gebhart/patrepeval huggingface dataset:
Pathogenic weight-control behaviors of female college gymnasts (1989)

In brief: To study the methods and extent to which iemale college gymnasts diet, data were collected from 42 gymnasts aged 17 to 22 years, who represented five teams in a major athletic conference. The survey showed that (1) all the participants were dieting; (2) 26 were using at least one form of pathogenic weight-control behavior; and (3) 21 of the 28 competitors who were told by their coaches that they were too heavy resorted to using pathogenic weight-control behaviors. The authors discuss the implications of the demands of gymnastics and the additional social pressure to maintain exceptional thinness.
In vivo gut transcriptome responses toLactobacillus rhamnosusGG andLactobacillus acidophilusin neonatal gnotobiotic piglets (2014)

Probiotics facilitate mucosal repair and maintain gut homeostasis. They are often used in adjunct with rehydration or antibiotic therapy in enteric infections. Lactobacillus spp have been tested in infants for the prevention or treatment of various enteric conditions. However, to aid in rational strain selection for specific treatments, comprehensive studies are required to delineate and compare the specific molecules and pathways involved in a less complex but biologically relevant model (gnotobiotic pigs). Here we elucidated Lactobacillus rhamnosus (LGG) and L. acidophilus (LA) specific effects on gut transcriptome responses in a neonatal gnotobiotic (Gn) pig model to simulate responses in newly colonized infants. Whole genome microarray, followed by biological pathway reconstruction, was used to investigate the host-microbe interactions in duodenum and ileum at early (day 1) and later stages (day 7) of colonization. Both LA and LGG modulated common responses related to host metabolism, gut integrity, and immunity, as well as responses unique to each strain in Gn pigs. Our data indicated that probiotic establishment and beneficial effects in the host are guided by: (1) down-regulation or upregulation of immune function-related genes in the early and later stages of colonization, respectively, and (2) alternations in metabolism of small molecules (vitamins and/or minerals) and macromolecules (carbohydrates, proteins, and lipids). Pathways related to immune modulation and carbohydrate metabolism were more affected by LGG, whereas energy and lipid metabolism-related transcriptome responses were prominently modulated by LA. These findings imply that identification of probiotic strain-specific gut responses could facilitate the rational design of probiotic-based interventions to moderate specific enteric conditions.
Polyacrylamide gels copolymerized with active esters. New medium for affinity systems (1975)

A new and versatile method for linking biologically active ligands to a polyacrylamide matrix is reported. Active esters of acrylic acid (N-succinimicyl acrylate and N-phthalimidyl acrylate) were synthesized, then copolymerized with acrylamide and N,N'-methylenebisacrylamide. Displacement of the active ester in the gel thus formed by various ligands containing aliphatic amino groups resulted in the formation of stable amid bonds between the ligands and the polyacrylamide gel. The affinity gel thus prepared has the following advantages: (i) resistance to chemical and microbiological degradation, (ii) ease of control of ligand level and higher levels of ligand possible, (iii) ease of control of porosity, and (iv) total displacement of the active ester under suitable conditions. Efficacy of this system was tested by preparation of 6-aminohexyl 2-acetamido-2-deoxy-beta-D-glucopyranoside derivative polyacrylamide gel by the described method. It was found to be more effective for purification of wheat germ agglutinin than the previously published affinity chromatography systems and the wheat germ hemagglutinin was obtained in crystalline form. In addition, partial resolution of isolectins was obtained from the affinity gel witha pH gradient.
Guidelines for the validation of qualitative multi‐residue methods used to detect pesticides in food (2012)

There is a current trend for many laboratories to develop and use qualitative gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) based multi-residue methods (MRMs) in order to greatly increase the number of pesticides that they can target. Before these qualitative MRMs can be used for the monitoring of pesticide residues in food, their fitness-for-purpose needs to be established by initial method validation. This paper sets out to assess the performances of two such qualitative MRMs against a set of parameters and criteria that might be suitable for their effective validation. As expected, the ease of detection was often dependent on the particular pesticide/commodity combinations that were targeted, especially at the lowest concentrations tested (0.01 mg/kg). The two examples also clearly demonstrated that the percentage of pesticides detected was dependent on many factors, but particularly on the capabilities of the automated software/library packages and the parameters and threshold settings selected for operation. Another very important consideration was the condition of chromatographic system and detector at the time of analysis. If the system was relatively clean, then the detection rate was much higher than if it had become contaminated over time from previous injections of sample extracts. The parameters and criteria suggested for method validation of qualitative MRMs are aimed at achieving a 95% confidence level of pesticide detection. However, the presence of any pesticide that is 'detected' will need subsequent analysis for quantification and, depending on the qualitative method used, further evidence of identity.
Specific α‐Galactosidase Inhibitors, N‐Methylcalystegines Structure/Activity Relationships of Calystegines from Lycium Chinense (1997)

An examination of the roots of Lycium chinense (Solanaceae) has resulted in the discovery of 14 calystegines, a cycloheptane bearing an amino group and three hydroxyl groups, and two polyhydroxylated piperidine alkaloids. Calystegines A7 and B5, in addition to the previously known calystegines A3, A5, A6, B1, B2, B3, B4, C1, C2 and N1, were isolated and determined as 1alpha,2beta,4alpha-trihydroxy-nortropane and 1alpha,2alpha,4alpha,7alpha-tetrahydroxy-nort ropane, respectively. L. chinense also had two polyhydroxytropanes bearing a methyl group on the nitrogen atom, unlike the previously reported nortropane alkaloids. They were established as N-methylcalystegines B2 and C1, and their N-methyl groups were found to be axially oriented from NOE experiments. 1Beta-amino-3beta,4beta,5alpha-trihydroxycyclohepta ne was also present in L. chinense and may be a biosynthetic precursor of the calystegines that occur in this plant. Two polyhydroxypiperidine alkaloids, fagomine and 6-deoxyfagomine, were isolated. Calystegine B2 is a potent competitive inhibitor of almond beta-glucosidase (Ki = 1.9 microM) and coffee bean alpha-galactosidase (Ki = 0.86 microM), while N-methylcalystegine B2 was a more potent competitive inhibitor of the latter enzyme (Ki = 0.47 microM) than the parent compound but showed a marked lack of inhibitory activities towards most other glycosidases. Since this compound is a very specific inhibitor of alpha-galactosidase and inhibits rat liver lysosomal alpha-galactosidase with a Ki of 1.8 microM, it may provide a useful experimental model for the lysosomal storage disorder, Fabry's disease. The addition of a hydroxyl group at C6exo, as in calystegines B1 and C1, enhances the inhibitory potential towards beta-glucosidase and beta-galactosidase but markedly lowers or abolishes inhibition towards alpha-galactosidase. Hence, the N-methylation of calystegine C1 did not enhance its inhibition of alpha-galactosidase. The chemical N-methylation of calystegines A3 and B4 markedly enhanced inhibition of coffee bean alpha-galactosidase, with Ki values of 5.2 microM and 36 microM, respectively, but almost eliminated their inhibitory potential towards beta-glucosidase and trehalase, respectively. Thus, methylation of the nitrogen atom significantly altered the specificity of the inhibitors.
HIV‐1 Trafficking to the Dendritic Cell–T‐Cell Infectious Synapse Uses a Pathway of Tetraspanin Sorting to the Immunological Synapse (2005)

Dendritic cells (DCs) are essential components of the early events of HIV infection. Here, we characterized the trafficking pathways that HIV-1 follows during its capture by DCs and its subsequent presentation to CD4(+) T cells via an infectious synapse. Immunofluorescence microscopy indicates that the virus-containing compartment in mature DCs (mDCs) co-labels for the tetraspanins CD81, CD82, and CD9 but contains little CD63 or LAMP-1. Using ratio imaging of pH-reporting fluorescent virions in live DCs, we show that HIV-1 is internalized in an intracellular endocytic compartment with a pH of 6.2. Significantly, we demonstrate that the infectivity of cell-free virus is more stable at mildly acidic pH than at neutral pH. Using electron microscopy, we confirm that HIV-1 accumulates in intracellular vacuoles that contain CD81 positive internal membranes but overlaps only partially with CD63. When allowed to contact T cells, HIV-1-loaded DCs redistribute CD81, and CD9, as well as internalized HIV-1, but not the immunological synapse markers MHC-II and T-cell receptor to the infectious synapse. Together, our results indicate that HIV-1 is internalized into a non-conventional, non-lysosomal, endocytic compartment in mDCs and further suggest that HIV-1 is able to selectively subvert components of the intracellular trafficking machinery required for formation of the DC-T-cell immunological synapse to facilitate its own cell-to-cell transfer and propagation.
Anti-Idiotypic Therapy of Leukemias and Lymphomas (2015)

Idiotypic determinants of the Ig expressed by the majority of B cell tumors present an attractive target for immunotherapeutic manipulations. The idiotypic Ig is molecularly defined and the behavior of the target cells placed under anti-idiotypic attack might have broader implications for cancer immunotherapy. Simple administration of monoclonal antibody reactive with these determinants clearly has only a limited effect on tumor load, due largely to the multiplicity of strategies by which the tumor cell can avoid such attack. These include modulation, change in idiotypic determinants due to somatic mutation, and complete loss of expression at the cell surface. If the first antibody treatment can be made more effective, for example by tailoring molecules to recruit available effector mechanisms more efficiently, or by the use of antibodies capable of delivering a lethal hit via a toxin, the tumor cell will presumably have less opportunity to escape. A second strategy is to immunize the tumor-bearing host with idiotypic Ig obtained from tumor cells. Once in place, such an immune response should suppress tumor growth on a continuing basis. In animal lymphoma, this approach appears to prolong survival although some of the escape mechanisms encountered for passive antibody therapy are apparently operative for active therapy. Study of these mechanisms should allow insight into how cells control expression of idiotypic determinants at the cell surface and open the possibility of further therapeutic intervention. A combined approach to the treatment of human lymphoma might be envisaged whereby tumor load is reduced by passive antibody, thus leaving the immune system relatively unscathed, and even perhaps releasing natural antitumor responses which could be further stimulated by immunization.
Selective Killing of AFP-Positive Hepatocellular Carcinoma Cells by Adeno-Associated Virus Transfer of the Herpes Simplex Virus Thymidine Kinase Gene (1996)

The use of viral thymidine kinase (TK) gene coupled with the administration of ganciclovir to render cancer cell death has been studied extensively. Many of these experiments utilized retrovirus to transfer the TK gene under the control of a nonspecific promoter. Because nonspecific expression of the viral TK gene may cause death of proliferating cells, other than cancer cells, we explored the use of a liver-specific promoter and a tumor-specific AFP enhancer to achieve regulated viral TK gene expression for treatment of hepatocellular carcinoma. We also used the adeno-associated virus (AAV) as vector for the delivery of the TK gene because this virus is not associated with any pathological consequences in humans. Because it can infect nondividing S-phase cells, AAV can transfer genes into noncycling tumor cells. A recombinant AAV virus was constructed to include the selectable marker neoR gene and the herpes simplex virus (HSV)-TK gene driven by the human AFP enhancer and the albumin promoter. The liver-predominant expression pattern of the TK gene was observed when this construct was tested in transgenic mice. When human hepatocellular carcinoma cell lines displaying different levels of AFP and albumin and nonhepatocyte tumor cell lines were infected with the recombinant AAV virus, ganciclovir treatment caused only AFP and albumin-positive hepatocellular carcinoma cells death, but not nonhepatocyte tumor cells or AFP and albumin-negative hepatic tumor cells. Moreover, the dose required to kill the cancer cells was inversely proportional to the level of AFP expression in the cells.
Macrophage inflammatory protein-1 alpha and monocyte chemoattractant peptide-1 elicit immediate and late cutaneous reactions and activate murine mast cells in vivo. (1994)

We have previously reported that monocyte chemoattractant protein-1 (MCP-1) is the most potent histamine-releasing factor (HRF) for basophils. Macrophage inflammatory protein-1 alpha (MIP-1 alpha) has modest histamine-releasing activity. The objective of this study was to investigate whether MCP-1 and MIP-1 alpha would activate mast cells in vivo and induce a cutaneous inflammatory reaction in mice. To this goal, mouse hind footpads were separately injected with 20 microliters of human recombinant MCP-1 or MIP-1 alpha (10(-7) M). Diluent was used as a control in the second footpad. The footpad-swelling response was measured at 30 min, 1 h, and then hourly for 6 h. Both MCP-1 (2.72 +/- 0.2 vs 2.1 +/- 0.03 mm for diluent, n = 8, p < 0.02) and MIP-1 alpha (3.0 +/- 0.1 vs 2.1 +/- 0.03 mm for diluent, n = 8, p < 0.02) induced an immediate swelling reaction. The immediate reaction was followed by a sustained late reaction that peaked within 1 h and lasted for more than 6 h. Histologic examination of the footpads, obtained at hour 2, revealed that MCP-1 caused mild mononuclear cell infiltrates, moderate degranulation of mast cells, and soft tissue swelling. In contrast, MIP-1 alpha induced a severe inflammatory reaction that consisted of neutrophils, mononuclear cells, and degranulated mast cells. Electron microscope examination of the tissue revealed features of extensive mast cell degranulation by MIP-1 alpha and to a lesser extent by MCP-1. Thus, we conclude that mast cells are activated on injection of MCP-1, whereas degranulation of mast cells and recruitment of leukocytes contribute to the footpad reaction induced with MIP-1 alpha.
A Review of Fulvestrant in Breast Cancer (2017)

Fulvestrant is a selective estrogen receptor degrader that binds, blocks and degrades the estrogen receptor (ER), leading to complete inhibition of estrogen signaling through the ER. This review article further explains the mechanism of action of the drug and goes on to review the trials carried out to optimize its dosing. Multiple trials have been undertaken to compare fulvestrant with other endocrine treatments, and results have shown it to have similar efficacy to anastrozole, tamoxifen and exemestane at 250 mg every 28 days. However, when given at 500 mg every 28 days, with an extra loading dose on day 14, it has demonstrated an improved progression-free survival (PFS) compared to anastrozole. We look at how fulvestrant has been used in combination with CDK4/6 inhibitors such as palbociclib (PALOMA-3) and ribociclib (MONALEESA-3) and drugs targeting the PI3K/AKT/mTOR pathway such as pictilisib (FERGI) and buparlisib (BELLE-2 and BELLE-3). We then go on to describe a selection of the ongoing clinical trials looking at combination therapy involving fulvestrant. Finally, we review the effect of fulvestrant in patients who have developed resistance to aromatase inhibitors via ESR1 mutation, where it has been shown to offer a PFS benefit that is further improved by the addition of the CDK4/6 inhibitor palbociclib. Whilst fulvestrant is clearly an effective drug as monotherapy, we believe that its role in the treatment of ER-positive breast cancer may be best reserved for combination therapy, and whilst there are multiple trials currently in progress, it would appear that the combination with CDK4/6 inhibitors would offer the greatest promise in terms of balancing benefit with toxicity.
erbB-2, p53, and Efficacy of Adjuvant Therapy in Lymph Node-Positive Breast Cancer (1998)

The hypothesis that patients whose breast tumors exhibit high erbB-2 expression benefit from dose-intensive CAF should be further validated before clinical implementation. Interactions between erbB-2 expression, p53 expression, and CAF dose underscore the complexities of predictive markers where multiple interactions may confound the outcome.
Hybrid NOrec (2011)

Transactional memory (TM) is a promising synchronization mechanism for the next generation of multicore processors. Best-effort Hardware Transactional Memory (HTM) designs, such as Sun's prototype Rock processor and AMD's proposed Advanced Synchronization Facility (ASF), can efficiently execute many transactions, but abort in some cases due to various limitations. Hybrid TM systems can use a compatible software TM (STM) in such cases. We introduce a family of hybrid TMs built using the recent NOrec STM algorithm that, unlike existing hybrid approaches, provide both low overhead on hardware transactions and concurrent execution of hardware and software transactions. We evaluate implementations for Rock and ASF, exploring how the differing HTM designs affect optimization choices. Our investigation yields valuable input for designers of future best-effort HTMs.
A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia (2006)

Outcomes for older adults with acute myelogenous leukemia (AML) are poor due to both disease and host-related factors. In this phase 2 study, we tested the oral farnesyltransferase inhibitor tipifarnib in 158 older adults with previously untreated, poor-risk AML. The median age was 74 years, and a majority of patients had antecedent myelodysplastic syndrome. Complete remission (CR) was achieved in 22 patients (14%); partial remission or hematologic improvement occurred in 15 patients, for an overall response rate of 23%. The median duration of CR was 7.3 months and the median survival of complete responders was 18 months. Adverse karyotype, age 75 years or older, and poor performance status correlated negatively with survival. Early death in the absence of progressive disease was rare, and drug-related nonhematologic serious adverse events were observed in 74 patients (47%). Inhibition of farnesylation of the surrogate protein HDJ-2 occurred in the large majority of marrow samples tested. Baseline levels of phosphorylated mitogen-activated protein kinase and AKT did not correlate with clinical response. Tipifarnib is active and well tolerated in older adults with poor-risk AML and may impart a survival advantage in those patients who experience a clinical response.
A General Method for Discovering Inhibitors of Protein−DNA Interactions Using Photonic Crystal Biosensors (2008)

Protein-DNA interactions are essential for fundamental cellular processes such as transcription, DNA damage repair, and apoptosis. As such, small molecule disruptors of these interactions could be powerful tools for investigation of these biological processes, and such compounds would have great potential as therapeutics. Unfortunately, there are few methods available for the rapid identification of compounds that disrupt protein-DNA interactions. Here we show that photonic crystal (PC) technology can be utilized to detect protein-DNA interactions, and can be used in a high-throughput screening mode to identify compounds that prevent protein-DNA binding. The PC technology is used to detect binding between protein-DNA interactions that are DNA-sequence-dependent (the bacterial toxin-antitoxin system MazEF) and those that are DNA-sequence-independent (the human apoptosis inducing factor (AIF)). The PC technology was further utilized in a screen for inhibitors of the AIF-DNA interaction, and through this screen aurin tricarboxylic acid was identified as the first in vitro inhibitor of AIF. The generality and simplicity of the photonic crystal method should enable this technology to find broad utility for identification of compounds that inhibit protein-DNA binding.
Validation of the Female Sexual Function Index (FSFI) in Women with Female Orgasmic Disorder and in Women with Hypoactive Sexual Desire Disorder (2003)

The Female Sexual Functioning Index (FSFI; Rosen et al., 2000) is a self-report measure of sexual functioning that has been validated on a clinically diagnosed sample of women with female sexual arousal disorder. The present investigation extended the validation of the FSFI to include women with a primary clinical diagnosis of female orgasmic disorder (FOD; n = 71) or hypoactive sexual desire disorder (HSDD; n = 44). Internal consistency and divergent validity of the FSFI were within the acceptable range for these populations of women. Significant differences between women with FOD and controls and between women with HSDD and controls were noted for each of the FSFI domain and total scores.
A systematic methodology for proteome-wide identification of peptides inhibiting the proliferation and migration of endothelial cells (2008)

We introduce a systematic computational methodology based on bioinformatics that has enabled us to identify and classify >120 endogenous peptide inhibitors of endothelial cell proliferation and migration. These peptides are derived from members of the type IV collagen, thrombospondin, and CXC chemokine protein families, as well as somatotropin hormones, serpins, and various kringle-containing proteins. Their activity in suppressing the proliferation and migration of endothelial cells in vitro provides proof of principle for the validity of this computational method. Interestingly, some of the peptides are derived from proteins known to be proangiogenic. By performing receptor neutralization studies, we have identified receptors to which these peptides bind. On the basis of this receptor-binding information, we evaluated several examples of peptide-based combinatorial screening strategies. In some cases, this combinatorial screening identified strong synergism between peptides. The current work provides a guideline for a computational-based peptidomics approach for the discovery of endogenous bioactive peptides.
Reflections for the 20th anniversary issue of RNA journal (2015)

The 20 years since the launch of the RNA journal have seen numerous remarkable advances in RNA research. Those that have had a transformative impact on biomedical research as a whole include the discovery of large repertoires of short and long non-coding RNAs and their widespread roles in normal and disease biology, and the development of powerful methods for manipulating the expression and function of individual genes, based in part on the former discoveries, as well as the more recent development of RNA-guided genome editing tools.