometry or P-selectin expression in immunofluorescence microscopy, respectively. In contrast to the conformation-unspecific blocker abciximab, activation-specific scFvs permit cell adhesion and spreading on immobilized fibrinogen, which is mediated by nonactivated GPIIb/IIIa. Mutagenesis studies and computer modeling indicate that exclusive binding of activation-specific scFv is mediated by RXD motifs in the heavy-chain complementary-determining region (CDR) 3 of the antibodies, which in comparison with other antibodies forms an exceptionally extended loop. In vivo experiments in a ferric-chloride thrombosis model of the mouse carotid artery demonstrate similar antithrombotic potency of activation-specific scFv, when compared with the conformation-unspecific blockers tirofiban and eptifibatide. However, in contrast to tirofiban and eptifibatide, bleeding times are not prolonged with the activation-specific scFvs, suggesting lower bleeding risks. In conclusion, activation-specific GPIIb/IIIa blockade via human single-chain antibodies represents a promising novel strategy for antiplatelet therapy.
Atlas of Maine 2015: Amount of Toxic Release and Brownfield Locations in Maine (2015)

Utilizing two data sets from the Environmental Protection Agency, the map below shows the total amount of toxic release at each monitored facility in Maine according to the Toxic Release Inventory 2011 and the locations of brownfields property in Maine under the Facility Registry System. A brownfield is a property, the expansion, redevelopment, or reuse of which may be complicated by the presence or potential presence of a hazardous substance, pollutant, or contaminant. Through this map, you can get an idea where these properties are and how much toxic were released around.
Preservation of hamster oocytes to assay the fertilizing capacity of human spermatozoa (1982)

Between 70 and 80% of zona-intact hamster ova survived freezing after slow cooling (approximately 0.3 degrees C/min) to -80 degrees C in Medium PB1 containing 1.5 or 2.0 M-DMSO before transfer to -196 degrees C. After slow warming (approximately 8 degrees C/min), there was no difference in survival if the DMSO was diluted out by a slow stepwise or a rapid single addition of medium. When slow cooling was terminated at -40 degrees C by direct transfer to -196 degrees C, up to 75% of the ova survived rapid warming (approximately 500 degrees C/min) and rapid dilution if the medium contained 2.0 M-DMSO. The survival rates were calculated on the basis of the number of thawed ova which retained their normal morphological appearance after a 1 h incubation before removal of the zona pellucida with trypsin. All of these ova were penetrated after incubation with mouse spermatozoa, indicating that the freezing procedure per se does not adversely affect the penetration of frozen-thawed hamster ova by heterologous spermatozoa. There was no difference in the penetration rate of human spermatozoa into frozen (34%) or fresh (42%) oocytes when a Hepes-buffered Tyrode solution containing 30 mg BSA/ml and 2.0 M-DMSO was used as the freezing medium. However, fewer ova frozen in Medium PB1 containing 4 mg BSA/ml and 2.0 M-DMSO were penetrated by human spermatozoa (18%) compared with freshly collected ova (38%). Zona-free ova did not survive the freezing procedure as well as zona-intact ova. The survival of hamster oocytes stored at -196 degrees C offers a convenient means of supplying and transporting these ova for the assessment of the fertilizing capacity of human and other heterologous spermatozoa.
Separating mitogenic and metabolic activities of fibroblast growth factor 19 (FGF19) (2010)

FGF19 and FGF21 are distinctive members of the FGF family that function as endocrine hormones. Their potent effects on normalizing glucose, lipid, and energy homeostasis in disease models have made them an interesting focus of research for combating the growing epidemics of diabetes and obesity. Despite overlapping functions, FGF19 and FGF21 have many discrete effects, the most important being that FGF19 has both metabolic and proliferative effects, whereas FGF21 has only metabolic effects. Here we identify the structural determinants dictating differential receptor interactions that explain and distinguish these two physiological functions. We also have generated FGF19 variants that have lost the ability to induce hepatocyte proliferation but that still are effective in lowering plasma glucose levels and improving insulin sensitivity in mice. Our results add valuable insight into the structure-function relationship of FGF19/FGF21 and identify the structural basis underpinning the distinct proliferative feature of FGF19 compared with FGF21. In addition, these studies provide a road map for engineering FGF19 as a potential therapeutic candidate for treating diabetes and obesity.
Oncogene Antioncogene and Cancer (2000)

The formation of cancer is a Process of many steps. Actually, cancer is caused by the mutation of some genes. There changes take place between two genes which act on each other. The two genes are oncogene and antioncogene,which,as the positive and negative adjusting factors of the growth of cell, take part in the formation of tumor together.