gebhart/patrepeval huggingface dataset:
Anisamide‐targeted stealth liposomes: A potent carrier for targeting doxorubicin to human prostate cancer cells (2004)

Certain human malignancies including prostate cancer overexpress sigma receptor, a membrane bound protein that binds haloperidol and various other neuroleptics with high affinity. An anisamide derivatized ligand possesses high affinity for sigma receptors and we hypothesized that its incorporation into the liposomes encapsulating doxorubicin (DOX) can specifically target and deliver the drug to prostate cancer cells that overexpress sigma receptors. A polyethylene glycol phospholipid was derivatized with an anisamide ligand, which was then incorporated into the DOX-loaded liposome. The resulting anisamide-conjugated liposomal DOX showed significantly higher toxicity to DU-145 cells than non-targeted liposomal DOX, the IC50 being 1.8 microM and 14 microM respectively. The cytotoxicity of the targeted liposomal DOX, however, was significantly blocked by haloperidol, suggesting that the enhanced cytotoxicity was specifically mediated by the sigma receptors. Fluorescence imaging studies after intravenous (i.v.) administration showed that incorporation of anisamide into liposomes significantly improved their accumulation into the tumor. A weekly injection of the targeted liposomal DOX for 4 weeks at a dose of 7.5 mg/kg led to a significant growth inhibition of established DU-145 tumor in nude mice with minimal toxicity. Free DOX was effective, but associated with significant toxicities. The present study is the first to demonstrate the use of small molecular weight ligand for mediating efficient targeting of liposomal drugs to sigma receptor expressing prostate cancer cells both in vitro and in vivo.
Renal and Cardiac Effects of DPP-4 Inhibitors from Preclinical Development to Clinical Research (2012)

Inhibitors of type 4 dipeptidyl peptidase (DDP-4) were developed and approved for the oral treatment of type 2 diabetes. Its mode of action is to inhibit the degradation of incretins, such as type 1 glucagon like peptide (GLP-1), and GIP. GLP-1 stimulates glucose-dependent insulin secretion from pancreatic beta-cells and suppresses glucagon release from alpha-cells, thereby improving glucose control. Besides its action on the pancreas type 1 glucagon like peptide has direct effects on the heart, vessels and kidney mainly via the type 1 glucagon like peptide receptor (GLP-1R). Moreover, there are substrates of DPP-4 beyond incretins that have proven renal and cardiovascular effects such as BNP/ANP, NPY, PYY or SDF-1 alpha. Preclinical evidence suggests that DPP-4 inhibitors may be effective in acute and chronic renal failure as well as in cardiac diseases like myocardial infarction and heart failure. Interestingly, large cardiovascular meta-analyses of combined phase II/III clinical trials with DPP-4 inhibitors point all in the same direction: a potential reduction of cardiovascular events in patients treated with these agents. A pooled analysis of pivotal phase III, placebo-controlled, registration studies of linagliptin further showed a significant reduction of urinary albumin excretion after 24 weeks of treatment. The observation suggests direct renoprotective effects of DPP-4 inhibition that may go beyond its glucose-lowering potential. Type 4 dipeptidyl peptidase inhibitors have been shown to be very well tolerated in general, but for those excreted via the kidney dose adjustments according to renal function are needed to avoid side effects. In conclusion, the direct cardiac and renal effects seen in preclinical studies as well as meta-analysis of clinical trials may offer additional potentials - beyond improvement of glycemic control - for this newer class of drugs, such as acute kidney failure, chronic kidney failure as well as acute myocardial infarction and heart failure.
DNA Interstrand Crosslinks: Natural and Drug‐Induced DNA Adducts that Induce Unique Cellular Responses (2005)

Tied down. DNA interstrand crosslinks are cytotoxic adducts formed naturally and by drugs used in antitumor therapy. Our current knowledge of the cellular responses induced by crosslinks and new methods for the synthesis of crosslinks developed to study the biological responses they induce are reviewed.
Splitting of channeling-radiation peaks in strained-layer superlattices (1991)

The peaks in the spectrum of channeling radiation from 106–109-eV electrons traversing crystalline targets are split into two families if the target is a strained-layer superlattice (SLS). We have studied one example of this effect, including the spectral shifts and, especially, the intensity variations that occur when the crystal is rocked. Because of their strong dependence on beam orientation relative to a channel axis, these phenomena should provide a sensitive measure of the strains in the SLS layers as well as of the population of the bound states. Because of the natural widths of the photon peaks in thin layers, good observability will be ensured for superlattice layers with a thickness of several hundred angstroms or more, although in practice this restriction may quite possibly be considerably relaxed, narrow widths not being essential to the observability of the effect.
Intimal thickening and medial necrosis in allograft arteriosclerosis (chronic rejection) are independently regulated. (1993)

Rat aortic allografts from the DA (RT1a) to the WF (RT1v) strain but not syngeneic DA-to-DA control grafts develop arteriosclerotic changes in the vascular wall that are virtually identical to human allografts during chronic rejection. A more prominent medial cell destruction in the rat aorta, leading ultimately to complete medial necrosis, is the major difference between rat and human allografts. If the adventitia of syngeneic grafts is exposed to starch before transplantation, these grafts also develop an inflammatory reaction in the adventitia and an extensive intimal thickening at the site of the granulomas, but the medial smooth muscle cells are preserved. In both types of transplants with an intact endothelium as determined by light microscopy, adventitial inflammatory cell proliferation was accompanied by smooth muscle cell replication in the media and thickening of the intima. We therefore propose that an adventitial proliferative response is a prerequisite for intimal thickening to occur. In the allograft but not in starch-exposed syngeneic grafts there was also a notable lymphoid activation in the adventitia, which was accompanied by medial necrosis. We suggest that the medial necrosis in the allograft is linked to a toxic effect of activated lymphoid cells on medial myocytes and is not a prerequisite for intimal proliferation. Instead, intimal proliferation and medial necrosis in the allograft seem to be independently regulated.
Rational design of a small molecule-responsive intramer controlling transgene expression in mammalian cells (2011)

Aptamers binding proteins or small molecules have been shown to be versatile and powerful building blocks for the construction of artificial genetic switches. In this study, we present a novel aptamer-based construct regulating the Tet Off system in a tetracycline-independent manner thus achieving control of transgene expression. For this purpose, a TetR protein-inhibiting aptamer was engineered for use in mammalian cells, enabling the RNA-responsive control of the tetracycline-dependent transactivator (tTA). By rationally attaching the theophylline aptamer as a sensor, the inhibitory TetR aptamer and thus tTA activity became dependent on the ligand of the sensor aptamer. Addition of the small molecule theophylline resulted in enhanced binding to the corresponding protein in vitro and in inhibition of reporter gene expression in mammalian cell lines. By using aptamers as adaptors in order to control protein activity by a predetermined small molecule, we present a simple and straightforward approach for future applications in the field of Chemical Biology. Moreover, aptamer-based control of the widely used Tet system introduces a new layer of regulation thereby facilitating the construction of more complex gene networks.
Antiviral therapy: current concepts and practices (1992)

Drugs capable of inhibiting viruses in vitro were described in the 1950s, but real progress was not made until the 1970s, when agents capable of inhibiting virus-specific enzymes were first identified. The last decade has seen rapid progress in both our understanding of antiviral therapy and the number of antiviral agents on the market. Amantadine and ribavirin are available for treatment of viral respiratory infections. Vidarabine, acyclovir, ganciclovir, and foscarnet are used for systemic treatment of herpesvirus infections, while ophthalmic preparations of idoxuridine, trifluorothymidine, and vidarabine are available for herpes keratitis. For treatment of human immunodeficiency virus infections, zidovudine and didanosine are used. Immunomodulators, such as interferons and colony-stimulating factors, and immunoglobulins are being used increasingly for viral illnesses. While resistance to antiviral drugs has been seen, especially among AIDS patients, it has not become widespread and is being intensely studied. Increasingly, combinations of agents are being used: to achieve synergistic inhibition of viruses, to delay or prevent resistance, and to decrease dosages of toxic drugs. New approaches, such as liposomes carrying antiviral drugs and computer-aided drug design, are exciting and promising prospects for the future.
Structure of human milk bile salt activated lipase (1991)

The structure and some functional sites of human milk bile salt activated lipase (BAL) were studied by cDNA cloning and chemical analysis of the enzyme. Eighteen cDNA clones of human BAL were identified from lactating human breast cDNA libraries in lambda gt11 and lambda gt10 with antibody and synthetic oligonucleotides as probes. The sequence of four clones was sufficient to construct a 3018-bp BAL cDNA structure. This sequence codes for an open reading frame of 742 amino acid residues. There is a putative signal sequence of 20 residues which is followed by the amino-terminal sequence of BAL, and the mature BAL contains 722 amino acid residues. The cDNA sequence also contains a 678-base 5'-untranslated sequence, a 97-base 3'-untranslated region, and a 14-base poly(A) tail. The sequence of a 1.8-kbp insert of clone G10-4A differs from that of the other cDNA in that it contains a deletion of 198 bases (1966-2163) corresponding to 66 amino acid residues. By use of BAL cDNA as probe, it was found that the major molecular species of BAL mRNA in human mammary gland HBL-100 cells had a size of 2.9 kb and two minor species had sizes of 3.8 and 5.1 kb by Northern blot analyses. The deduced BAL protein structure contains in the carboxyl-terminal region 16 repeating units of 11 amino acids each. The repeating units have the basic structure Pro-Val-Pro-Pro-Thr-Gly-Asp-Ser-Gly-Ala-Pro with only minor substitutions. The amino acid sequence of human BAL is related to that of pancreatic lysophospholipase, cholesterol esterase, cholinesterase, acetylcholinesterase, and thyroglobulin. Ten of the 14 cyanogen bromide fragments of diisopropyl fluorophosphate inhibited human milk BAL were isolated, determined for N-terminal sequences, analyzed for amino sugars, and tested for some functional properties. These chemical studies established that the active site of human milk BAL is located at serine-194, the N-glycosylation site is present at asparagine-187, the O-glycosylation region is in the 16 repeating units near the C-terminus, and the heparin binding domain is in the N-terminal region. We have also determined the location of disulfide bridges as Cys64-Cys80 and Cys246-Cys257. The cyanogen bromide cleavage and the partial sequencing of CNBr peptides also confirmed the location of methionines in the polypeptide chain as well as the deduced cDNA sequence of BAL.
Abilities of OspA proteins from different seroprotective groups of Borrelia burgdorferi to protect hamsters from infection (1995)

The ability of vaccination with recombinant OspA from six seroprotective groups of Borrelia burgdorferi sensu lato to induce protection against infection with homologous and other Lyme spirochetes was examined in hamsters. Antisera generated against the OspA proteins of B. burgdorferi sensu stricto S-1-10 and C-1-11 (seroprotective groups 1 and 2, respectively), Borrelia afzelii BV1 (seroprotective group 4), and Borrelia garinii LV4 (seroprotective group 5) were able to kill the homologous spirochete in vitro but not other isolates. Surprisingly, antisera against B. afzelii PKo (seroprotective group 6) and B. burgdorferi sensu lato LV5 (seroprotective group 3) OspA proteins were unable to kill the homologous organism, although LV5 OspA antisera killed the heterologous isolates S-1-10 and LV4. In vivo vaccination studies supported the in vitro findings, confirming that vaccination with a single OspA protein does not provide complete protection against challenge with all Lyme disease spirochetes. In addition, OspA antibodies from some isolates may not protect against the homologous isolate. The induction of protective antibodies against other B. burgdorferi proteins may be necessary to insure a comprehensive Lyme disease vaccine.
Chondroprotective drugs in degenerative joint diseases (2005)

Catabolic cytokine and anabolic growth factor pathways control destruction and repair in osteoarthritis (OA). A unidirectional TNF-alpha/IL-1-driven cytokine cascade disturbs the homeostasis of the extracellular matrix of articular cartilage in OA. Although chondrocytes in OA cartilage overexpress anabolic insulin-like growth factor (IGF) and its specific receptor (IGFRI) autocrine TNF-alpha released by apoptotic articular cartilage cells sets off an auto/paracrine IL-1-driven cascade that overrules the growth factor activities that sustain repair in degenerative joint disease. Chondroprotection with reappearance of a joint space that had disappeared has been documented unmistakably in peripheral joints of patients suffering from spondyloarthropathy when treated with TNF-alpha-blocking agents that repressed the unidirectional TNF-alpha/IL-1-driven cytokine cascade. A series of connective tissue structure-modifying agents (CTSMAs) that directly affect IL-1 synthesis and release in vitro and down-modulate downstream IL-1 features, e.g. collagenase, proteoglycanase and matrix metalloproteinase activities, the expression of inducible nitric oxide synthase, the increased release of nitric oxide, and the secretion of prostaglandin E(2), IL-6 and IL-8, have been shown to possess disease-modifying OA drug (DMOAD) activities in experimental models of OA and in human subjects with finger joint and knee OA. Examples are corticosteroids, some sulphated polysaccharides, chemically modified tetracyclines, diacetylrhein/rhein, glucosamine and avocado/soybean unsaponifiables.
[Influence of delta-sleep-inducing peptide on the activity of proteolytic enzymes in the rat brain under hypokinesia]. (1993)

Single administration of the delta-sleep-inducing peptide (DSIP) in a dose of 12 micrograms/100 g to intact animals makes the activity of neutral proteinases and cathepsin D higher in the rat brain and blood serum. Hypokinesia of different duration changes activity of neutral and acidic proteinases and induces accessibility of cathepsin D to the cytosol as a result of damage in lysosomal membrane. Injection DSIP induces a decrease A/B of cathepsin D to the control level under 1-h hypokinesia condition and normalizes the neutral proteolytic activity under 6-h hypokinesia condition.
Juvenile rheumatoid arthritis (1999)

The heterogeneous nature of juvenile rheumatoid arthritis is further defined in publications from the past year. Decreased IL-10 production, an anti-inflammatory cytokine, and soluble IL-6 receptor are associated with systemic juvenile rheumatoid arthritis (JRA). IL-4 may have an anti-inflammatory role in the pathogenesis of pauciarticular JRA and may protect, along with IL-10, against the development of joint erosions. Active JRA is associated with lower levels of platelet activating factor acetylhydrolase, which may contribute to the loss of anti-inflammatory activity and increased risk of atherogenesis. The phase 3 clinical trial of etanercept confirmed its efficacy and safety in JRA. Intra-articular steroids are safe and effective in the treatment of JRA. Methotrexate does have disease-modifying effects. The risk of hepatotoxicity with methotrexate use increases with serial transaminase abnormalities and with obesity. Osteoclasts are responsible for joint erosions. Cyclosporine A, mycophenolate mofetil, and methotrexate are effective in the treatment of refractory uveitis. During the past year a number of scientific publications have contributed significantly to our understanding and treatment of juvenile rheumatoid arthritis.
Electrophoretically detected germinal mutations induced in the mouse by ethylnitrosourea. (1981)

Male DBA/2J and C57BL/6J mice were treated with ethylnitrosourea (EtNU) at a dose of 250 mg/kg of body weight. After a sterile period of 11 weeks, the treated animals were mated with untreated females; treated DBA with C57 and treated C57 with DBA. A small control group of untreated males was established, and a larger control group from earlier experiments was also used for comparison. Tissue samples removed surgically from the parents and F1 offspring were examined by electrophoresis. Nine newly arisen mutants attributable to induction by EtNU were found in 22,512 loci tested for mutation. No mutations were encountered in 290,252 control locus tests. A preliminary study conducted concomitantly with the electrophoretic analyses for dominant lethal effects and physical malformation showed no increase over background due to EtNU treatment of spermatogonia, which suggests that mutations induced by EtNU tend not to be expressed in this way. The nature of the mutants identified by electrophoresis facilitates follow-up analyses leading to increased understanding of the molecular basis and the physiological effects of induced mutations in mammalian organisms.
T cell clones specific for an amphipathic alpha-helical region of sperm whale myoglobin show differing fine specificities for synthetic peptides. A multiview/single structure interpretation of immunodominance. (1986)

The T cell response to sperm whale myoglobin in the H-2d haplotype has been shown to be largely focused on a limited region around glutamic acid 109 recognized in association with I-Ad. T cell clones 9.27 and 1.2 have been previously (4, 5) shown to reflect this specificity and MHC restriction. In this study we have used a panel of synthetic peptides from the region 102-118 of myoglobin to characterize the specificities of these representative clones. The segment from 106-118 was found to represent a consensus region for recognition by both clones. However, we saw significant differences between clones in the hierarchy of responsiveness to peptides within the panel. In as much as the peptide and the I-Ad molecule remain constant, these differences derive from differences in how each T cell receptor interacts with the antigen. This peptide segment is an amphipathic alpha helix in native myoglobin, meaning that one side is hydrophobic and the other hydrophilic. It is one of the prototype cases that led us to find that amphipathic helices constitute the majority of immunodominant sites recognized by helper T cells (1). It is likely that the peptide will refold into an amphipathic helix stabilized by the interface at the surface of the presenting cell. When such secondary conformation is considered, these data are consistent with a model of multiple T cell specificities arising from multiple views of a single antigen conformation at a single Ia-binding site and do not require postulation of multiple conformations or binding sites. Additionally, the finding of distinct specificities suggests that the immunodominance of this site depends not on the dominance of a single clone, but on the focusing of a polyclonal response on a single region of the molecule in association with I-Ad. The immunodominance of this particular region of the protein may thus depend on intrinsic features of the site, such as potential to form an amphipathic helix, as well as extrinsic factors such as binding properties of the I-A molecule.
Interactions among genes in the ErbB-Neuregulin signalling network are associated with increased susceptibility to schizophrenia (2007)

These new findings suggest that observed associations between NRG1 and schizophrenia may be mediated through functional interaction not just with ERBB4, but with other members of the NRG and ERBB families. There is evidence that genetic interaction among these loci may increase susceptibility to schizophrenia.
Defective induction of antigen‐reactive proliferating T cells in B cell‐deprived mice (1981)

Mice were injected from day of birth onward with rabbit anti-mouse IgM antiserum or purified rabbit anti-mouse IgM antibodies. These mice completely lacked Ig-positive cells or serum Ig, as analyzed by specific fluoresceinated antibodies on the fluorescence-activated cell sorter (FACS-II), by polyclonal B cell mitogens and by specific precipitation in agar. These animals were then primed in vivo by antigen emulsified in complete Freund's adjuvant, and, subsequently, their draining lymph nodes were tested for their T cell proliferative responses in vitro, to the relevant antigen and were found to be severely impaired. However, the antigen-presenting capacity of both spleen cells and thioglycollate-induced peritoneal cells was found to be intact.
Process Scale Bioseparations for the Biopharmaceutical Industry (2006)

Process scale bioseparations for the biopharmaceutical industry , Process scale bioseparations for the biopharmaceutical industry , کتابخانه مرکزی دانشگاه علوم پزشکی تهران
High-flow microinfusion: tissue penetration and pharmacodynamics (1994)

High-flow microinfusion provides a means for delivering macromolecules to large volumes of brain in easily obtainable time intervals. Slowly degraded approximately 180-kDa macromolecules, delivered at a constant volumetric flow rate of 3 microliters/min into homogeneous brain tissue (e.g., gray matter), would penetrate to a 1.5-cm radius in 12 h. The predicted concentration profile is relatively flat until it declines precipitously at the flow front. Hence, tissues are dosed rather uniformly, providing control over the undesired toxicity that may occur with alternative methods that depend on large concentration gradients for tissue transport. The penetration advantage of high-flow (convective) over low-flow (diffusive) microinfusion has been assessed at fixed pharmacodynamic effect. A 12-h high-flow microinfusion of a macromolecule degraded with a characteristic time of 33.5 h would provide 5- to 10-fold increases in volume over low-flow infusion and total treatment volumes > 10 cm3. Slower degradation rates would result in larger treatment volumes; more rapid degradation rates would reduce the volume but still favor convective over diffusive administration. This technique may be applicable to a variety of diagnostic and therapeutic agents such as radioimmunoconjugates, immunotoxins, enzymes, growth factors, and oligonucleotides.
Fabrication of thin-film V-groove inductors using composite magnetic materials (2002)

A new fabrication process is described for high performance embedded or integrated inductors for power converters. The process includes etching V-grooves in a silicon substrate, depositing granular composite magnetic materials, and electroplating the copper conductors.