gebhart/patrepeval huggingface dataset:
Quantification of islet size and architecture (2012)

Human islets exhibit distinct islet architecture particularly in large islets that comprise of a relatively abundant fraction of α-cells intermingled with β-cells, whereas mouse islets show largely similar architecture of a β-cell core with α-cells in the periphery. In humans, islet architecture is islet-size dependent. Changes in endocrine cell mass preferentially occurred in large islets as demonstrated in our recent study on pathological changes of the pancreas in patients with type 2 diabetes. ( 1) The size dependency of human islets in morphological changes prompted us to develop a method to capture the representative islet distribution in the whole pancreas section combined with a semi-automated analysis to quantify changes in islet architecture. The computer-assisted quantification allows detailed examination of endocrine cell composition in individual islets and minimizes sampling bias. The standard immunohistochemistry based method is widely applicable to various specimens, which is particularly useful for large animal studies but is also applied to a large-scale analysis of the whole organ section from mice. In this article, we describe the method of image capture, parameters measured, data analysis and interpretation of the data.
Single Injections of Vascular Endothelial Growth Factor Trap Block Ovulation in the Macaque and Produce a Prolonged, Dose-Related Suppression of Ovarian Function (2005)

Follicular development is associated with intense angiogenesis and increased permeability of blood vessels under the control of locally produced angiogenic factors such as vascular endothelial growth factor (VEGF). The aim of the present study was to evaluate the effects of transient inhibition of VEGF on pituitary-ovarian function in the macaque. Animals were given a single, iv injection of a potent, receptor-based VEGF antagonist, the VEGF Trap. VEGF Trap was given at a dose of 4, 1, or 0.25 mg/kg in the midfollicular phase or at 1.0 mg/kg in the late follicular phase. Controls were treated with vehicle or a control protein, recombinant human Fc (1 mg/kg). Blood samples were collected once daily for 12 d after injection, and three times per week thereafter until normal ovulatory cycles had resumed. The VEGF Trap produced a rapid suppression of estradiol and inhibin B concentrations at all doses tested, followed by a marked and sustained increase in LH and FSH. Ovulation and formation of a functional corpus luteum, as evidenced by increased serum progesterone levels, failed to occur at the anticipated time. Normal ovarian activity resumed when plasma concentrations of unbound VEGF Trap fell below about 1 mg/liter. When treatment was initiated in the midfollicular phase, control macaques ovulated 7.2 +/- 0.4 d later, but ovulation was delayed in a dose-dependent manner by VEGF Trap, occurring 23 +/- 0.7, 30 +/- 1.4, and 43 +/- 0.8 d after injection of 0.25, 1, or 4 mg/kg, respectively. Thus, the VEGF Trap exerts a potent, dose-dependent, but reversible inhibitory effect on ovarian function.
First trimester serum screening for down's syndrome (1995)

Screening for Down's Syndrome has been shown to be effective at 10 weeks of pregnancy. A multicentre study (the first trimester serum screening study) has shown that there are two biochemical markers of choice at this time in pregnancy, namely pregnancy associated placental protein A (PAPP-A) and the free beta-sub-unit of human chorionic gonadotrophin (free beta-hCG). When used together with maternal age these two biochemical markers have an estimated detection rate of 62% and a 5% false-positive rate. The results are consistent with those obtained from a systematic review of the world literature. Other markers are less predictive of Down's syndrome though there is still some uncertainty over the value of dimeric inhibin-A at 10 weeks of pregnancy. Nuchal translucency measurement, from an ultrasound examination performed at about 10 weeks of pregnancy, is associated with Down's syndrome and is emerging as an important potential screening marker. At present there is uncertainty over its quantitative performance and performance when combined with biochemical markers. The resolution of these issues is currently the subject of active research. Ten week screening for Down's syndrome is an advance that is now technically possible though there is still insufficient information to justify its use in routine screening practice.
Role of glutathione in the multidrug resistance protein 4 (MRP4/ABCC4)-mediated efflux of cAMP and resistance to purine analogues (2002)

Multidrug resistance protein 4 (MRP4/ABCC4) is a member of the MRP subfamily, which in turn is a member of the superfamily of ATP-binding-cassette (ABC) transporters. Within the MRP subfamily, ABCC4, ABCC5 (MRP5), ABCC11 (MRP8) and ABCC12 (MRP9) have similar predicted membrane topologies. All lack the additional transmembrane domain, TMD0, which is present in the other MRPs. Using cells stably overexpressing ABCC4, this study shows that ABCC4 exports GSH. ABCC4 also facilitates the efflux of cAMP. Depletion of intracellular GSH with dl-buthionine-(S,R)-sulphoximine led to decreased export of cAMP and a corresponding increase in intracellular cAMP was observed. ABCC4 also mediates resistance to purine analogues 9-(2-phosphonylmethoxyethyl)-adenine and 6-thioguanine. This resistance can be reversed by the presence of dl-buthionine-(S,R)-sulphoximine. We conclude that as well as nucleotide and nucleoside analogues, ABCC4 can mediate the export of GSH. In addition, GSH plays an important role in the function of ABCC4. Depletion of intracellular GSH adversely affects the export of cAMP by ABCC4. Resistance to nucleoside analogues is also adversely affected by depletion of cellular GSH.
Quantitative structure-activity relationships of antitumor guanidinothiazolecarboxamides with survival enhancement for therapy in the 3LL Lewis lung carcinoma model (1991)

Guanidinothiazolecarboxamides (GTCs) are a novel class of antitumor agents found to be systemically active against experimental pulmonary metastases of 3LL Lewis lung carcinoma. A series of substituted benzothiazole GTCs were found to produce enhancement of survival in this model by using 8 days of intraperitoneal dosing initiated 2 days after intravenous tumor challenge. Quantitative structure-activity relationships have been discovered in the GTC series with survival enhancement correlated to substituent parameters. Optimal correlations were found between the probit transform of the drug-induced increased lifespan (ILS) and field and pi parameters. Among the most effective analogues in this series was N-(5-fluorobenzothiazol-2-yl)-2-guanidinothiazole-4-carboxam ide.
Role of Th17 Cells in the Pathogenesis of Human IBD (2014)

The gastrointestinal tract plays a central role in immune system, being able to mount efficient immune responses against pathogens, keeping the homeostasis of the human gut. However, conditions like Crohn's disease (CD) or ulcerative colitis (UC), the main forms of inflammatory bowel diseases (IBD), are related to an excessive and uncontrolled immune response against normal microbiota, through the activation of CD4(+) T helper (Th) cells. Classically, IBD was thought to be primarily mediated by Th1 cells in CD or Th2 cells in UC, but it is now known that Th17 cells and their related cytokines are crucial mediators in both conditions. Th17 cells massively infiltrate the inflamed intestine of IBD patients, where they produce interleukin- (IL-) 17A and other cytokines, triggering and amplifying the inflammatory process. However, these cells show functional plasticity, and they can be converted into either IFN- γ producing Th1 cells or regulatory T cells. This review will summarize the current knowledge regarding the regulation and functional role of Th17 cells in the gut. Deeper insights into their plasticity in inflammatory conditions will contribute to advancing our understanding of the mechanisms that regulate mucosal homeostasis and inflammation in the gut, promoting the design of novel therapeutic approaches for IBD.
Antithrombin III Toyama: replacement of arginine-47 by cysteine in hereditary abnormal antithrombin III that lacks heparin-binding ability. (1984)

Structural analyses of a hereditary abnormal antithrombin III, antithrombin III Toyama, which has normal progressive antithrombin activity but no heparin cofactor activity, have been carried out to elucidate the molecular abnormality causing recurrent thrombophlebitis of a patient and to identify an amino acid residue essential for the binding with heparin. Abnormal antithrombin III was reduced, S-pyridylethylated, and treated with cyanogen bromide. Eleven fragments were isolated by the combination of Sephadex G-50 gel filtration and reversed-phase HPLC and compared with those from normal antithrombin III. One large fragment (CN-III) that appeared to have a different amino acid composition from that of the corresponding fragment from normal antithrombin III was digested with trypsin, and the digests were separated by HPLC. The abnormal peptide was identified by comparing the peptide map with that from normal antithrombin III. Amino acid sequence analysis of the abnormal peptide indicated that the arginine-47 of normal antithrombin III had been replaced by cysteine in antithrombin III Toyama. One base mutation, C leads to T, in the 5' terminal position of the arginine-47 genetic codon (CGT) is probably responsible for this substitution. These results also suggest that arginine-47 is an essential amino acid residue for the binding with heparin.
Serum Paraoxonase Activity, Concentration, and Phenotype Distribution in Diabetes Mellitus and Its Relationship to Serum Lipids and Lipoproteins (1995)

Human serum paraoxonase is physically associated with HDL and has been implicated in the detoxification of organophosphates and possibly in the prevention of LDL lipid peroxidation. We investigated the serum activity and concentration of paraoxonase in 78 patients with type 1 diabetes mellitus, 92 with type 2 diabetes, and 82 nondiabetic control subjects. Paraoxonase activity was generally lower in diabetics than in control subjects. This decrease was unrelated to differences in paraoxonase phenotype distribution or its serum concentration. Rather, the difference in paraoxonase activity was explained by its specific activity, which was lower in diabetics, indicating either the presence of a circulating inhibitor or disturbance of the interaction of paraoxonase with HDL affecting its activity. Paraoxonase specific activity was lowest in patients with peripheral neuropathy, suggesting an association of paraoxonase with neuropathy. In control subjects but not patients with diabetes, paraoxonase correlated with HDL cholesterol and apolipoprotein A-1. Our results indicate that the low paraoxonase activity in diabetes is due to decreased specific activity. In other studies low serum paraoxonase activity has been associated with increased susceptibility to atherosclerosis, and the present results also suggest an association with peripheral neuropathy, which could be due to reduced capacity to detoxify lipid peroxides in diabetes.
Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial (2013)

After loss of response to NSAIs in postmenopausal women with hormone-receptor-positive advanced breast cancer, maximum double endocrine treatment with 250 mg fulvestrant combined with oestrogen deprivation is no better than either fulvestrant alone or exemestane.
Acute and chronic arsenic toxicity (2003)

Arsenic toxicity is a global health problem affecting many millions of people. Contamination is caused by arsenic from natural geological sources leaching into aquifers, contaminating drinking water and may also occur from mining and other industrial processes. Arsenic is present as a contaminant in many traditional remedies. Arsenic trioxide is now used to treat acute promyelocytic leukaemia. Absorption occurs predominantly from ingestion from the small intestine, though minimal absorption occurs from skin contact and inhalation. Arsenic exerts its toxicity by inactivating up to 200 enzymes, especially those involved in cellular energy pathways and DNA synthesis and repair. Acute arsenic poisoning is associated initially with nausea, vomiting, abdominal pain, and severe diarrhoea. Encephalopathy and peripheral neuropathy are reported. Chronic arsenic toxicity results in multisystem disease. Arsenic is a well documented human carcinogen affecting numerous organs. There are no evidence based treatment regimens to treat chronic arsenic poisoning but antioxidants have been advocated, though benefit is not proven. The focus of management is to reduce arsenic ingestion from drinking water and there is increasing emphasis on using alternative supplies of water.
Isozyme-specific enzyme inhibitors. 11. (L-homocysteine)-ATP S-C5' covalent adducts as inhibitors of rat methionine adenosyltransferases (1986)

The title compounds (14a,b) were 5' epimers of a derivative of a phosphonate isostere of ATP in which the CH2OP alpha system of ATP was replaced by CH(R)CH2P alpha [R = L-S(CH2)2CH(NH2)CO2H]. They resisted synthesis via attempted S-alkylation of the corresponding epimeric 5'-mercapto derivatives. A practicable route to 14a,b commenced with Michael condensation of L-homocysteine with the diphenyl ester of the 5',6'-vinyl phosphonate analogue of 2',3'-O-isopropylideneadenosine 5'-phosphate. The resulting epimeric 5' thioethers were separated by reverse-phase HPLC. The two phenyl groups were replaced by benzyl groups, after which the alpha-amino acid residue was protected as an N-Boc methyl ester. Both benzyl groups were removed by hydrogenolysis, and the resulting phosphonic acid was converted into its pyrophosphoryl derivative. Blocking groups were then removed under conditions that furnished 14a and 14b without racemization of their L-amino acid residues. Also synthesized were the P beta-NH-P gamma imido analogue (15a) of 14a and the sulfoxide derivative (16a) of 14a. The structures of 14a and 16a were verified by FAB mass spectra, which revealed the protonated molecular ions of their sodium salts. All adducts appeared to function as dual substrate site inhibitors (competitive to ATP and to methionine) of the rat normal tissue (MAT-2) form of methionine adenosyltransferase (MAT); 14a and 15a [KM(ATP)/Ki = 4 and 9, respectively] were the most effective. Adduct 15a was the most effective inhibitor [KM(ATP)/Ki = 13] of the MAT-T form from rat hepatoma tissue; the kinetic data indicated dual-site inhibition by 15a with apparently complete coverage of the ATP site and incomplete coverage of the methionine site. The inhibition properties of the adducts indicated little preference in the order in which the two MAT forms bound ATP and methionine.
Design, synthesis, antineoplastic activity, and chemical properties of bis(carbamate) derivatives of 4,5-bis(hydroxymethyl)imidazole (1989)

A series of bis(carbamate) derivatives of 1,2-substituted 4,5-bis(hydroxymethyl)imidazoles were prepared and evaluated against murine P388 lymphocytic leukemia. Electron-withdrawing substituents at either N-1 or C-2 gave rise to inactive compounds. However, electron-donating substituents gave active compounds and the 2-(methylthio)-1-methyl derivative 2i (carmethizole), as the bis(N-methylcarbamate), was found to be very active. The derivative 2i, referred to by the name carmethizole, was also shown to be active against the MX-1 mammary xenograft, the human amelanotic melanoma cell line (LOX) xenograft, the M5076 sarcoma, and L1210 lymphocytic leukemia. The solution stability, water solubility, pKa, and log P of carmethizole are also reported.
A fast and accurate face detector based on neural networks (2001)

Detecting faces in images with complex backgrounds is a difficult task. Our approach, which obtains state of the art results, is based on a neural network model: the constrained generative model (CGM). Generative, since the goal of the learning process is to evaluate the probability that the model has generated the input data, and constrained since some counter-examples are used to increase the quality of the estimation performed by the model. To detect side view faces and to decrease the number of false alarms, a conditional mixture of networks is used. To decrease the computational time cost, a fast search algorithm is proposed. The level of performance reached, in terms of detection accuracy and processing time, allows us to apply this detector to a real world application: the indexing of images and videos.
Tannin inhibits HIV-1 entry by targeting gp41. (2004)

Tannin inhibits HIV-1 entry into target cells by interfering with the gp41 six-helix bundle formation, thus blocking HIV-1 fusion with the target cell.
Humanization and molecular modeling of the anti-CD4 monoclonal antibody, OKT4A (1996)

OKT4A, a murine mAb that recognizes an epitope on the CD4 receptor, is a potent immunosuppressive agent in vitro and in a variety of nonhuman primate models of graft rejection and autoimmune disease. Initial human cardiac transplant trials suggest that OKT4A does not cause either cytokine release syndrome or CD4+ cell depletion, but does induce a human anti-mouse Ab (HAMA) response despite strong concurrent immunosuppression. To further investigate the potential of OKT4A as an immunomodulator, it was necessary to decrease its immunogenicity. Therefore, we developed a humanized version of this Ab (gOKT4A-4), which has the same binding affinity and in vitro immunosuppressive properties of OKT4A, but retains only three murine sequence-derived amino acid residues outside of the complementarity-determining regions (CDRs). Detailed computer modeling of both OKT4A and gOKT4A-4 provided a computational rationale for the changes necessary to regain activity after humanization. This has also provided a plausible representation of the Ag binding site. Preliminary clinical results with gOKT4A-4 suggest that we have eliminated the immunogenicity observed in the parent murine Ab.
Two stage co-channel interference cancellation in orthogonal multicarrier CDMA in a frequency selective fading channel (2002)

We have proposed a multi-carrier DS-SS CDMA system that eliminates the effect of multipath fading. Instead of multipath diversity, frequency diversity is obtained. This paper presents a co-channel interference cancellation technique and applies it to the multi-carrier CDMA system. Any bit of the desired user gets interference from two bits of any other user. The interference cancellation technique first removes the interference contributed by the first interfering bit then removes all interference.
1-Methyl-3H-pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-ones. Design, Synthesis, and Biological Activity of New Antitumor Agents (2005)

1-Methylpyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-ones 4, synthesized in good to excellent yields, were designed as novel alkylating agents because of their peculiar chemical behavior. All derivatives showed antiproliferative activity against more than 50 types of tumor cell lines with GI(50) reaching sub-micromolar values. SAR studies revealed that the presence of a chlorine atom is well-tolerated in both positions 8 and 9, whereas in the case of the methyl group, switching from the 8 to the 9 position gives rise to the most active compound of the series, 4g, either for the number of cell lines inhibited and for selectivity against leukaemia and renal cancer subpanels. COMPARE and 3D-MIND computations indicate, for compounds 4, an activity profile analogous to rifamycins and cytidine analogues.
Selenium heterocycles. XXXV . Synthesis and pyrrolysis of aryloxy‐, arylthio‐, and arylseleno‐1,2,3‐selenadiazoles (1982)

Abstract A series of 4‐substituted‐5‐arylthio‐1,2,3‐selenadiazoles, 4‐substituted‐5‐arylseleno‐1,2,3‐selenadiazoles and 4‐aryloxymethyl‐1,2,3‐selenadiazoles were synthesized. Pyrrolysis of these compounds afforded the corresponding acetylenes XI, XIII (X = S, Se) and XII, respectively. Oxidation of 4‐substituted‐5‐arylthio‐1,2,3‐selenadiazoles (XIV) with m ‐chloroperbenzoic acid gave 4‐substituted‐5‐arylsulfinyl‐1,2,3‐selenadiazoles (XV) and 4‐substituted‐5‐arylsulfonyl‐1,2,3‐selenadiazoles (XVI).
Issues in the manufacture and transplantation of genetically modified hematopoietic stem cells (2000)

The advent of safe and practical means to correct, enhance or protect blood cells at the genetic level offers tantalizing therapeutic perspectives. At present, gene delivery using a replication-defective retrovirus is the most efficient method to stably transduce hematopoietic cells. The successful adaptation of retroviral infection to hematopoietic stem cells requires optimized transduction conditions that maximize gene transfer while preserving the cells' potential for engraftment and longterm hematopoiesis. The successful establishment of effective transduction protocols hinges on retrovirus biology as well as stem cell and transplantation biology. Interestingly, the genetic approach could permit novel strategies to promote host repopulation by transplanted stem cells. However, regulated and predictable expression of any transgene integrated at random chromosomal locations cannot be taken for granted. Investigation of the control of transgene expression and prevention of vector silencing will become increasingly important.
Molecular Heterogeneity of Ehrlichia chaffeensis Isolates Determined by Sequence Analysis of the 28-Kilodalton Outer Membrane Protein Genes and Other Regions of the Genome (2002)

Ehrlichia chaffeensis, a tick-transmitted rickettsial agent, is responsible for human monocytic ehrlichiosis (HME). In this study, we genetically mapped 10 isolates obtained from HME patients. Sequence analysis of the 28-kDa outer membrane protein (OMP) multigene locus spanning 6 of the 22 tandemly arranged genes identified three distinct genetic groups with shared homology among isolates within each group. Isolates in Groups I and III contained six genes each, while Group II isolates had a gene deletion. There were two regions on the locus where novel gene deletion or insertion mutations occurred, resulting in the net loss of one gene in Group II isolates. Numerous nucleotide differences among genes in isolates of each group also were detected. The shared homology among isolates in each group for the 28-kDa OMP locus suggests the derivation of clonal lineages. Transcription and translation analysis of the locus revealed differences in the expressed genes of different group isolates. Analysis of the 120-kDa OMP gene and variable-length PCR target gene showed size variations resulting from loss or gain of long, direct repeats within the protein coding sequences. To our knowledge this is the first study that looked at several regions of the genome simultaneously, and we provide the first evidence of heterogeneity resulting from gene deletion and insertion mutations in the E. chaffeensis genome. Diversity in different genomic regions could be the result of a selection process or of independently evolved genes.