gebhart/patrepeval huggingface dataset:
Prospects for Hypoxia-Activated Anticancer Drugs (2004)

The occurrence of hypoxic cells in solid tumors, and their resistance to radiotherapy and many chemotherapeutic drugs, has engendered an interest in non-toxic prodrugs that can be activated selectively under hypoxic conditions. Despite this, no such compounds are yet registered for clinical use, due to the difficulty of their design and of measuring the extent of hypoxia clinically, and the failure of early examples. A new appreciation of the critical importance of the extravascular diffusion of the parent prodrug from the blood vessels to the remote hypoxic cells, and the back-diffusion of the activated cytotoxin from the hypoxic cells to surrounding tumor cells, is now guiding drug design in this area. New principles for the selective activation of prodrugs have also been reported, including using the reducing species generated in cells by radiotherapy itself, and using non-pathogenic anaerobic bacteria as a hypoxia-dependent vector for the delivery of prodrug-activating enzymes in a suicide gene therapy context.
Critical role of NK1+ T cells in IL-12-induced immune responses in vivo. (1998)

CD1-dependent NK1+ T cells rapidly produce IL-4 upon stimulation through the TCR. These cells may therefore play an important role in the initiation of Th2 responses. Here, we show that NK1+ T cells constitutively express receptors for IL-12 and IFN-gamma, and that IL-12 induces production of perforin in these cells. Moreover, while IL-12 induces high levels of IFN-gamma and cytotoxic activity of hepatic or splenic mononuclear cells against tumor cells, this effect of IL-12 is significantly reduced in CD1-deficient mice with impaired NK1+ T cells development. These results indicate that NK1+ T cells play a critical role in IL-12-induced production of IFN-gamma to initiate Th1 immune responses and as IL-12-induced cytotoxic effector cells to initiate antitumor immunity.
Studies using antigen-presenting cells lacking expression of both B7-1 (CD80) and B7-2 (CD86) show distinct requirements for B7 molecules during priming versus restimulation of Th2 but not Th1 cytokine production. (1998)

The differentiation of CD4+ T cells into a Th1 vs Th2 phenotype profoundly influences the outcome of autoimmune and infectious diseases. B7 costimulation has been shown to affect the production of both Th1 and Th2 cytokines, depending on the system studied. There is, consequently, great interest in manipulating the B7 costimulatory signal for therapeutic purposes. To optimally manipulate this key immunoregulatory pathway, the contribution of B7 costimulation to cytokine production requires further clarification. We have compared the B7 requirement for cytokine production by naive vs previously activated T cells using DO11.10 TCR transgenic CD4+ T cells and splenic APCs from mice lacking B7 expression. Our data indicate that induction of IL-4 production and Th2 differentiation by naive T cells is highly dependent on B7 molecules, whereas IL-4 production by previously activated T cells is B7 independent. The predominant contribution of B7-mediated signals to Th1 cytokine production by both naive and primed T cells is upon IL-2 production (and expansion) rather than IFN-gamma (effector cytokine) production. Thus, our studies demonstrate that the antigenic experience of a T cell at the time of B7 blockade may determine whether blockade predominantly affects T cell expansion, differentiation, or effector cytokine production. These differential effects of B7 costimulation on IL-2 vs IFN-gamma production and on IL-4 production by naive vs primed T cells have important implications for understanding how B7:CD28/CTLA4 blockade can be effectively used to manipulate cytokine production in vivo.
Ineffectiveness of enzyme therapy on regeneration in the transected spinal cord of the rat (1980)

✓ The potential clinical significance of the experiments of Matinian and Andreasian prompted repetition of their experiments. A laminectomy was made at T-5 or T-8 in 92 young female rats, and a fine wire probe was passed beneath the intact cord. The cord was then transected and the probe lifted through the incision so as to ensure the completeness of the transection. Rats were injected with various enzymes of American or Russian manufacture, including trypsin, hyaluronidase, elastase, elastase plus trypsin, or vehicle. At autopsy 4 to 6 months later, all rats were paraplegic. The stumps of the spinal cord were separated by cysts and a fibroglial scar. Nerve fibers did not cross the lesion site, nor was there conduction of nerve impulses across the site of injury. There were no significant behavioral, histological, or electrophysiological differences between any of the treatment groups. Transection of the spinal cord was then performed in additional animals using Matinian and Andreasian's original surgical method (without passing a probe beneath the intact cord). Most of these rats began walking within 2 to 3 weeks, without enzyme therapy. Histological analysis revealed intact nerve fibers in the ventrolateral region of the spinal cord, indicating that the spinal cord had not been completely transected. It is concluded that: 1) enzyme treatment neither facilitates nerve regeneration nor permits functional restitution in rats with spinal cord transection; and 2) previously reported findings were apparently the result of incomplete spinal transection.
Amelioration of arthritis through mobilization of peptide-specific CD8+ regulatory T cells (2013)

Current therapies to treat autoimmune disease focus mainly on downstream targets of autoimmune responses, including effector cells and cytokines. A potentially more effective approach would entail targeting autoreactive T cells that initiate the disease cascade and break self tolerance. The murine MHC class Ib molecule Qa-1b (HLA-E in humans) exhibits limited polymorphisms and binds to 2 dominant self peptides: Hsp60(p216) and Qdm. We found that peptide-induced expansion of tetramer-binding CD8(+) Tregs that recognize Qa-1-Hsp60(p216) but not Qa-1-Qdm strongly inhibited collagen-induced arthritis, an animal model of human rheumatoid arthritis. Perforin-dependent elimination of autoreactive follicular Th (T(FH)) and Th17 cells by CD8(+) Tregs inhibited disease development. Infusion of in vitro-expanded CD8(+) Tregs increased the efficacy of methotrexate treatment and halted disease progression after clinical onset, suggesting an alternative approach to this first-line treatment. Moreover, infusion of small numbers of Qa-1-Hsp60(p216)-specific CD8(+) Tregs resulted in robust inhibition of autoimmune arthritis, confirming the inhibitory effects of Hsp60(p216) peptide immunization. These results suggest that strategies designed to expand Qa-1-restricted (HLA-E-restricted), peptide-specific CD8(+) Tregs represent a promising therapeutic approach to autoimmune disorders.
Lung Perfusion with Oxygenated Blood during Aortic Clamping Prevents Lung Injury (2004)

To evaluate the protective effect of continuous pulmonary perfusion with oxygenated blood during aortic crossclamping, 12 mixed-breed piglets (7-12 kg) were placed on cardiopulmonary bypass for 130 minutes. An experiment group of 6 (group E) had continuous pulmonary perfusion with oxygenated blood during cardiopulmonary bypass, while the other 6 served as controls (group C). Pulmonary function was measured at the beginning and end of cardiopulmonary bypass and one hour later. Histology was compared before and after cardiopulmonary bypass. Pulmonary function after cardiopulmonary bypass was significantly better in group E than group C. There was preservation of the normal pulmonary parenchyma in group E, whereas group C had marked intra-alveolar edema and abundant intra-alveolar neutrophils. Anoxia of lung tissue during aortic crossclamping on cardiopulmonary bypass is probably the major factor in lung injury. Continuous pulmonary perfusion was effective in preventing lung injury during aortic crossclamping.
Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS) (2006)

Treatment with IV desmoteplase 3 to 9 hours after ischemic stroke onset appears safe. At a dose of 125 microg/kg desmoteplase appeared to improve clinical outcome, especially in patients fulfilling all MRI criteria. The results of DEDAS generally support the results of its predecessor study, Desmoteplase in Acute Ischemic Stroke (DIAS).
Large-scale Expansion and Exploitation of Pluripotent Stem Cells for Regenerative Medicine Purposes: Beyond the T Flask (2011)

Human pluripotent stem cells will likely be a significant part of the regenerative medicine-driven healthcare revolution. In order to realize this potential, culture processes must be standardized, scalable and able to produce clinically relevant cell numbers, whilst maintaining critical biological functionality. This review comprises a broad overview of important bioprocess considerations, referencing the development of biopharmaceutical processes in an effort to learn from current best practice in the field. Particular focus is given to the recent efforts to grow human pluripotent stem cells in microcarrier or aggregate suspension culture, which would allow geometric expansion of productive capacity were it to be fully realized. The potential of these approaches is compared with automation of traditional T-flask culture, which may provide a cost-effective platform for low-dose, low-incidence conditions or autologous therapies. This represents the first step in defining the full extent of the challenges facing bioprocess engineers in the exploitation of large-scale human pluripotent stem cell manufacture.
Reduction of Diabetic Macular Edema by Oral Administration of the Kinase Inhibitor PKC412 (2004)

Orally administered PKC412 at doses of 100 mg/d or higher may significantly reduce macular edema and improve visual acuity in diabetic subjects. However, concern regarding liver toxicity with systemic therapy makes local delivery an appealing approach.
Enhancement in Drug Delivery (2006)

Providing a significant cross-fertilization of ideas across several disciplines, Enhancement in Drug Delivery offers a unique comprehensive review of both theoretical and practical aspects of enhancement agents and techniques used for problematic administration routes. It presents an integrated evaluation of absorption enhancers and modes fo
Molecular cloning of a 10-deacetylbaccatin III-10-O-acetyl transferase cDNA fromTaxusand functional expression inEscherichia coli (2000)

The cDNA clone for a 10-deacetylbaccatin III-10-O-acetyl transferase, which catalyzes formation of the last diterpene intermediate in the Taxol biosynthetic pathway, has been isolated from Taxus cuspidata. By using consensus sequences from an assembly of transacylases of plant origin and from many deduced proteins of unknown function, a homology-based PCR cloning strategy was employed to amplify initially a 911-bp gene fragment of the putative taxane C-10 hydroxyl acetyl transferase from Taxus. This amplicon was used to screen a cDNA library constructed from mRNA isolated from methyl jasmonate-induced Taxus cells, from which the full-length 10-deacetylbaccatin III-10-O-transacetylase sequence was obtained. Expression of the ORF from pCWori(+) in Escherichia coli JM109 afforded a functional enzyme, as determined by (1)H-NMR and MS verification of the product baccatin III derived from 10-deacetylbaccatin III and acetyl CoA. The full-length cDNA has an ORF of 1,320 bp corresponding to a deduced protein of 440 residues with a calculated molecular weight of 49,052, consistent with the size of the operationally soluble, monomeric, native acetyl transferase. The recombinant acetyl transferase has a pH optimum of 7.5, has K(m) values of 10 microM and 8 microM for 10-deacetylbaccatin III and acetyl CoA, respectively, and is apparently regiospecific toward the 10-hydroxyl group of the taxane ring. Amino acid sequence comparison of 10-deacetylbaccatin III-10-O-acetyl transferase with taxadienol-5-O-acetyl transferase and with other known acyl transferases of plant origin indicates a significant degree of similarity between these enzymes (80% and 64-67%, respectively).
Playback: A method for evaluating the usability of software and its documentation (1984)

Human factors evaluations of software products and accompanying user publications must be conducted so that developers can be certain that the target user population can learn to use the product with a minimum of difficulty and be able to perform the intended tasks efficiently. A methodology is described for obtaining objective measures of product usability by collecting perfor-mance data on the user interface without affecting the user or the system being evaluated. The log of stored activity is later played back through the host system for analysis.
Rapid response systems: A systematic review* (2007)

We found weak evidence that rapid response systems are associated with a reduction in hospital mortality and cardiac arrest rates, but limitations in the quality of the original studies, the wide confidence intervals, and the presence of heterogeneity limited our ability to conclude that rapid response systems are effective interventions. Large randomized controlled trials are needed to clarify the efficacy of rapid response systems before they should become standard of care.
Molecular cloning and characterization of an activated human c-raf-1 gene. (1987)

Results of previous studies have shown that a raf-related transforming DNA sequence is present in NIH 3T3 transformants that are derived from GL-5-JCK human glioblastoma DNA transfection. The transforming DNA was molecularly cloned by using cosmid vector pJB8 to determine its structure and origin. Analyses of selected clones revealed that the transforming DNA consisted of three portions of human DNA sequences, with the 3' half of the c-raf-1 gene as its middle portion. This raf region was about 20 kilobases long and contained exons 8 to 17 and the poly(A) addition site. RNA blot analysis showed that the raf-related transforming DNA was transcribed into 5.3-, 4.8-, and 2.5-kilobase mRNAs; the 2.5-kilobase transcript was thought to be the major transcript. Immunoprecipitation analyses revealed that a 44-kilodalton raf-related protein was specifically expressed in the NIH 3T3 transformants. The raf-related transforming DNA was considered to be activated when its amino-terminal sequence was truncated and the DNA was coupled with a foreign promoter sequence. On hybridization analysis of the original GL-5-JCK glioblastoma DNA, no rearrangement of c-raf-1 was detectable in the tumor DNA. The rearrangement of c-raf-1 may have occurred during transfection or may have been present in a small population of the original tumor cells as a result of tumor progression.
Serotonin transporter (5-HTT) gene variants associated with autism? (1997)

An association study was performed to elucidate the role of the serotonin transporter (5-HTT) gene as a susceptibility factor for autism as treatment of patients with antidepressant drugs which selectively target 5-HTT reduced autistic or concomitant symptoms, such as repetitive behavior and aggression, and ameliorate language use. Using the transmission/disequilibrium test (TDT) an analysis was done for a common polymorphism in the upstream regulatory region (5-HTTLPR), a VNTR in intron 2 of the gene and a haplotype of both loci in 52 trios fulfilling stringent criteria for autism and an extended group of 65 trios including patients showing no language delay in their first 3 years of life. A higher frequency and preferential transmission of the long allele of the 5-HTTLPR was observed, but the TDT gave a statistically significant value ( P = 0. 032) only for the extended patient group. This result is in contrast to a recent study by a US group presenting preliminary evidence for preferential transmission of the short allele of 5-HTTLPR in 86 trios. Both studies failed to reveal significant linkage disequilibrium between the VNTR in intron 2 of the gene and autism. In our study haplotype analysis of the 5-HTTLPR and the VNTR in intron 2 supplied evidence for an association of 5-HTT and autism in the stringent ( P = 0.069) and extended patient group ( P = 0.049). Overall, we were not able to replicate the findings of the first study on 5-HTT and autism and instead observed a tendency for association of the opposite genetic variant of the gene with the disorder. The implications for genetic variants of the serotonin transporter in the etiology of autism and possible subgroups of patients, therefore, needs clarification in further studies with other and larger patient samples.
Studies in Fetal Wound Healing IV. Hyaluronic Acid-Stimulating Activity Distinguishes Fetal Wound Fluid from Adult Wound Fluid (1989)

Recent clinical and experimental evidence suggests that the fetus responds to injury in a fashion fundamentally different from that of the adult. Our initial experience with human open fetal surgery reinforces experimental observations that the fetal wounds heal without the scarring, inflammation, and contraction that often accompany adult wounds. In this study we examine fetal wound fluid in an attempt to elucidate the control mechanisms that endow the fetus with unique healing properties. The extracellular matrix of fetal wounds is rich in hyaluronic acid, a glycosaminoglycan found in high concentrations whenever there is tissue proliferation, regeneration, and repair. We establish that wound fluid from the fetus contains high levels of hyaluronic acid-stimulating activity that may underlie the elevated deposition of hyaluronic acid in the fetal wound matrix. In contrast there was no hyaluronic acid-stimulating activity present in adult wound fluid. Hyaluronic acid, in turn, fosters an extracellular environment permissive for cell motility and proliferation that may account for the unique properties observed in fetal wound healing.
Evidence for the involvement of Fas ligand and perforin in the induction of vascular leak syndrome. (1998)

Endothelial cell injury resulting in vascular leak syndrome (VLS) is one of the most widely noted phenomenons in a variety of clinical diseases. In the current study we used IL-2-induced VLS as a model to investigate the role of cytolytic lymphocytes in the cytotoxicity of endothelial cells. Administration of IL-2 (75,000 U/mouse, three times a day for 3 days) into BL/6 wild-type mice triggered significant VLS in the lungs, liver, and spleen. Interestingly, perforin-knockout (KO) mice exhibited a marked decrease in IL-2-induced VLS in all three organs tested. Also, Fas ligand-defective (gld) mice and Fas-deficient (lpr) mice exhibited decreased VLS in the liver and spleen, but not in the lungs. The decreased VLS seen in perforin-KO, gld, and lpr mice was not due to any defect in lymphocyte migration or homing to various organs because histopathologic studies in these mice demonstrated significant and often greater perivascular infiltration of lymphocytes compared with the IL-2-treated wild-type mice. Ultrastructural studies of the lungs demonstrated significant damage to the endothelial cells in IL-2-treated wild-type mice and decreased damage in perforin-KO mice. IL-2 administration caused up-regulation of CD44 in all strains of mice tested and triggered increased LAK activity against an endothelial cell line in wild-type and gld mice, but not in perforin-KO mice. The current study demonstrates for the first time that perforin and Fas ligand may actively participate in endothelial cell injury and induction of VLS in a variety of organs.
Prostacyclin in endotoxemia-induced acute kidney injury: cyclooxygenase inhibition and renal prostacyclin synthase transgenic mice (2007)

Sepsis-related acute kidney injury (AKI) is the leading cause of AKI in intensive care units. Endotoxin is a primary initiator of inflammatory and hemodynamic consequences of sepsis and is associated with experimental AKI. The present study was undertaken to further examine the role of the endothelium, specifically prostacyclin (PGI(2)), in the pathogenesis of endotoxemia-related AKI. A low dose of endotoxin (LPS, 1 mg/kg) in wild-type (WT) mice was associated with stable glomerular filtration rate (GFR) (164.0 +/- 16.7 vs. 173.3 +/- 6.7 microl/min, P = not significant) as urinary excretion of 6-keto-PGF(1alpha), the major metabolite of PGI(2), increased. When cyclooxygenase inhibition with indomethacin abolished this rise in 6-keto-PGF(1alpha), the same low dose of LPS significantly decreased GFR (110.7 +/- 12.1 vs. 173.3 +/- 6.7 microl/min, P < 0.05). The same dose of indomethacin did not alter GFR in WT mice. To further study the role of PGI(2) in endotoxemia, renal-specific PGI synthase (PGIs) transgenic (Tg) mice were developed that had increased PGIs expression only in the kidney and increased urinary 6-keto-PGF(1alpha). These Tg mice, however, demonstrated endotoxemia-related AKI with low-dose LPS (1 mg/kg) (GFR: 12.6 +/- 3.9 vs. 196.5 +/- 21.0 microl/min P < 0.01), which did not alter GFR in WT mice (164.0 +/- 16.7 vs. 173.3 +/- 6.7 microl/min, P = not significant). An elevation in renal cAMP, however, suggested an activation of the PGI(2)-cAMP-renin system in these Tg mice. Moreover, angiotensin-converting enzyme inhibition afforded protection against endotoxin-related AKI in these Tg mice. Thus endothelial PGIs-mediated PGI(2), as previously shown with endothelial nitric oxide synthase-mediated nitric oxide, contributes to renal protection against endotoxemia-related AKI. This effect may be overridden by excessive activation of the renin-angiotensin system in renal-specific PGIs Tg mice.
Impact of trench width roughness on the graphoepitaxial assembly of block copolymers (2008)

In this paper, the authors investigated constraints on the quality of topographic features needed for graphoepitaxial assembly of cylinder forming poly(styrene-b-methyl methacrylate) (PS-b-PMMA) thin films, showing the impact of trench width roughness (TWR) on feature size uniformity and defect formation. Topographically patterned substrates were prepared using chemically amplified photoresist and reactive ion etching in conjunction with commercially available lithographic tools and masks. A dose/focus array was utilized to systematically produce trenches with widths between 40 and 400nm with roughness of 5–35nm on top of which block copolymers were assembled. Scanning electron microscopy images were taken and analyzed using IMAGEJ software for the metrology of the trenches and ordered block copolymer domains after the removal of the PMMA cylinders. Analysis showed little or no change in domain size variation of the block copolymer with respect to the TWR of lithographically defined features. The impact of TWR on defect formation is qualitatively investigated by classifying all images as having few, some, or many defects. From this analysis, the commensurability between the natural length scale of the block copolymer (l0) and the trench width (W) had a significant effect on defectivity, whereas TWR did not play a dominant role.
Arginase contributes to endothelial cell oxidative stress in response to plasma from women with preeclampsia (2009)

Increased arginase expression in preeclampsia can induce uncoupling of NOS as a source of superoxide in the maternal vasculature in preeclampsia. However, l-arginine supplementation in the face of oxidative stress could lead to a further increase in peroxynitrite.