gebhart/patrepeval huggingface dataset:
Synthesis of Thieno[2,3-d]pyrimidines and Aminopyrimidines from 2-Alkoxy-5-cyano-4-thioxopyrimidine Intermediates (1998)

b-Chloro-a-cyanocinnamonitrile reacts in an one-pot reaction with potassium thiocyanate and alkanol to form 2-alkoxy-6-phenyl-5-cyano-1,4dhydro-4-pyrimidinthions. The products were S-alkylated to yield thieno[2,3d]pyrimidines on cyclization and aminopyrimidines on substitution of alkoxy and alkylthio groups.Substituted and heterocondensed pyrimidines are widespread natural products.'A lot of synthetic HETEROCYCLES, Vol.48.No. 6.1998 KSCN t R-OH KSCN b 6 0 1 EtOH R-OH 1 Numbering of C-atoms relates to "C NMR spectra Scheme 1 after addition of alkanol.Dimroth ~earrangement'~ of this intermediate forms finally 2-alkoxy-6-phenyl-4thioxo-IH-pyrimidine-5-carbonitriles (2).When the reaction was canied out in the presence of water, 2-
In vivoexcision and amplification of large segments of theEscherichia coligenome (1994)

In vivo excision and amplification of large segments of a genome offer an alternative to heterologous DNA cloning. By obtaining predetermined fragments of the chromosome directly from the original organism, the problems of clone stability and clone identification are alleviated. This approach involves the insertion of two recognition sequences for a site-specific recombinase into the genome at predetermined sites, 50-100 kb apart. The integration of these sequences, together with a conditional replication origin (ori), is targeted by homologous recombination. The strain carrying the insertions is stably maintained until, upon induction of specifically engineered genes, the host cell expresses the site-specific recombinase and an ori-specific replication protein. The recombinase then excises and circularizes the genomic segment flanked by the two insertions. This excised DNA, which contains ori, is amplified with the aid of the replication protein and can be isolated as a large plasmid. The feasibility of such an approach is demonstrated here for E. coli. Using the yeast FLP/FRT site-specific recombination system and the pi/gamma-ori replication initiation of plasmid R6K, we have devised a procedure that should allow the isolation of virtually any segment of the E. coli genome. This was shown by excising, amplifying and isolating the 51-kb lacZ--phoB and the 110-kb dapX--dsdC region of the E. coli MG1655 genome.
The Curative and Palliative Potential of the Monoclonal Antibody MOv18 Labelled with211At in Nude Mice with Intraperitoneally growing Ovarian Cancer Xenografts - A Long-Term Study (2000)

The purpose of the present study was to investigate the therapeutic efficacy of 211At-labelled specific monoclonal antibody MOv18 in nude mice with intraperitoneal growth of the human ovarian cancer cell line OVCAR3. In the first part of the study the antibody was injected intraperitoneally when the cancer growth was microscopic. The injected activity was 485-555 kBq. The median survival for treated mice was 213 days compared to 138 days for untreated mice (p < 0.014, log-rank test). No obvious toxicity was seen. Thirty-three percent of the mice were apparently free of cancer after 7 months and were probably cured. In the second part of the study mice with macroscopic cancer and signs of ascites were injected intraperitoneally with the same 211At-labelled antibody (377-389 kBq). This treatment possibly delayed the production of ascites. Hopefully radioimmunotherapy with regionally administered 211At-labelled antibody will be of value in women with ovarian cancer as well.
Aberrant insulin signaling in Alzheimer's disease: current knowledge (2015)

Alzheimer's disease (AD) is the most common form of dementia affecting elderly people. AD is a multifaceted pathology characterized by accumulation of extracellular neuritic plaques, intracellular neurofibrillary tangles (NFTs) and neuronal loss mainly in the cortex and hippocampus. AD etiology appears to be linked to a multitude of mechanisms that have not been yet completely elucidated. For long time, it was considered that insulin signaling has only peripheral actions but now it is widely accepted that insulin has neuromodulatory actions in the brain. Insulin signaling is involved in numerous brain functions including cognition and memory that are impaired in AD. Recent studies suggest that AD may be linked to brain insulin resistance and patients with diabetes have an increased risk of developing AD compared to healthy individuals. Indeed insulin resistance, increased inflammation and impaired metabolism are key pathological features of both AD and diabetes. However, the precise mechanisms involved in the development of AD in patients with diabetes are not yet fully understood. In this review we will discuss the role played by aberrant brain insulin signaling in AD. In detail, we will focus on the role of insulin signaling in the deposition of neuritic plaques and intracellular NFTs. Considering that insulin mitigates beta-amyloid deposition and phosphorylation of tau, pharmacological strategies restoring brain insulin signaling, such as intranasal delivery of insulin, could have significant therapeutic potential in AD treatment.
ACTR-46. AG-120, A FIRST-IN-class MUTANT IDH1 INHIBITOR IN PATIENTS WITH RECURRENT OR PROGRESSIVE IDH1 MUTANT GLIOMA: UPDATED RESULTS FROM THE PHASE 1 NON-ENHANCING GLIOMA POPULATION (2017)

Isocitrate dehydrogenase 1/2 (IDH1/2) mutations occur in >70% of low-grade gliomas (LGG) and lead to an altered metabolic state associated with production of D-2-hydroxyglutarate (2-HG), resulting in genetic/epigenetic dysregulation and oncogenesis. AG-120 is a potent oral inhibitor of mutant IDH1 (mIDH1) under clinical evaluation in an ongoing phase 1 study that treated 66 pretreated (median 2 prior systemic therapies) glioma patients in dose escalation and expansion cohorts. Safety and preliminary results were presented previously (SNO2016). We present updated results from the non-enhancing glioma patient population. Key eligibility: mIDH1 recurrent or progressive disease, ECOG 0–1, no surgery/radiation within 6 months. MRI response was assessed every 8 weeks using RANO and LGG-RANO criteria by local and independent central review. Exploratory analyses: change in tumor growth rate (FLAIR tumor volume, non-enhancing glioma expansion cohort) and pharmacodynamic evaluations of tissue and serum. As of 10March2017, 35 patients with non-enhancing glioma were enrolled in dose escalation (n=11) and expansion (n=24), and 51% (n=18) remain on AG-120. M/F 23/12, median age 38 years, 1p19q intact in 54% (n=19) of patients, 74% reported anticonvulsant use. Frequent (≥5 patients) adverse events (AEs) grade 1–2: diarrhea (26%), headache (26%), nausea (20%), anemia (17%), neutrophil decrease (17%), and vomiting (17%). 7 (20%) patients experienced a grade 3–4 AE (hypophosphatemia most frequent, n=2, unrelated), with no dose reduction due to AEs. 73% and 88% of patients achieved stable disease as best response in the dose escalation (RANO) and expansion (LGG-RANO) cohorts, respectively. Median duration on AG-120 was 14.7 months (range 1.4–25.0); 63% remained on AG-120 for ≥1 year. Updated safety, response, and exploratory imaging analyses will be presented. AG-120 monotherapy is associated with a favorable safety profile and prolonged stable disease in a previously treated non-enhancing mIDH1 glioma patient population, and warrants further clinical evaluation.
Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2',3'-dideoxynucleosides. (1986)

Human T-lymphotropic virus type III (HTLV-III)/lymphadenopathy-associated virus (LAV) is a a newly discovered lymphotropic retrovirus that is cytopathic for helper/inducer T cells in vitro. This virus is the etiologic agent of the acquired immunodeficiency syndrome and related diseases. In the current study, we tested the capacity of purine and pyrimidine nucleoside derivatives to inhibit the infectivity and cytopathic effect of human T-lymphotropic virus type III in vitro. With the ribose moiety of the molecule in a 2',3'-dideoxy configuration, every purine (adenosine, guanosine, and inosine) and pyrimidine (cytidine and thymidine) nucleoside tested suppressed the virus, although the thymidine derivative seemed to have substantially less activity in our system than the others. In general, we observed essentially complete suppression of the virus at doses that were lower by a factor of 10 to 20 than those needed to inhibit the proliferation of the target T cells and the immune reactivity of normal T cells in vitro. An analysis of five adenosine congeners, which differed only in the sugar moiety, revealed that reduction (an absence of hydroxyl determinants) at both the 2' and 3' carbons of the ribose was necessary for an anti-viral effect, and an additional reduction at the 5' carbon nullified the anti-viral activity. These observations may be of value in developing a new class of experimental drugs for the therapy of human T-lymphotropic virus type III infections.
Toward Maintaining the Genome: DNA Damage and Replication Checkpoints (2002)

DNA checkpoints play a significant role in cancer pathology, perhaps most notably in maintaining genome stability. This review summarizes the genetic and molecular mechanisms of checkpoint activation in response to DNA damage. The major checkpoint proteins common to all eukaryotes are identified and discussed, together with how the checkpoint proteins interact to induce arrest within each cell cycle phase. Also discussed are the molecular signals that activate checkpoint responses, including single-strand DNA, double-strand breaks, and aberrant replication forks. We address the connection between checkpoint proteins and damage repair mechanisms, how cells recover from an arrest response, and additional roles that checkpoint proteins play in DNA metabolism. Finally, the connection between checkpoint gene mutation and genomic instability is considered.
Adenophostin, a Potent Agonist of the Inositol 1,4,5-Trisphosphate Receptor, Is Useful for Fertilization of Mouse Oocytes Injected with Round Spermatids Leading to Normal Offspring1 (1998)

Precursor male gametes such as round spermatids and secondary spermatocytes are known to possess the potential to achieve fertilization and embryonic development when injected into mature oocytes, but in previous studies, injected mouse spermatids did not activate the oocytes. In this study, we confirmed that this was the case because spermatids by themselves could not induce an increase in intracellular Ca2+ concentration ([Ca2+]i) of oocytes, the pivotal signal in oocyte activation. Repetitive rises in [Ca2+]i (Ca2+ oscillations), lasting for at least 3 h as observed at fertilization, were produced by a single injection of adenophostin B isolated from fungal products, a novel nonmetabolizable agonist of the inositol 1,4,5-trisphosphate receptor (InsP3r), which mediates Ca2+ release from the endoplasmic reticulum. Ca2+ oscillations were blocked by an antibody against the type 1 InsP3r. About 95% of oocytes were activated by adenophostin (0.3–0.4 μM in the oocyte). Simultaneous injection of a round spermatid and adenophostin resulted in 55% fertilization success in association with male and female pronucleus formation and development to two-cell embryos. Furthermore, 25% of two-cell embryos that were transplanted to foster mothers developed to normal offspring. All infants grew into adults that reproduced healthy second generations. Adenophostin will be useful for parthenogenetic oocyte activation in the biotechnology of animal reproduction. Injection combined with precursor spermatozoa may be applicable to assisted conception therapy for patients with defective spermatogenesis.
Optimal timing for collections of blood progenitor cells following induction chemotherapy and granulocyte-macrophage colony-stimulating factor for autologous transplantation in advanced breast cancer. (1993)

Circulating progenitor cells collected during periods of rapid hematopoietic reconstitution can be used successfully as hematopoietic support for super-dose chemotherapy. A major problem for collection of peripheral blood progenitor cells has been determination of optimal time to start leukapheresis and of the adequate amount of progenitor cells. This study has demonstrated that an induction chemotherapy with augmented dosage of CEF (cyclophosphamide, epirubicin, 5-fluorouracil) in conjunction with granulocyte-macrophage colony-stimulating factor (CM-CSF) successfully mobilized peripheral blood progenitor cells in 15 patients with metastatic breast cancer. By monitoring the granulocyte-macrophage colony-forming units (CFU-GM), erythrocyte burst-forming units (BFU-E), and CD34+ cells in peripheral blood daily after leukocyte nadir, we have identified an optimal 'window' in which concentrations of blood progenitor cells reached a maximum range. Although the time interval between chemotherapy and the time for maximum stimulation could vary from between 13 days to 19 days, maximum mobilization started consistently 2 days after the white blood cells (WBC) recovered to > 2.0 x 10(9)/l after nadir, and remained elevated for 4 to 5 days. A significant reduction of progenitor cells in peripheral blood and in the corresponding leukapheresis products was observed, however, from cycle 1 versus subsequent cycles (p < 0.0001), but there was no significant difference between cycles 2 and 3. When used as the sole source of hematopoietic support for super-dose chemotherapy with cyclophosphamide, mitoxantrone, and carboplatin, these progenitor cells induce rapid and sustained reconstitution in all patients. The median time from reinfusion to recovery of absolute neutrophil count (ANC) to > 0.5 x 10(9)/l was 13 days (range 9-18 days) and to an unmaintained platelet count of > 50 x 10(9)/l, 12 days (range 10-35 days). Autologous transplantation with stimulated blood progenitor cells can be an efficient alternative to bone marrow transplantation. With optimal timing for collections, as few as two leukapheresis procedures are required to obtain an adequate progenitor cell dose.
A QoS adaptive transport system (1996)

Distributed audio and video applications need to adapt to fluctuations in delivered quality of service (QoS). By trading off temporal and spatial quality to available bandwidth, or manipulating the playout time of continuous media in response to variation in delay, audio and video flows can be made to adapt to fluctuating QoS with minimal perceptual distortion. In this paper we describe the implementation of a QoS adaptive transport system that incorporates a QoS oriented API and a range of mechanisms to assist applications in exploiting QoS and adapting to fluctuations in QoS. The system, which is an instantiation of the QoS Architecture (QoS-A), is implemented in a multi ATM switch network environment with Linux based PC end systems and continuous media file servers. A performance evaluation of the system configured to support Video-on-Demand application scenario is presented and discussed.
Micropatterned Immobilization of Epidermal Growth Factor To Regulate Cell Function (1998)

Photoreactive epidermal growth factor (EGF) was synthesized by conjugating mouse EGF with photoreactive polyallylamine, which was synthesized by the coupling reaction of polyallylamine with N-[4-(azidobenzoyl)oxy]succinimide. The EGF derivative was pattern-immobilized onto a polystyrene plate by UV irradiation in the presence of a photomask in a prescribed micropattern. The patterned immobilization of EGF on the polystyrene plate was confirmed by immunostaining with anti-EGF antibody. Chinese hamster ovary (CHO) cells overexpressing EGF receptors were cultured on the micropatterned plate. The phosphorylated tyrosine residues of signal proteins, including EGF receptors, were detected only in the cells adhered in the EGF-immobilized area, and cell growth was observed only in the EGF-immobilized area. The cells growing in the EGF-immobilized area were partially stained by anti-phosphotyrosine antibody, when the area of EGF immobilization was smaller than the cell. The partial staining of activated proteins indicates that immobilization of EGF inhibited the free lateral diffusion and internalization of the activated EGF-EGF receptor complex. The enhanced cell growth is due to juxtacrine stimulation realized by immobilized EGF.
Biochemical mechanisms affecting susceptibility to noise-induced hearing loss. (1989)

In magnesium (Mg)-deficient rats and guinea pigs, noise-induced hearing loss (NIHL) was found to be correlated to the decrease of Mg in serum and perilymph. Also, in noise-exposed humans, NIHL increased with decreasing serum Mg. During the process of mechanoelectrical transduction within the hair cells in the inner ear, membrane permeability of K+ and Ca2+ will transiently increase. Mg deficiency may additionally increase membrane permeability and, therefore, energy-dependent K+ and Ca2+ turnover. The increased release of catecholamines in Mg deficiency may affect the hair cells, either directly by increasing the intracellular concentration of free Ca2+ and/or indirectly by reducing the blood flow. Also, thromboxane A2, which is increased in Mg deficiency, may reduce the blood flow in the inner ear. By these mechanisms, Mg deficiency may cause energy depletion and irreversible damage to the hair cells.
Reconstitution of Ca 2+ -Regulated Membrane Fusion by Synaptotagmin and SNAREs (2004)

We investigated the effect of synaptotagmin I on membrane fusion mediated by neuronal SNARE proteins, SNAP-25, syntaxin, and synaptobrevin, which were reconstituted into vesicles. In the presence of Ca2+, the cytoplasmic domain of synaptotagmin I (syt) strongly stimulated membrane fusion when synaptobrevin densities were similar to those found in native synaptic vesicles. The Ca2+ dependence of syt-stimulated fusion was modulated by changes in lipid composition of the vesicles and by a truncation that mimics cleavage of SNAP-25 by botulinum neurotoxin A. Stimulation of fusion was abolished by disrupting the Ca2+-binding activity, or by severing the tandem C2 domains, of syt. Thus, syt and SNAREs are likely to represent the minimal protein complement for Ca2+-triggered exocytosis.
Earliest Eligible Virtual Deadline First : A Flexible and Accurate Mechanism for Proportional Share Resource Allocation (1995)

We propose and analyze a new proportional share allocation algorithm for time shared resources. We assume that the resource is allocated in time quanta of size q. To each client, we associate a weight which determines the relative share from the resource that the client should receive. We define the notion of fairness in the context of an idealized system in which the resource is assumed to be granted in arbitrarily small intervals of time. Mainly, we show that in steady conditions our algorithm guarantees that the difference between the service time that a client should receive in the idealized system and the service time it actually receives in the real system is bounded by the size q of a time quantum. The algorithm provides support for dynamic operations, such as a client joining or leaving the competition (for the resource), and changing a client&amp;apos;s weight. By using an efficient augmented binary search tree data structure we implement these operations in O(log n), where n represe...
Sustained-Release Subconjunctival 5-Fluorouracil (1996)

Sustained-release systems for subconjunctival 5-FU may be useful in filter maintenance.
Tumor necrosis factor alpha has a protective role in a murine model of systemic candidiasis (1994)

The role of tumor necrosis factor alpha (TNF-alpha) in host defense against systemic Candida albicans infection was evaluated in a murine model of systemic candidiasis in which uniform death occurred between 5 and 6 days after infection. TNF-alpha was first detected at 16 h postinfection and progressively increased thereafter. Peak levels (700 to 900 pg/ml) were measured in mice near death. Administration of 0.5 to 1.0 mg of polyclonal immunoglobulin G (IgG) TNF-alpha antibody (TNF-alpha Ab) to mice 2 h preinfection neutralized serum TNF-alpha for up to 30 h. However, this regimen shortened survival from a mean of 5.5 days for IgG controls to 3.4 days (P = 1.9 x 10(-12)). Semiquantitative cultures of spleen, lung, liver, and kidney conducted at 1, 2, and 3 days postinfection found colony counts of spleen and kidney to be significantly higher for TNF-alpha Ab recipients but only for the first 48 h. Administration of 1.5 and 1.0 mg of TNF-alpha Ab at 2 h before and 48 h after fungal injection, respectively, shortened the mean survival from 4.9 to 2.3 days (P = 5.2 x 10(-8)). This regimen neutralized serum TNF-alpha throughout infection. With this regimen, colony counts of all organs were significantly higher in TNF-alpha Ab recipients at 1, 2, and 3 days postinfection. Histopathologic studies showed an increase in the number and size of C. albicans foci in tissues. Peripheral leukocyte counts and inflammatory response in tissue were similar for TNF-alpha Ab and IgG sham recipients. In vitro, incubation of C. albicans with four to eight times the peak serum levels of TNF-alpha for up to 24 h did not inhibit the rate of germ tube or pseudohypha formation. Thus, TNF-alpha that was produced during infection with C. albicans augmented host resistance against this organism and prolonged survival. The protective effect of TNF-alpha was not mediated by increased leukocytes in blood or tissues nor by a direct anticandidal effect of TNF-alpha. This study suggests that the administration of exogenous TNF-alpha may enhance host resistance against systemic C. albicans infection and may improve host survival.
Vaccination with ant‐idiotype antibodies mimicking a renal cell carcinoma‐associated antigen induces tumor immunity (1994)

We have previously isolated and characterized 6 different internal image mouse monoclonal anti-idiotype antibodies (Ab2) directed against the paratope of mouse monoclonal antibody G250 (MAbG250, Ab1), which specifically reacts with human renal cell carcinoma (RCC). These Ab2s (NUH31, 44, 51, 71, 82 and 91) demonstrated specificity for the combining site of Ab1, and appeared to recognize 2 partly overlapping idiotopes on Ab1. In this study, we further characterize the fine specificity of the Ab2, investigate whether the immunogenicity of Ab2 could be enhanced by conjugation to a carrier and investigate the anti-tumor efficacy of Ab3 sera in mice challenged with RCC. Immunization of animals with Ab2 conjugated to keyhole limpet hemocyanin as carrier protein resulted in a 2-fold increase in antigen-specific anti-anti-idiotype antibodies (Ab3) as compared with immunization using Ab2 alone. Specific reactivity was observed with antigen-positive cell lysates, and all Ab3 sera contained immunoglobulin resembling Ab1 (Ab1'), as shown by competitive Ab1-antigen binding assays. Fine-specificity studies of Ab3 sera revealed that the Ab2s can be divided into 4 mutually exclusive groups, showing that the 6 Ab2s recognize 4 slightly different idiotopes in the Ab1 binding pocket. Treatment of RCC-challenged mice with Ab3 sera resulted in significant tumor growth inhibition and lower tumor take rates as compared with control groups. Ab3 sera obtained from NUH-91-immunized animals showed superior characteristics as compared to the other Ab3 sera: no tumors remained after 5 weeks of Ab3-NUH91 treatment. Our findings indicate that the Ab2 elicit powerful anti-tumor effects in immune-competent animals.