gebhart/patrepeval huggingface dataset:
Two integrin-binding peptides abrogate T cell-mediated immune responses in vivo. (1991)

Two VLA proteins (or beta 1 integrins; originally called very late activation antigens) that bind to distinct determinants on fibronectin (FN) are increased on activated immune or memory T cells. VLA-4 binds to the peptide sequence Gly-Pro-Glu-Ile-Leu-Asp-Val-Pro-Ser-Thr (GPEILDVPST in single-letter code) on the alternatively spliced CS-1 form of FN, whereas VLA-5 binds to an Arg-Gly-Asp sequence found on all forms of FN. It has been proposed that the migration of immune T cells out of blood vessels and through connective tissue to a site of antigenic challenge is facilitated by the interaction of such integrins with matrix protein molecules. We have examined directly the role of T-cell integrins in vivo by using the well-characterized, T-cell-mediated contact hypersensitivity (CHS) response to the hapten trinitrochlorobenzene (TNCB). We demonstrate that the cells that transfer CHS to TNCB adhere to FN in the presence of Ca2+/Mg2+, and T-cell populations depleted of FN-adherent cells do not transfer immunity. We further show that TNCB-immune T cells treated with the synthetic peptides GPEILDVPST or Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP in single-letter code), ligands for VLA-4 and VLA-5, respectively, lose their ability to mediate this immune response in a murine model, whereas the control peptides Val-Ile-Pro-Asp-Leu-Thr-Glu-Ser-Pro-Gly and Gly-Arg-Gly-Glu-Ser-Pro have no effect. Neither GPEILDVPST nor GRGDSP significantly inhibited the proliferative response of TNCB-immune T cells in vitro. These data suggest that FN-binding integrins on T cells play a role in the localization of T cells to sites of antigenic challenge in tissue.
Endothelial Progenitor Cells (2004)

Infusion of different hematopoietic stem cell populations and ex vivo expanded endothelial progenitor cells augments neovascularization of tissue after ischemia and contributes to reendothelialization after endothelial injury, thereby, providing a novel therapeutic option. However, controversy exists with respect to the identification and the origin of endothelial progenitor cells. Overall, there is consensus that endothelial progenitor cells can derive from the bone marrow and that CD133/VEGFR2 cells represent a population with endothelial progenitor capacity. However, increasing evidence suggests that there are additional bone marrow-derived cell populations (eg, myeloid cells, “side population” cells, and mesenchymal cells) and non-bone marrow-derived cells, which also can give rise to endothelial cells. The characterization of the different progenitor cell populations and their functional properties are discussed. Mobilization and endothelial progenitor cell-mediated neovascularization is critically r...
DNA double-strand break repair: a tale of pathway choices (2016)

Deoxyribonucleic acid double-strand breaks (DSBs) are cytotoxic lesions that must be repaired either through homologous recombination (HR) or non-homologous end-joining (NHEJ) pathways. DSB repair is critical for genome integrity, cellular homeostasis and also constitutes the biological foundation for radiotherapy and the majority of chemotherapy. The choice between HR and NHEJ is a complex yet not completely understood process that will entail more future efforts. Herein we review our current understandings about how the choice is made over an antagonizing balance between p53-binding protein 1 and breast cancer 1 in the context of cell cycle stages, downstream effects, and distinct chromosomal histone marks. These exciting areas of research will surely bring more mechanistic insights about DSB repair and be utilized in the clinical settings.
Overexpression of vascular permeability factor (VPF/VEGF) and its endothelial cell receptors in delayed hypersensitivity skin reactions. (1995)

Delayed hypersensitivity (DH) is a T cell-mediated form of immune response characterized by a predominantly perivascular, mononuclear cell infiltrate. The venules in DH reactions are hyperpermeable to plasma proteins, leading to extravasation of plasma fibrinogen and its extravascular clotting to form a fibrin gel that promotes induration and angiogenesis. The mechanisms responsible for microvascular hyperpermeability in DH are unknown. Recently, a cytokine named vascular permeability factor (VPF, also known as vascular endothelial growth factor or VEGF) has been implicated in the chronic vascular hyperpermeability and angiogenesis of solid and ascites tumors, healing wounds, rheumatoid arthritis, and psoriasis. These findings suggested that VPF/VEGF might also have a role in the pathogenesis of DH. Two model systems were studied: allergic contact dermatitis to poison ivy in human volunteers and classical tuberculin hypersensitivity in rats. In both, in situ hybridization revealed that the mRNAs encoding VPF/VEGF were strikingly overexpressed in keratinocytes of the epidermis; scattered mononuclear cells infiltrating the dermis also overexpressed VPF/VEGF mRNA, to a greater extent in rat tuberculin than in human contact reactions. In contact reactions, mRNAs for two VPF/VEGF vascular endothelial cell receptors, flt-1 and KDR, were also strikingly overexpressed. Abundant fibrin deposition in both models confirmed that dermal microvessels were indeed hyperpermeable to plasma fibrinogen. These results implicate VPF/VEGF as a potentially important mediator in the pathogenesis of cell-mediated immunity and provide further evidence that products of epithelial cells may regulate the inflammatory response.
TGN1412: From Discovery to Disaster (2010)

After a drug is confirmed as safe and efficacious in preclinical studies, it is tested in healthy human volunteers for first in man trials. In 2006, a phase I clinical study was conducted for a CD28 superagonist antibody TGN1412 in six human volunteers. After very first infusion of a dose 500 times smaller than that found safe in animal studies, all six human volunteers faced life-threatening conditions involving multiorgan failure for which they were moved to intensive care unit. After this particular incident, a lot was changed over how first in man trials are approved by regulatory authorities and the way clinical trials are conducted. This review primarily deals with preclinical studies conducted by TeGenero, results of which encouraged them to test the antibody on human subjects, reasons why this drug failed in human trial and aftermath of this drug trial. In addition, another drug-Fialuridine which failed in phase 2 clinical trial leading to death of five human subjects is briefly reviewed.
Studies on radiation-induced mammary gland neoplasia in the rat. 5. Induction by localized irradiation. (1960)

Previous studies from this laboratory had demonstrated that a single large whole-body x-nay exposure of SpragueDawley rats was followed in months by a large increase in the incidence of maximary gland neoplasia. In addition, the dose-effect relstionship appeared to be linear within limits, and intact ovarian function was demonstrated to be necessary for maximum incidence of neoplasia. In the present dose-effect relationship appeared to be linear within limits, and intact ovaria function was demonstrated to be necessary for maximum incidence of neoplasia. In the present experiments, designad to determine if the breast tissue must be directiy irradinted for maximal neoplasia indnction, groups of approximately 30 female Sprague-Dawley rats were irradiated on the fifty-fifth day of age as follows: 400 r total-body irradiation; 400 r entire left half of body; 400 r to chest; 400 r to lower half of body; 400 r with one hind linhb shielded; and 400 r through a gnid. With half-body exposure and with exposure through the gnid, approximately one-half of the total number of neoplasms seen after totalbody irradiation was observed. Shielding of the leg had no effect on the incidence of neoplasia. With half-body irradiation, more than 90% of all breast neoplasms occurred inmore » tissues exposed directly to the beam. The results indicate cleanly teat direct radiation injury to the breast is necessary for an increased incidence of radiation-induced neoplasia under the conditions employed. It appears from these and previous studies that radiation-indnced damage in the target organ is necessary for an increased incidence of the neoplasia observed, but that the primary damage may lie dominant and not manifest itself maximally as neoplasia unless an additional secondary mechanism (presumably cyclic ovarian activity in the data presented) is operative, The implications of the results with regard to a possible somatic mutation mechanism of radistion neoplasia induction are discussed. (auth)« less
The biosynthetic gene cluster for the macrolactone ring of the immunosuppressant FK506 (1998)

Biosynthesis of the macrolactone ring of FK506 involves 10 elongation cycles that mechanistically resemble the steps in fatty acid synthesis. Sequencing of a 40-kb DNA segment of the FK506 gene cluster from Streptomyces sp. MA6548 has revealed two additional polyketide synthases (PKS) genes fkbB and fkbC which lie upstream of fkbA, a PKS gene recently shown to be responsible for the last four condensation steps of the FK506 biosynthesis [Motamedi, H., Cai, S. J., Shafiee, A. & Elliston, K. O. (1997) Eur. J. Biochem. 244, 74-80]. fkbB and fkbC are contiguous and encode respectively, the first (790129 Da) and the second (374438 Da) components of the FK506 polyketide synthase, a complex of three multidomain polypeptides. The predicted domain structures of FkbB and FkbC are analogous to that of FkbA and comprise 30 fatty-acid-synthase(FAS)-like domains arranged in 6 modules. Each module performs a specific extension cycle in the assembly of the carbon skeleton of the FK506 macrolactone ring. The component activities for the initiation of the polyketide chain consisting of a dihydrocyclohexenylcarbonyl coenzyme A (CoA) synthetase and a dihydrocyclohexenylcarbonyl CoA reductase required for the formation of the dihydrocyclohexylcarbonyl CoA starter unit and an acyl-carrier-protein to which the starter unit is anchored and translocated to the appropriate site on the PKS multienzyme are located at the N-terminal region of the FkbB polypeptide. A third gene, fkbL, lies at one end of the cluster and encodes lysine cyclodeaminase which catalyzes alpha-deamination and cyclization of the lysine into pipecolate. A fourth gene fkbP located at the other end of the sequence reported here encodes a peptide synthetase required for the activation and incorporation of the pipecolate moiety into the completed acyl chain. Finally the cluster carries a gene, fkbO, whose product is presumed to carry out a post-polyketide oxidation step of the FK506 marocycle.
Efficient Detection of Carbapenemase Activity in Enterobacteriaceae by Matrix-Assisted Laser Desorption Ionization−Time of Flight Mass Spectrometry in Less Than 30 Minutes (2015)

The recognition of carbapenemase-producing Enterobacteriaceae (CPE) isolates is a major laboratory challenge, and their inappropriate or delayed detection may have negative impacts on patient management and on the implementation of infection control measures. We describe here a matrix-assisted laser desorption ionization-time of flight (MALDI-TOF)-based method to detect carbapenemase activity in Enterobacteriaceae. After a 20-min incubation of the isolate with 0.5 mg/ml imipenem at 37°C, supernatants were analyzed by MALDI-TOF in order to identify peaks corresponding to imipenem (300 Da) and an imipenem metabolite (254 Da). A total of 223 strains, 77 CPE (OXA-48 variants, KPC, NDM, VIM, IMI, IMP, and NMC-A) and 146 non-CPE (cephalosporinases, extended-spectrum β-lactamases [ESBLs], and porin defects), were tested and used to calculate a ratio of imipenem hydrolysis: mass spectrometry [MS] ratio = metabolite/(imipenem + metabolite). An MS ratio cutoff was statistically determined to classify strains as carbapenemase producers (MS ratio of ≥0.82). We validated this method first by testing 30 of our 223 isolates (15 CPE and 15 non-CPE) 10 times to calculate an intraclass correlation coefficient (ICC of 0.98), showing the excellent repeatability of the method. Second, 43 strains (25 CPE and 18 non-CPE) different from the 223 strains used to calculate the ratio cutoff were used as external controls and blind tested. They yielded sensitivity and specificity of 100%. The total cost per test is <0.10 U.S. dollars (USD). This easy-to-perform assay is time-saving, cost-efficient, and highly reliable and might be used in any routine laboratory, given the availability of mass spectrometry, to detect CPE.
Inflammatory response in the elderly (2003)

Ageing is associated with increased levels of chronic inflammation. This plays a major role in the decline in immune function and lean body mass. Anti-inflammatory nutrient therapy may slow the rate of decline. The pro- and anti-inflammatory cytokine genotype is linked negatively and positively, respectively, with life-span, because of its influence on inflammation.
New approaches to the treatment of opioid-induced constipation. (2008)

Opiates are indispensable for the treatment of moderate to severe pain. The gastrointestinal tract is one of the major victims of the undesired effects of opiates, because the enteric nervous system expresses all major subtypes of opioid receptors. As a result, propulsive motility and secretory processes in the gut are inhibited by opioid analgesics, and the ensuing constipation is one of the most frequent and troublesome adverse reactions. Many treatments involving laxatives, prokinetic drugs and opioid-sparing regimens have been explored to circumvent opioid-induced bowel dysfunction, but the outcome has in general been unsatisfactory. Specific antagonism of peripheral opioid receptors offers a more rational approach to the management of the adverse actions of opioid analgesics in the gut. This goal is currently addressed by the use of opioid receptor antagonists with limited absorption such as oral naloxone and by the development of peripherally restricted opioid receptor antagonists such as methylnaltrexone and alvimopan. These investigational drugs hold considerable promise in preventing constipation due to opiate treatment, whereas the analgesic action of opiates remains unabated. Postoperative ileus associated with opioid-induced postsurgical pain control is likewise ameliorated by the compounds. With this proof of concept, several phase III studies are under way to define optimal dosage, dosing regimen as well as long-term efficacy and safety of methylnaltrexone and alvimopan. In addition, there is preliminary evidence that these peripherally restricted opioid receptor antagonists may act as prokinetic drugs in their own right.
The Effect of Sub-clinical Hypoxia on Pilot Performance (1987)

The effect of low altitude hypoxia on human performance was examined. Subjects were tested at rest in a hypobaric chamber at sea level and at simulated altitudes of 4000, 8000 and 12000 feet on consecutive days using a double blind crossover experimental design. A symptoms questionnaire demonstrated a statistically significant increase in sleepiness at 8000 ft; and in headaches at 12000 ft. Psychological testing showed a statistically significant impairment in the tracking component of a dual task at 8000 ft, and in a memory task at 12000 ft. Vision testing demonstrated a statistically significant decrement in colour vision at 12000 ft (tending to a deuteranope defect). It was concluded that pilot performance is impaired by hypoxia even at 8000 ft, and recommended that the aircraft altitude ceiling above which pressurization and/or oxygen masks are mandatory should be reduced from the present value of 10000 ft to below 8000 ft.
Inhibitory effects of cannabinoid CB 1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis (2003)

Stimulation of cannabinoid CB1 receptors by 2-methyl-arachidonyl-2'-fluoro-ethylamide (Met-F-AEA) inhibits the growth of a rat thyroid cancer cell-derived tumor in athymic mice by inhibiting the activity of the oncogene product p21ras. Here we report that Met-F-AEA also blocks the growth of tumors previously induced in nude mice by the s.c. injection of the same rat thyroid carcinoma cells. Met-F-AEA significantly inhibited, in tumors as well as transformed cells, the expression of the vascular endothelial growth factor, an angiogenetic factor known to be up-regulated by p21ras, as well as of one of its receptors, flt-1/VEGFR-1. The levels of the cyclin-dependent kinase inhibitor p27(kip1), which is down-regulated by p21ras, were instead increased by Met-F-AEA. All these effects were antagonized by the selective CB1 receptor antagonist SR141716A. Met-F-AEA inhibited in vitro the growth of a metastasis-derived thyroid cancer cell line more potently than a primary cancer cell line. Therefore, the hypothesis that CB1 receptor stimulation interferes not only with angiogenesis but also with metastatic processes was tested in a widely used model of metastatic infiltration in vivo, the Lewis lung carcinoma (3LL) in C57Bl/6 mice. Three weeks from the paw injection of 3LL cells, Met-F-AEA reduced significantly the number of metastatic nodes, in a way antagonized by SR141716A. Our findings indicate that CB1 receptor agonists might be used therapeutically to retard tumor growth in vivo by inhibiting at once tumor growth, angiogenesis, and metastasis.
Isolation of human megakaryocytes by immunomagnetic beads (1989)

A simple method was developed to purify human megakaryocytes to homogeneity from normal bone marrow aspirates. An initial separation of marrow between 1.020 and 1.050 g/ml. Percoll density cut was used to enrich megakaryocytes. After washing, the cells were suspended with immunomagnetic beads which were coated with sheep anti-mouse IgG antibody and treated with anti-human glycoprotein (GP) IIb/IIIa monoclonal antibody, or the cells were treated with human platelet GP IIb/IIIa monoclonal antibody and suspended with the immunomagnetic beads which were coated with sheep anti-mouse IgG antibody. Megakaryocytes were selectively separated using a magnet. All of the isolated cells were morphologically recognizable megakaryocytes. 1.5-3.1 x 10(4) megakaryocytes were obtained from 1.7-4.5 x 10(8) bone marrow nuleated cells. These cells were all positive in immunoenzymatic staining for GP IIb/IIIa. Megakaryocytes obtained by this method responded to recombinant human GM-CSF (rhGM-CSF) showing an increased 3H-thymidine (3H-dT) incorporation. These data show that this method is useful for obtaining pure megakaryocyte populations which can be submitted to comprehensive biological studies.
Cancer phase I clinical trials: efficient dose escalation with overdose control (1998)

We describe an adaptive dose escalation scheme for use in cancer phase I clinical trials. The method is fully adaptive, makes use of all the information available at the time of each dose assignment, and directly addresses the ethical need to control the probability of overdosing. It is designed to approach the maximum tolerated dose as fast as possible subject to the constraint that the predicted proportion of patients who receive an overdose does not exceed a specified value. We conducted simulations to compare the proposed method with four up-and-down designs, two stochastic approximation methods, and with a variant of the continual reassessment method. The results showed the proposed method effective as a means to control the frequency of overdosing. Relative to the continual reassessment method, our scheme overdosed a smaller proportion of patients, exhibited fewer toxicities and estimated the maximum tolerated dose with comparable accuracy. When compared to the non-parametric schemes, our method treated fewer patients at either subtherapeutic or severely toxic dose levels, treated more patients at optimal dose levels and estimated the maximum tolerated dose with smaller average bias and mean squared error. Hence, the proposed method is promising alternative to currently used cancer phase I clinical trial designs.
[Clinical evaluation of serum S100ao protein in patients with urogenital diseases and healthy volunteers]. (1990)

We investigated the clinical significance of the serum S100ao protein in patients with urogenital diseases. The serum levels of S100ao protein were measured in 179 patients with urogenital diseases and 180 healthy volunteers. The mean value of S100ao protein in serum from healthy volunteers was 203 +/- 107 pg/ml (Mean +/- SD). Therefore, the cut-off level was set to 524 pg/ml (Mean +/- 3SD). The levels of S100ao protein in serum were significantly higher in men than in women (P less than 0.05). The levels of S100ao protein in serum were significantly high in the patients in their fifties and sixties compared with the other patients (P less than 0.01). When serum levels exceeding the cut-off level were considered to be positive, the percentages of positivity in each disease were as follows: renal cell carcinoma; 38.7%, bladder tumor; 9.1%, prostatic carcinoma; 12.5%, testicular tumor; 0%, benign prostatic hypertrophy; 7.4%, urolithiasis; 7.1% and chronic renal failure; 100%. The levels of S100ao protein in serum were significantly correlated with those of BUN, serum creatinine and endogenous creatinine clearance, respectively. S100ao protein in serum was increased immediately after operation and returned to the normal range within one to two weeks after operation. As described above, the level of S100ao protein in serum was affected by renal function, operative procedures and age. However, the positive rate of S100ao protein was so high in patients with renal cell carcinoma that serum S100ao protein might be a valuable tumor marker in those patients.
Low-dose, beta-particle emission from 'stent' wire results in complete, localized inhibition of smooth muscle cell proliferation. (1994)

We conclude that very low doses of beta-particle emission from a 32P-impregnated stent wire (activity levels as low as 0.006 microCi/cm of wire) completely inhibit the growth and migration of both rat and human SMCs within a range of 5.5 to 10.6 mm from the wire. Endothelial cells appear to be much more radioresistant than SMCs. These data suggest that an intra-arterial stent impregnated with a low concentration of 32P may have a salutary effect on the restenosis process. Whether this approach can be used successfully and safely to inhibit restenosis in vivo and in the clinical setting is under investigation.
Curcumin induces apoptosis in human breast cancer cells through p53‐dependent Bax induction (2002)

The aim of this study was to determine the mechanisms of curcumin-induced human breast cancer cell apoptosis. From quantitative image analysis data showing an increase in the percentage of cells with a sub-G0/G1 DNA content, we demonstrated curcumin-induced apoptosis in the breast cancer cell line MCF-7, in which expression of wild-type p53 could be induced. Apoptosis was accompanied by an increase in p53 level as well as its DNA-binding activity followed by Bax expression at the protein level. Further experiments using p53-null MDAH041 cell as well as low and high p53-expressing TR9-7 cell, in which p53 expression is under tight control of tetracycline, established that curcumin induced apoptosis in tumor cells via a p53-dependent pathway in which Bax is the downstream effector of p53. This property of curcumin suggests that this molecule could have a possible therapeutic potential in breast cancer patients.