gebhart/patrepeval huggingface dataset:
Novel 7-Substituted Camptothecins with Potent Antitumor Activity (2000)

The natural alkaloid camptothecin is the lead compound of a new class of antitumor agents with a unique mechanism of action (i.e. inhibition of DNA topoisomerase I). The pharmacological interest of these agents has generated a large number of derivatives and analogues endowed with potent cytotoxic activity, two of them being in clinical use as antitumor drugs. We have synthesized a new series of camptothecins substituted in position 7 with an alkyl or alkenyl chain bearing cyano and/or carbethoxy groups. These compounds showed potent cytotoxic activity in vitro against the human non-small-cell lung carcinoma H460 cell line, most of them exhibiting IC(50) values in the 0.05-1 microM range, more active than topotecan used as a reference compound. In particular 7-cyano-20S-camptothecin (5a) showed high in vitro cytotoxicity against a topotecan-resistant H460 cell subline (H460/TPT) and a cisplatin-resistant ovarian carcinoma subline (IGROV-1/Pt 1). In an in vivo evaluation of the antitumor activity, 5a appeared significantly more effective than topotecan in the H460 tumor model and comparable with topotecan in a small-cell lung carcinoma model and a colon carcinoma model. The efficacy and good tolerability of this compound increase interest for further preclinical development.
Skeletal muscle myostatin mRNA expression is fiber-type specific and increases during hindlimb unloading (1999)

Transgenic mice lacking a functional myostatin (MSTN) gene demonstrate greater skeletal muscle mass resulting from muscle fiber hypertrophy and hyperplasia (McPherron, A. C., A. M. Lawler, and S. -J. Lee. Nature 387: 83-90, 1997). Therefore, we hypothesized that, in normal mice, MSTN may act as a negative regulator of muscle mass. Specifically, we hypothesized that the predominately slow (type I) soleus muscle, which demonstrates greater atrophy than the fast (type II) gastrocnemius-plantaris complex (Gast/PLT), would show more elevation in MSTN mRNA abundance during hindlimb unloading (HU). Surprisingly, MSTN mRNA was not detectable in weight-bearing or HU soleus muscle, which atrophied 42% by the 7th day of HU in female ICR mice. In contrast, MSTN mRNA was present in weight-bearing Gast/PLT muscle and was significantly elevated (67%) at 1 day but not at 3 or 7 days of HU. However, the Gast/PLT muscle had only atrophied 17% by the 7th day of HU. Because the soleus is composed only of type I and IIa fibers, whereas the Gast/PLT expresses type IId/x and IIb in addition to type I and IIa, it was necessary to perform a more careful analysis of the relationship between MSTN mRNA levels and myosin heavy-chain (MHC) isoform expression (as a marker of fiber type). A significant correlation (r = 0.725, P < 0. 0005) was noted between the percentage of MHC isoform IIb expression and MSTN mRNA abundance in several muscles of the mouse hindlimb. These results indicate that MSTN expression is not strongly associated with muscle atrophy induced by HU; however, it is strongly associated with MHC isoform IIb expression in normal muscle.
Therapeutic applications and design of mast cell tryptase inhibitors. (1999)

In recent years, a role for the mast cell has emerged as a multifunctional, key effector cell in the immune system and may also serve to modulate the inflammatory response and immune-nervous system interactions. Mast cell stimulation leads to the secretion of several classes of mediators including proteolytic enzymes, most notably the trypsin-like serine proteinase, tryptase. Recent immunological and biological studies have demonstrated an association of mast cells and tryptase activity with a broad range of allergic and inflammatory conditions affecting nearly all the major systems of the human body. At present, there is sufficient evidence to strongly suggest that tryptase activity is a key aspect of some common and serious allergic and inflammatory diseases, particularly asthma. Due to the increasing prevalence of asthma in industrialized society, the inhibition of tryptase is viewed as a potentially important and novel therapeutic mechanism for disease intervention. Recent advances in the design of potent and selective inhibitors of tryptase provide a great deal of promise for the development of safe and effective drugs for the treatment of asthma and possibly a range of other diseases in the early 21st century.
Recurrent Rearrangements in Synaptic and Neurodevelopmental Genes and Shared Biologic Pathways in Schizophrenia, Autism, and Mental Retardation (2009)

Weakly to moderately recurrent CNVs (transmitted or occurring de novo) seem to be causative or contributory factors for these diseases. Most of these CNVs (which contain genes involved in neurotransmission or in synapse formation and maintenance) are present in the 3 pathologic conditions (schizophrenia, autism, and mental retardation), supporting the existence of shared biologic pathways in these neurodevelopmental disorders.
Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing (2013)

We explored the detection of genome-wide hypomethylation in plasma using shotgun massively parallel bisulfite sequencing as a marker for cancer. Tumor-associated copy number aberrations (CNAs) could also be observed from the bisulfite DNA sequencing data. Hypomethylation and CNAs were detected in the plasma DNA of patients with hepatocellular carcinoma, breast cancer, lung cancer, nasopharyngeal cancer, smooth muscle sarcoma, and neuroendocrine tumor. For the detection of nonmetastatic cancer cases, plasma hypomethylation gave a sensitivity and specificity of 74% and 94%, respectively, when a mean of 93 million reads per case were obtained. Reducing the sequencing depth to 10 million reads per case was found to have no adverse effect on the sensitivity and specificity for cancer detection, giving respective figures of 68% and 94%. This characteristic thus indicates that analysis of plasma hypomethylation by this sequencing-based method may be a relatively cost-effective approach for cancer detection. We also demonstrated that plasma hypomethylation had utility for monitoring hepatocellular carcinoma patients following tumor resection and for detecting residual disease. Plasma hypomethylation can be combined with plasma CNA analysis for further enhancement of the detection sensitivity or specificity using different diagnostic algorithms. Using the detection of at least one type of aberration to define an abnormality, a sensitivity of 87% could be achieved with a specificity of 88%. These developments have thus expanded the applications of plasma DNA analysis for cancer detection and monitoring.
Changes in CD45 isoform expression accompany antigen-induced murine T-cell activation. (1989)

Leukocytes express a family of plasma membrane proteins called CD45 or the leukocyte common antigen. Isoforms of various molecular masses, 180-240 kDa, are produced by alternative splicing and usage of three exons, named A, B, and C, that encode the N-terminal portion of the external domain. By using monoclonal antibodies that precipitate B exon-dependent and B exon-independent isoforms we find that both murine CD4+ and murine CD8+ T cells selectively down-regulate the B exon-dependent forms of CD45 during an immune response. This change was monitored by using fluorescence-activated cell sorter (FACS) analysis and immunoprecipitation from surface radioiodinated and metabolically labeled cells. The loss of the 190-kDa B exon-dependent isoform during T-cell activation is accompanied by an increased production of a 180-kDa form, which does not contain the B exon-encoded sequence. This accounts for our observation that the overall expression of CD45, as assessed by FACS analysis, does not change.
Drebrin E is involved in the regulation of axonal growth through actin–myosin interactions (2009)

Drebrin is a well-known side-binding protein of F-actin in the brain. Immunohistochemical data suggest that the peripheral parts of growing axons are enriched in the drebrin E isoform and mature axons are not. It has also been observed that drebrin E is concentrated in the growth cones of PC12 cells. These data strongly suggest that drebrin E plays a role in axonal growth during development. In this study, we used primary hippocampal neuronal cultures to analyze the role of drebrin E. Immunocytochemistry showed that within axonal growth cones drebrin E specifically localized to the transitional zone, an area in which dense networks of F-actins and microtubules overlapped. Over-expression of drebrin E caused drebrin E and F-actin to accumulate throughout the growth cone and facilitated axonal growth. In contrast, knockdown of drebrin E reduced drebrin E and F-actin in the growth cone and prevented axonal growth. Furthermore, inhibition of myosin II ATPase masked the promoting effects of drebrin E over-expression on axonal growth. These results suggest that drebrin E plays a role in axonal growth through actin-myosin interactions in the transitional zone of axonal growth cones.
Fuzzy combination of Kohonen's and ART neural network models to detect statistical regularities in a random sequence of multi-valued input patterns (2002)

A fuzzy simplified ART (SART) implementation is now proposed to combine SART architecture with a Kohonen-based soft learning strategy which employs a fuzzy membership function. Fuzzy SART consists of an attentional and an orienting subsystem. The fuzzy SART attentional subsystem is a self-organizing feedforward flat homogeneous network performing learning by examples. During the processing of a given data set, the fuzzy SART orienting subsystem: 1) adds a new neuron to the attentional subsystem whenever the system fails to recognize an input pattern; and 2) removes a previously allocated neuron from the attentional subsystem if the neuron is no longer able to categorize any input pattern. The performance of fuzzy SART is compared with that of the CGR fuzzy ART model when a 2D data set and the 4D IRIS data set are processed. Unlike the CGR fuzzy ART system, fuzzy SART: 1) requires no input data preprocessing; 2) features stability to small changes in input parameters and in the order of the input sequence; and 3) is competitive when compared to other neural network models found in the literature.
Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease (2000)

With the ultimate goal of developing safe and effective in vivo gene therapy for the treatment of Canavan disease and other neurological disorders, we developed a non-viral lipid-entrapped, polycation-condensed delivery system (LPD) for central nervous system gene transfer, in conjunction with adeno-associated virus (AAV)-based plasmids containing recombinant aspartoacylase (ASPA). The gene delivery system was tested in healthy rodents and primates, before proceeding to preliminary studies in 2 children with Canavan disease. Toxicity and expression testing was first carried out in human 293 cells, which demonstrated effective transduction of cells and high levels of functional ASPA activity. We performed in vivo toxicity and expression testing of LPD/pAAVaspa and LPD/pAAVlac in rodents, which demonstrated widespread gene expression for more than 10 months after intraventricular delivery, and local expression in deep brain nuclei and white matter tracts for more than 6 months after intraparenchymal injections, with no significant adverse effects. We also performed intraventricular delivery of LPD/pAAVaspa to 2 cynomologous monkeys, with 2 additional monkeys receiving LPD and saline controls. None of the monkeys demonstrated significant adverse effects, and at 1 month the 2 LPD/pAAVaspa monkeys were positive for human ASPA transcript by reverse transcriptase polymerase chain reaction of brain tissue punches. Finally, we performed the first in vivo gene transfer study for a human neurodegenerative disease in 2 children with Canavan disease to assess the in vivo toxicity and efficacy of ASPA gene delivery. Our results suggest that LPD/pAAVaspa is well tolerated in human subjects and is associated with biochemical, radiological, and clinical changes.
The Loss of Postprandial Glycemic Control Precedes Stepwise Deterioration of Fasting With Worsening Diabetes (2007)

The deterioration of glucose homeostasis in individuals with type 2 diabetes progressed from postprandial to fasting hyperglycemia following a three-step process. The first step related to the three diurnal postmeal periods considered as a whole, the second step occurred during the morning period, and the third and final step corresponded to sustained hyperglycemia over the nocturnal fasting periods. Such a description of the key stages in the evolution of type 2 diabetes may be of interest for implementing antidiabetes treatment.
Effects of molecular weight and degree of acetylation on the release of nitric oxide from chitosan‐nitric oxide adducts (2010)

Abstract A series of chitosans with different molecular weights and degrees of acetylation (DAs) are reacted with nitric oxide (NO) to form [NONO] − groups. The effects of molecular weight and DA on NO release are investigated by Griess assay. Heterogeneous reaction of NH 2 groups of chitosan with NO was shown to be influenced greatly by the crystalline form of chitosan. Total NO release exhibited a bell‐shaped distribution at different DAs ranging from 6 to 95%, peaking at about 50%. When DA is held constant, total NO release is directly proportional to the molecular weight. X‐ray diffraction patterns indicate that the total NO release of chitosan‐NO adducts is in general agreement with the intensity of reflections at low Bragg angles (2θ = 8.6°–11.1°), and in turn, a relaxed hydration crystalline form and NO molecules could penetrate this crystal and react with the chitosan molecules. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010
<title>Effect of relative humidity on the mechanical properties of UV-curable optical fiber coatings</title> (1993)

Optical fiber used in telecommunication networks encounters environments ranging from essentially dry to very high relative humidity. Mechanical properties of optical fibers must be maintained in these different environments. The mechanical properties of a number of UV cured inner and outer primary optical fiber coatings were examined as a function of relative humidity. It was observed that the mechanical property changes as a function of relative humidity were related to the water sensitivity of these coatings. Coatings with higher peak water absorption showed a larger decrease in mechanical properties.
Transmission of IPv6 over IPv4 Domains without Explicit Tunnels (1999)

This memo specifies the frame format for transmission of IPv6 [IPV6] packets and the method of forming IPv6 link-local addresses over IPv4 domains.It also specifies the content of the Source/Target Linklayer Address option used in the Router Solicitation, Router Advertisement, Neighbor Solicitation, and Neighbor Advertisement and Redirect messages, when those messages are transmitted on an IPv4 multicast network.The motivation for this method is to allow isolated IPv6 hosts, located on a physical link which has no directly connected IPv6 router, to become fully functional IPv6 hosts by using an IPv4 domain that supports IPv4 multicast as their virtual local link.It uses IPv4 multicast as a "virtual Ethernet".
Blockade of NKG2D signaling prevents the development of murine CD4+T cell-mediated colitis (2007)

It has been recently demonstrated that NKG2D is an activating costimulatory receptor on natural killer (NK) cells, natural killer T (NKT) cells, activated CD8(+) T cells, and gammadelta T cells, which respond to cellular stress, such as inflammation, transformation, and infection. Here we show that intestinal inflammation in colitic SCID mice induced by adoptive transfer of CD4(+)CD45RB(high) T cells is characterized by significant increase of CD4(+)NKG2D(+) T cells and constitutive expression of NKG2D ligands, such as H60, Mult-1, and Rae-1, by lamina propria CD11c(+) dendritic cells. Furthermore, treatment with nondepleting and neutralizing anti-NKG2D MAb after transfer of CD4(+)CD45RB(high) T cells into SCID mice significantly suppressed wasting disease with colitis, abrogated leukocyte infiltration, and reduced production of IFN-gamma by lamina propria CD4(+) T cells. These findings demonstrate that NKG2D signaling pathway is critically involved in CD4(+) T cell-mediated disease progression and suggest a new therapeutic target for inflammatory bowel diseases.
Pathogenesis of NIDDM: A Balanced Overview (1992)

Non-insulin-dependent diabetes mellitus (NIDDM) results from an imbalance between insulin sensitivity and insulin secretion. Both longitudinal and cross-sectional studies have demonstrated that the earliest detectable abnormality in NIDDM is an impairment in the body's ability to respond to insulin. Because the pancreas is able to appropriately augment its secretion of insulin to offset the insulin resistance, glucose tolerance remains normal. With time, however, the beta-cell fails to maintain its high rate of insulin secretion and the relative insulinopenia (i.e., relative to the degree of insulin resistance) leads to the development of impaired glucose tolerance and eventually overt diabetes mellitus. The cause of pancreatic "exhaustion" remains unknown but may be related to the effect of glucose toxicity in a genetically predisposed beta-cell. Information concerning the loss of first-phase insulin secretion, altered pulsatility of insulin release, and enhanced proinsulin-insulin secretory ratio is discussed as it pertains to altered beta-cell function in NIDDM. Insulin resistance in NIDDM involves both hepatic and peripheral, muscle, tissues. In the postabsorptive state hepatic glucose output is normal or increased, despite the presence of fasting hyperinsulinemia, whereas the efficiency of tissue glucose uptake is reduced. In response to both endogenously secreted or exogenously administered insulin, hepatic glucose production fails to suppress normally and muscle glucose uptake is diminished. The accelerated rate of hepatic glucose output is due entirely to augmented gluconeogenesis. In muscle many cellular defects in insulin action have been described including impaired insulin-receptor tyrosine kinase activity, diminished glucose transport, and reduced glycogen synthase and pyruvate dehydrogenase. The abnormalities account for disturbances in the two major intracellular pathways of glucose disposal, glycogen synthesis, and glucose oxidation. In the earliest stages of NIDDM, the major defect involves the inability of insulin to promote glucose uptake and storage as glycogen. Other potential mechanisms that have been put forward to explain the insulin resistance, include increased lipid oxidation, altered skeletal muscle capillary density/fiber type/blood flow, impaired insulin transport across the vascular endothelium, increased amylin, calcitonin gene-related peptide levels, and glucose toxicity.
SoftBound (2009)

The serious bugs and security vulnerabilities facilitated by C/C++'s lack of bounds checking are well known, yet C and C++ remain in widespread use. Unfortunately, C's arbitrary pointer arithmetic, conflation of pointers and arrays, and programmer-visible memory layout make retrofitting C/C++ with spatial safety guarantees extremely challenging. Existing approaches suffer from incompleteness, have high runtime overhead, or require non-trivial changes to the C source code. Thus far, these deficiencies have prevented widespread adoption of such techniques. This paper proposes SoftBound, a compile-time transformation for enforcing spatial safety of C. Inspired by HardBound, a previously proposed hardware-assisted approach, SoftBound similarly records base and bound information for every pointer as disjoint metadata. This decoupling enables SoftBound to provide spatial safety without requiring changes to C source code. Unlike HardBound, SoftBound is a software-only approach and performs metadata manipulation only when loading or storing pointer values. A formal proof shows that this is sufficient to provide spatial safety even in the presence of arbitrary casts. SoftBound's full checking mode provides complete spatial violation detection with 67% runtime overhead on average. To further reduce overheads, SoftBound has a store-only checking mode that successfully detects all the security vulnerabilities in a test suite at the cost of only 22% runtime overhead on average.
The effects of the selective and non‐peptide CXCR2 receptor antagonist SB225002 on acute and long‐lasting models of nociception in mice (2009)

This study evaluated the antinociceptive effects of the selective and non-peptide CXCR2 antagonist SB225002 in mouse models of pain. As assessed in different tests of spontaneous nociception, intraperitoneal (i.p.) administration of SB225002 caused consistent and dose-related reduction of acetic acid-induced abdominal constrictions, whereas it did not significantly affect the nociception evoked by formalin, capsaicin, glutamate or phorbol ester acetate (PMA). Systemic treatment with SB225002 strikingly reduced the spontaneous nociception induced by 8-bromo-cAMP (8-Br-cAMP), or mechanical hypernociception induced by prostaglandin E(2) (PGE(2)), epinephrine, or the keratinocyte-derived chemokine (KC). In the carrageenan model, SB225002 markedly reduced mechanical hypernociception when administered by i.p., intrathecal (i.t.) or intracerebroventricular (i.c.v.) routes, or even when co-administered with carrageenan into the mouse paw, indicating peripheral and central sites of action for SB225002. In addition, i.p. treatment with SB225002 significantly attenuated the increase in MPO activity or the elevation of IL-1beta, TNFalpha or KC levels following carrageenan injection. In the persistent models of pain evoked by complete Freund's adjuvant (CFA) or by the partial ligation of the sciatic nerve (PLSN), the repeated administration of SB225002 displayed prominent and long-lasting antinociceptive effects. Notably, SB225002 did not evoke unspecific central effects, as evaluated in the open-field and rota-rod tests, or even in the latency responses for thermal stimuli. Our data confirm the previous notion on the critical role exerted by chemokines in pain, indicating that selective CXCR2 antagonists, such as SB225002, might well represent interesting and innovative alternatives for the management of both acute and chronic pain.