gebhart/patrepeval huggingface dataset:
New 2-Piperazinylbenzimidazole Derivatives as 5-HT3Antagonists. Synthesis and Pharmacological Evaluation (1997)

A series of 2-piperazinylbenzimidazole derivatives were prepared and evaluated as 5-HT3 receptor antagonists. Their 5-HT3 receptor affinities were evaluated by radioligand binding assays, and their abilities to inhibit the 5-HT-induced Bezold-Jarisch reflex in anesthetized rats were determined. Compound 7e (lerisetron, pKi = 9.2) exhibited higher affinity for the 5-HT3 receptor than did tropisetron and granisetron, while compound 7q (pKi = 7.5) had very low affinity for this receptor, showing that substitution on the N1 atom of the benzimidazole ring is essential for affinity and activity. The effect of substitution on the aromatic ring of benzimidazole by several substituents in different positions is also discussed. A strong correlation between the 5-HT3 antagonistic activity of the studied compounds and the position of substitution on the aromatic ring was established. Thus, while the 4-methoxy derivative 7m showed weak affinity for the 5-HT3 receptor (pKi = 6.7), the 7-methoxy derivative 7n exhibited the highest affinity (pKi = 9.4). Compounds 7e and 7n are now under further investigation as drugs for the treatment of nausea and emesis evoked by cancer chemotherapy and radiation.
Nutrient Restriction and Radiation Therapy for Cancer Treatment: When Less Is More (2013)

Calorie restriction (CR), or a diet modification aiming to reduce the total intake of calories by 20%-40%, has been shown to increase longevity across multiple species. Recently, there has been growing interest in investigating the potential role of CR as a treatment intervention for age-related diseases, such as cancer, because an increasing body of literature has demonstrated a metabolic component to both carcinogenesis and tumor progression. In fact, many of the molecular pathways that are altered with CR are also known to be altered in cancer. Therefore, manipulation of these pathways using CR can render cancer cells, and most notably breast cancer cells, more susceptible to standard cytotoxic treatment with radiation and chemotherapy. In this review article we demonstrate the laboratory and clinical evidence that exists for CR and show compelling evidence through the molecular pathways CR induces about how it may be used as a treatment in tandem with radiation therapy to improve our rates of disease control.
Plasma triglyceride and coronary heart disease. (1991)

Although the literature on epidemiological associations between plasma triglyceride and CHD is not completely consistent, trends do emerge from the studies described here. First, the majority of observational studies demonstrate a significant univariate relation, although the results of case-control and cross-sectional studies are more uniform than those from prospective study designs. In many but not all studies, triglyceride remains a significant predictor of CHD in multivariate statistical analyses after controlling for TC or LDL-C. Perhaps the least consistent result is that the triglyceride association does not persist in some analyses controlling for HDL-C, while in other studies, the association remains significant. Although most studies have been conducted in men, the studies providing data on women, normocholesterolemic subjects, and diabetic subjects have generally found triglyceride to be, at the very least, a univariate risk factor. The results of intervention trials differ considerably, but no such study to date has been specifically designed to evaluate triglyceride-lowering effects on primary prevention of CHD. Important statistical properties must be taken into consideration in evaluating triglyceride as a risk factor for CHD. The large variability of triglyceride measurements and the correlation of triglyceride values with other lipid measures appears to result in the underestimation of the association between triglyceride and disease in multivariate analyses. Finally, individual genetic susceptibility may play an important role in the relation between plasma triglyceride levels and CHD. For example, risk of CHD clearly varies among the well-established familial forms of hypertriglyceridemia. A predominance of small, dense, LDL particles (LDL subclass pattern B) also appears to be a genetic trait associated with both increased risk of MI and increases in plasma triglyceride levels.
A Bioassay for HIV-1 Based on Env-CD4 Interaction (1990)

The binding of human immunodeficiency virus type 1 (HIV-1) gp120env to CD4 is the first event leading to infection and represents an important target for possible therapeutic intervention. To provide a tool for screening and quantitation of the effects of drugs inhibiting the Env-CD4 interaction, we developed a simple, fast and quantitative bioassay measuring the fusion between two cell lines generated by stable transfection: one expressing high levels of HIV-1 proteins but no infectious virus (HL2/3), and the other expressing the CD4 receptor and containing an inducible chloramphenicol acetyltransferase (CAT) gene linked to the HIV-1 long terminal repeat (HLCD4-CAT). Upon cocultivation of HL2/3 and HLCD4-CAT cells, efficient cell fusion is observed within 8 h. The efficiency of fusion can be evaluated visually and quantitated by measuring CAT enzyme. This novel bioassay allows testing for drugs capable of interfering with the CD4-Env interaction. HL2/3 cell line secretes gp120env in the medium and can be used for the production of Env protein.
Flexible Transparent Conducting Hybrid Film Using a Surface-Embedded Copper Nanowire Network: A Highly Oxidation-Resistant Copper Nanowire Electrode for Flexible Optoelectronics (2014)

We report a flexible high-performance conducting film using an embedded copper nanowire transparent conducting electrode; this material can be used as a transparent electrode platform for typical flexible optoelectronic devices. The monolithic composite structure of our transparent conducting film enables simultaneously an outstanding oxidation stability of the copper nanowire network (14 d at 80 °C), an exceptionally smooth surface topography (R(rms) < 2 nm), and an excellent opto-electrical performances (Rsh = 25 Ω sq(-1) and T = 82%). A flexible organic light emitting diode device is fabricated on the transparent conducting film to demonstrate its potential as a flexible copper nanowire electrode platform.
Plasma monocyte chemoattractant protein 1 is a marker for joint inflammation in rheumatoid arthritis. (2001)

By linear regression analysis plasma MCP-1 levels correlated significantly with the swollen joint count (Day 1: R = 0.47, p = 0.005; Day 30: R = 0.53, p < 0.001) and the RAI (Day 1: R = 0.37, p = 0.03; Day 30: R = 0.41, p = 0.01). The correlations of swollen joint count and RAI with ESR and CRP were significant only on Day 30 for the ESR (R = 0.40, p = 0.02). No association was found between plasma MCP-1 levels and the ESR/CRP levels. MCP-1 levels in plasma in RA patients were elevated compared to controls (p < 0.001) and MCP-I levels in SF were higher than in plasma (p < 0.001). No correlation was found between SF MCP-1 levels and in vitro migration of mononuclear cells towards SF. MCP-1 appears to participate in the disease process in RA, and plasma MCP-1 may be useful in monitoring joint inflammation.
Novel Phosphoramidite Building Blocks in Synthesis and Applications Toward Modified Oligonucleotides (2003)

In recent years modified oligonucleotides (oligos) have become an area of increased research activity. These synthetic biopolymers have long been used as molecular probes to understand better the interaction between proteins and nucleic acids at molecular level, which in fact is responsible for all aspects of cellular or viral gene expression. Modified oligos have also been used as therapeutic and diagnostic agents. For example, the antisense oligos are used to block gene expression by binding especially with complimentary sequences of target mRNA. Also, over the past decade efforts are made to modify the native phosphodiester linkages to improve nuclease resistance and membrane permeation of naturally occurring oligonucleotide for therapeutic applications. Therefore, design and synthesis of modified oligonucleotides for a wide range of applications are of interest for bioorganic chemists and biologists. The advent of the phosphoramidite chemistry has accelerated the development of oligos with modified nucleobases, phosphate-protecting groups and modified sugars. In this review, we have presented the recently reported nucleoside based phosphoramidites with modified base, sugar or backbone units and their subsequent conversion into modified DNA and RNA analogs. The effect of such modification on structural, thermodynamic, and hybridization properties of the modified oligos and their duplex with natural complementary oligos have also been discussed for some cases. Similarly, we have highlighted the role of modified nucleoside phosphoramidite building blocks in synthesis of oligos modified with optically or electrochemically active molecules. Nucleoside phosphoramidites or small oligos immobilized over solid supports through different linkages or groups and their biological applications has also been mentioned.
Selective gas detection using a carbon nanotube sensor (2003)

A circular disk resonator is used to study the gas sensing properties of carbon nanotubes. It detects the presence of gases based on the change in the dielectric constant rather than electrical conductivity of single walled carbon nanotubes (SWNTs) upon gas exposure. A conducting circular disk is coated with electric arc prepared SWNTs and degassed by heating under a high vacuum. It exhibits noticeable shifts in resonant frequency to both polar (NH3 and CO) and nonpolar gases (He, Ar, N2, and O2). Gas concentrations as low as 100 ppm can be detected using this sensor configuration.
OX40, PD‐1 and CTLA‐4 are selectively expressed on tumor‐infiltrating T cells in head and neck cancer (2016)

The tumor microenvironment of squamous cell carcinoma of the head and neck (SCCHN) has been shown to be immune suppressive. Therefore, strategies aimed at overcoming this issue could have a positive therapeutic impact. Hence, we investigated the expression of the known immune-modulatory proteins OX40, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in SCCHN on different T-cell subsets of tumor-infiltrating lymphocytes (TIL) to ascertain whether these proteins could potentially be targeted alone or in combination for future clinical trials. T cells from peripheral blood (PBL) and tumor were analyzed for the expression of OX40, PD-1 and CTLA-4 in 29 patients undergoing surgery. These proteins were all expressed significantly higher in T-cell subsets isolated from tumors compared with PBL of the same patient. OX40 expression was significantly greater in the TIL regulatory T-cell (Treg) population relative to conventional CD4 and CD8 TIL or the Treg isolated from PBL. PD-1 expression was increased in all T-cell subsets relative to PBL. CTLA-4 was also increased in all TIL subsets relative to blood, and similar to OX40, its highest level of expression was observed in the Treg TIL. The highest frequency of PD-1, CTLA-4 and OX40 triple-positive cells were found in the Treg population isolated from the tumor. We analyzed both human papilloma virus-positive and -negative patients and found similar levels and expression patterns of these two patient populations for all three proteins. These data suggest that there may be therapeutic advantages of targeting these pathways independently or in combination for patients with this disease.
Emerging Infectious Diseases of Wildlife-- Threats to Biodiversity and Human Health (2000)

Emerging infectious diseases (EIDs) of free-living wild animals can be classified into three major groups on the basis of key epizootiological criteria: (i) EIDs associated with “spill-over” from domestic animals to wildlife populations living in proximity; (ii) EIDs related directly to human intervention, via host or parasite translocations; and (iii) EIDs with no overt human or domestic animal involvement. These phenomena have two major biological implications: first, many wildlife species are reservoirs of pathogens that threaten domestic animal and human health; second, wildlife EIDs pose a substantial threat to the conservation of global biodiversity.
Biology, classification and treatment of human mastocytosis. (1996)

Mastocytosis is a term collectively used for a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells. Clinical symptoms occur from the release of chemical mediators and the pathologic infiltration of cells. Three major groups of patients with mastocytosis can be distinguished: i) cutaneous mastocytosis, ii) mastocytosis involving the skin and one or more extracutaneous organ(s), and iii) visceral mastocytosis without involvement of the skin. Groups ii) and iii) account for approximately 15-20% of all cases and have been referred to as systemic mastocytosis. Cutaneous mastocytosis typically presents as urticaria pigmentosa or diffuse cutaneous mastocytosis. These patients usually have a benign course. In contrast, systemic mastocytosis is a diffuse hematologic process with an increased risk to develop aggressive disease. In these patients, additional hematologic abnormalities or a second hematologic process, such as a myeloproliferative or myelodysplastic syndrome, or acute leukemia, may develop. Malignant mastocytosis and mast cell leukemia are rare forms of mastocytosis and characterized by uncontrolled and progressive proliferation and infiltration of mast cells in diverse organs. These patients often present without cutaneous lesions and have a very unfavorable prognosis. Because of the immature morphology of the cells it is often difficult to establish the diagnosis in such patients. However, the use of antibodies to mast cell antigens has recently improved the diagnostic efficiency in patients with suspected mast cell disease. No effective therapy for patients with malignant mastocytosis is known, although some patients may benefit from corticosteroid and interferon alpha treatment. The present article gives an overview of current knowledge about the biology, heterogeneity and treatment of human mastocytosis.
Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant (2016)

Mutations in ESR1 have been associated with resistance to aromatase inhibitor (AI) therapy in patients with ER+ metastatic breast cancer. Little is known of the impact of these mutations in patients receiving selective oestrogen receptor degrader (SERD) therapy. In this study, hotspot mutations in ESR1 and PIK3CA from ctDNA were assayed in clinical trial samples from ER+ metastatic breast cancer patients randomized either to the SERD fulvestrant or fulvestrant plus a pan-PI3K inhibitor. ESR1 mutations are present in 37% of baseline samples and are enriched in patients with luminal A and PIK3CA-mutated tumours. ESR1 mutations are often polyclonal and longitudinal analysis shows distinct clones exhibiting divergent behaviour over time. ESR1 mutation allele frequency does not show a consistent pattern of increases during fulvestrant treatment, and progression-free survival is not different in patients with ESR1 mutations compared with wild-type patients. ESR1 mutations are not associated with clinical resistance to fulvestrant in this study.
Mutation of a Highly Conserved Arginine in Motif IV ofEscherichia coli DNA Helicase II Results in an ATP-binding Defect (1997)

A site-directed mutation in motif IV of Escherichia coli DNA helicase II (UvrD) was generated to examine the functional significance of this region. The highly conserved arginine at position 284 was replaced with alanine to construct UvrD-R284A. The ability of the mutant allele to function in methyl-directed mismatch repair and UvrABC-mediated nucleotide excision repair was examined by genetic complementation assays. The R284A substitution abolished function in both DNA repair pathways. To identify the biochemical defects responsible for the loss of biological function, UvrD-R284A was purified to apparent homogeneity, and its biochemical properties were compared with wild-type UvrD. UvrD-R284A failed to unwind a 92-base pair duplex region and was severely compromised in unwinding a 20-base pair duplex region. The Km of UvrD-R284A for ATP was significantly greater than 3 mM compared with 80 microM for UvrD. A large decrease in ATP binding was confirmed using a nitrocellulose filter binding assay. These data suggested that the R284A mutation severely reduced the affinity of helicase II for ATP. The reduced unwinding activity and loss of biological function of UvrD-R284A was probably the result of decreased affinity for ATP. These results implicate motif IV of superfamily I helicases in nucleotide binding and represent the first characterization of a helicase mutation outside motifs I and II that severely impacted the Km for ATP.
Treatment of atrial fibrillation (2008)

Novel antiarrhythmic agents, including atrial specific agents with improved efficacy and safety profile, are currently under development. New antithrombotic agents with efficacy similar to warfarin which do not require regular INR testing appear to be promising, but there are lack of data about their long-term safety. There is increasing evidence that inflammation and fibrosis may play a major role in the initiation and maintenance of AF. Statins by means of their pleotropic effects and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers by preventing atrial remodelling may prove useful in preventing the development of AF. However, there is insufficient evidence to expand the use of these agents to a wider patient population at risk of AF. It needs to be seen if strategies towards primary and secondary prevention with treatment of underlying heart disease and modification of risk factors have a larger effect than specific interventions in preventing the burden of AF in the general population.
Immunological Neutralization of Various Erythropoietins. (1963)

Increased serum erythropoietin levels were produced in mice, rats, rabbits, and a sheep in response to hypoxia or phenylhydrazine anemia. In all cases, including that of the rabbit, the serum erythropoietin was neutralized on addition of serum from rabbits previously immunized with an erythropoietin extract of human urinary origin. Also, an erythropoietin extract prepared from phenylhydrazine anemic sheep plasma was neutralized by such serum. These data suggest that erythropoietins of the various animal species studied are similar.
Characterization of human interferon species using gel extraction and monoclonal antibodies: implications on clinical use of interferon preparations. (1986)

Human interferons from various sources have been characterized using sodium dodecyl sulfate polyacrylamide gel electrophoresis followed by electrotransfer onto nitrocellulose and reaction with specific polyclonal and monoclonal antibodies. When gel slices were extracted, alpha-interferon subspecies possessed antiviral activity predominantly in the 18.6-19.7K region bands, the beta-interferon in the 22.1K band, and gamma-interferon in the 16.5-18.0K bands. Three of the monoclonal antibodies (Ab 138, Ab 126, Ab 098) reacted with a characteristic triplet of biologically active bands (18.6K, 19.1K, 19.7K) obtained using the Namalwa cell interferons, while two (Ab 194 and Ab 232) reacted only with the 18.6K band and Ab 523 reacted with the 19.7K band. With the human leukocyte interferons, Ab 098, Ab 194, and Ab 232 reacted with the active 18.6K band. The Ab 138, Ab 126, and Ab 523 reacted specifically with certain lower molecular weight active bands (13K region). A comparison of the antiviral activity and reactivity towards monoclonal and polyclonal antibodies presents a differentiation of the subspecies of interferons in the wide array of closely related proteins in interferon preparations packaged for clinical use.
Enforced fucosylation of neonatal CD34+ cells generates selectin ligands that enhance the initial interactions with microvessels but not homing to bone marrow (2004)

Hematopoietic progenitor/stem cell homing to the bone marrow requires the concerted action of several adhesion molecules. Endothelial P- and E-selectins play an important role in this process, but their ligands on a large subset of neonate-derived human CD34+ cells are absent, leading to a reduced ability to interact with the bone marrow (BM) microvasculature. We report here that this deficiency results from reduced alpha1,3-fucosyltransferase (FucT) expression and activity in these CD34+ cells. Incubation of CD34+ cells with recombinant human FucTVI rapidly corrected the deficiency in nonbinding CD34+ cells and further increased the density of ligands for both P- and E-selectins on all cord blood-derived CD34+ cells. Intravital microscopy studies revealed that these FucTVI-treated CD34+ cells displayed a marked enhancement in their initial interactions with the BM microvasculature, but unexpectedly, homing into the BM was not improved by FucTVI treatment. These data indicate that, although exogenous FucT enzyme activity can rapidly modulate selectin binding avidity of cord blood CD34+ cells, further studies are needed to understand how to translate a positive effect on progenitor cell adhesion in bone marrow microvessels into one that significantly influences migration and lodgement into the parenchyma.
The Raft-Promoting Property of Virion-Associated Cholesterol, but Not the Presence of Virion-Associated Brij 98 Rafts, Is a Determinant of Human Immunodeficiency Virus Type 1 Infectivity (2004)

Lipid rafts are enriched in cholesterol and sphingomyelin and are isolated on the basis of insolubility in detergents, such as Brij 98 and Triton X-100. Recent work by Holm et al. has shown that rafts insoluble in Brig 98 can be found in human immunodeficiency virus type 1 (HIV-1) virus-like particles, although it is not known whether raft-like structures are present in authentic HIV-1 and it is unclear whether a virion-associated raft-like structure is required for HIV replication. Independently, it was previously reported that virion-associated cholesterol is critical for HIV-1 infectivity, although the specific requirement of virion cholesterol in HIV-1 was not examined. In the present study, we have demonstrated that infectious wild-type HIV-1 contains Brij 98 rafts but only minimal amounts of Triton X-100 rafts. To directly assess the functional requirement of virion-associated rafts and various features of cholesterol on HIV-1 replication, we replaced virion cholesterol with exogenous cholesterol analogues that have demonstrated either raft-promoting or -inhibiting capacity in model membranes. We observed that variable concentrations of exogenous analogues are required to replace a defined amount of virion-associated cholesterol, showing that structurally diverse cholesterol analogues have various affinities toward HIV-1. We found that replacement of 50% of virion cholesterol with these exogenous cholesterol analogues did not eliminate the presence of Brij 98 rafts in HIV-1. However, the infectivity levels of the lipid-modified HIV-1s directly correlate with the raft-promoting capacities of these cholesterol analogues. Our data provide the first direct assessment of virion-associated Brij 98 rafts in retroviral replication and illustrate the importance of the raft-promoting property of virion-associated cholesterol in HIV-1 replication.