gebhart/patrepeval huggingface dataset:
Self-Assembly into Nanoparticles Is Essential for Receptor Mediated Uptake of Therapeutic Antisense Oligonucleotides (2015)

Antisense oligonucleotides (ASOs) have the potential to revolutionize medicine due to their ability to manipulate gene function for therapeutic purposes. ASOs are chemically modified and/or incorporated within nanoparticles to enhance their stability and cellular uptake, however, a major challenge is the poor understanding of their uptake mechanisms, which would facilitate improved ASO designs with enhanced activity and reduced toxicity. Here, we study the uptake mechanism of three therapeutically relevant ASOs (peptide-conjugated phosphorodiamidate morpholino (PPMO), 2'Omethyl phosphorothioate (2'OMe), and phosphorothioated tricyclo DNA (tcDNA) that have been optimized to induce exon skipping in models of Duchenne muscular dystrophy (DMD). We show that PPMO and tcDNA have high propensity to spontaneously self-assemble into nanoparticles. PPMO forms micelles of defined size and their net charge (zeta potential) is dependent on the medium and concentration. In biomimetic conditions and at low concentrations, PPMO obtains net negative charge and its uptake is mediated by class A scavenger receptor subtypes (SCARAs) as shown by competitive inhibition and RNAi silencing experiments in vitro. In vivo, the activity of PPMO was significantly decreased in SCARA1 knockout mice compared to wild-type animals. Additionally, we show that SCARA1 is involved in the uptake of tcDNA and 2'OMe as shown by competitive inhibition and colocalization experiments. Surface plasmon resonance binding analysis to SCARA1 demonstrated that PPMO and tcDNA have higher binding profiles to the receptor compared to 2'OMe. These results demonstrate receptor-mediated uptake for a range of therapeutic ASO chemistries, a mechanism that is dependent on their self-assembly into nanoparticles.
Influence of Orally Administered Probiotic Lactobacillus Strains on Vaginal Microbiota in Women with Breast Cancer during Chemotherapy: A Randomized Placebo-Controlled Double-Blinded Pilot Study (2017)

The orally administered <i>Lactobacillus</i> preparation has the potential to improve the vaginal microbiota in women undergoing chemotherapy for breast cancer.
Tandem Ring Opening and Oximation of Ethyl 3‐Aroyl‐1‐cyano‐4‐hydroxy‐2,4,6‐triarylcyclohexanecarboxylate by Hydroxylamine (2007)

Abstract The reaction of hydroxylamine hydrochloride with ethyl 3‐aroyl‐1‐cyano‐4‐hydroxy‐2,4,6‐triarylcyclohexanecarboxylate has led to the formation of ethyl 2‐[amino(hydroxyimino)methyl]‐3‐aryl‐5‐(hydroxyimino)‐5‐arylpentanoate via a tandem ring opening and oximation process. The structures of the products are confirmed by NMR and X‐ray techniques, and the conformational features of the product arrived at are compared with a molecular dynamics simulation study.
Phase I Study of an Oral Histone Deacetylase Inhibitor, Suberoylanilide Hydroxamic Acid, in Patients With Advanced Cancer (2005)

Oral SAHA has linear pharmacokinetics and good bioavailability, inhibits histone deacetylase activity in PBMNCs, can be safely administered chronically, and has a broad range of antitumor activity.
Nanostructured Copper Interfaces for Enhanced Boiling (2008)

On the boil: Nanostructured Cu interfaces display enhanced boiling performance at low superheated temperatures compared to untreated Cu, caused by a large increase in the density of active bubble nucleation sites. The enhancement is caused by nanobubbles, which percolate through the interconnected network of nanopores and enable stable nucleation of bubbles at microscale cavities (defects) on the film surface (see picture). Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2296/2008/smll200700991_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
G-protein coupled transmembrane signaling mechanisms (1995)

This book discusses recent major advances made in the molecular biology, signal transduction processes, pharmacology, and therapeutic applications of key receptors and receptor systems.
Pyrrolo[2,3- d ]pyrimidines. Part 3. 1 Synthesis of Some Novel 4-Substituted Pyrrolo[2,3- d ]pyrimidines and Their Related Triazolo Derivatives (1997)

Syntheses and rearrangements of 3-amino-5-aryl-4-imino-7-(p-tolyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidines 3 to the 4-hydrazino-7H-pyrrolo[2,3-d]pyrimidines 4 were carried out; the 2-(unsubstituted or substituted) 9-aryl-7-(p-tolyl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines 6–12 and 14, ureas 13a–c and thioureas 13d–h were obtained from 3 and the hydrazones 15 from 4.
Introduction (2013)

It was a decade of disasters. The new millennium was not kind to the United States. In only the first decade of the twenty-first century, four events stand out. The first, emerging out of 9/11, was the War on Terror and especially the invasion of Iraq in 2003, which caused the deaths of 4,400 US military personnel and left 32,000 wounded. Its cost, always a guesstimate, is anywhere between $740 billion and $1 trillion.1 The true cost is probably higher but unknowable. How do we factor in the cost of depression, poor health, and substance abuse of returning troops long after the conflict has ended? By almost any criterion, it was a tragedy. American lives and treasure were lost; a hundred thousand Iraqis died and millions more were displaced and fled the country. The United States was tainted, not strengthened, by the war and at the end of the war was less rather than more secure from terrorism. Indeed, the reasons for and conduct of the war probably led to the recruitment of many more would-be terrorists. The invasion of Iraq motivated rather than weakened our enemies and undercut support from our traditional allies across the world. Begun under dubious premises, it soon became a blunder of epic proportions. The title of Thomas Ricks's 2006 book, one of the best books on the American military campaign in Iraq, says it all, Fiasco.
Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma (2010)

Human solid tumors frequently have pronounced heterogeneity of both neoplastic and normal cells on the histological, genetic, and gene expression levels. While current efforts are focused on understanding heterotypic interactions between tumor cells and surrounding normal cells, much less is known about the interactions between and among heterogeneous tumor cells within a neoplasm. In glioblastoma multiforme (GBM), epidermal growth factor receptor gene (EGFR) amplification and mutation (EGFRvIII/DeltaEGFR) are signature pathogenetic events that are invariably expressed in a heterogeneous manner. Strikingly, despite its greater biological activity than wild-type EGFR (wtEGFR), individual GBM tumors expressing both amplified receptors typically express wtEGFR in far greater abundance than the DeltaEGFR lesion. We hypothesized that the minor DeltaEGFR-expressing subpopulation enhances tumorigenicity of the entire tumor cell population, and thereby maintains heterogeneity of expression of the two receptor forms in different cells. Using mixtures of glioma cells as well as immortalized murine astrocytes, we demonstrate that a paracrine mechanism driven by DeltaEGFR is the primary means for recruiting wtEGFR-expressing cells into accelerated proliferation in vivo. We determined that human glioma tissues, glioma cell lines, glioma stem cells, and immortalized mouse Ink4a/Arf(-/-) astrocytes that express DeltaEGFR each also express IL-6 and/or leukemia inhibitory factor (LIF) cytokines. These cytokines activate gp130, which in turn activates wtEGFR in neighboring cells, leading to enhanced rates of tumor growth. Ablating IL-6, LIF, or gp130 uncouples this cellular cross-talk, and potently attenuates tumor growth enhancement. These findings support the view that a minor tumor cell population can potently drive accelerated growth of the entire tumor mass, and thereby actively maintain tumor cell heterogeneity within a tumor mass. Such interactions between genetically dissimilar cancer cells could provide novel points of therapeutic intervention.
Expression of RHAMM/CD168 and other tumor-associated antigens in patients with B-cell chronic lymphocytic leukemia (2006)

Antigen targeted immunotherapies might represent a novel treatment for B-cell chronic lymphocytic leukemia (B-CLL). We screened the mRNA expression of tumor-associated antigens (TAAs) from the literature (fibromodulin, survivin, OFA-iLRP, BAGE, G250, MAGE1, PRAME, proteinase, syntaxin, hTERT, WT-1) and TAAs defined previously by serological analysis of cDNA expression libraries from leukemic cells (PINCH, HSJ2, MAZ, MPP11, RHAMM/CD168, NY-Ren60). Peripheral blood mononuclear cells from 43 B-CLL patients and 20 healthy volunteers (HVs) were examined by conventional and quantitative RT-PCR. mRNA of RHAMM/CD168, fibromodulin, syntaxin and NY-Ren60 was expressed in 55-90%, and mRNA of HSJ2, MAZ and OFAiLRP was expressed in 90-100% of the patients. No expression of WT-1, hTERT, BAGE, G250, MAGE1 or survivin was observed. Low (2-20%) expression frequencies of MPP11, PINCH, PRAME and proteinase were detected. RHAMM/CD168, fibromodulin, PRAME and MPP11 showed expression in B-CLL patients, but not in HVs. Because of the exquisite tissue expression of RHAMM/CD168 and its high expression frequency in CLL patients, mixed lymphocyte peptide culture (MLPC), enzyme-linked immunosorbent spot (ELISPOT) and flow cytometry were performed for antigen specific T-cells. In MLPC, RHAMM specific responses by CD8+HLA-A2/R3tetramer+CCR7-CD45RAhigh effector T-cells were detected. RHAMM/CD168 might be a possible target for future immunotherapies in both ZAP-70(+) and ZAP-70(-) B-CLL patients.
Radiolabelled antimicrobial peptides for imaging of infections (1998)

At present, it is difficult to distinguish between bacterial infections and sterile inflammatory processes using radiopharmaceuticals. This is so for a variety of reasons, including binding to bacteria with low affinity (e.g. infection) and binding to a specific micro-organism (e.g. radiolabelled monoclonal antibodies or F(ab)2 fragments thereof against micro-organisms). In this review, we propose that radiolabelled antimicrobial peptides should be the first choice in the development of new radiopharmaceuticals for imaging of bacterial infections. Antimicrobial peptides are a recently discovered component of the innate defence system of plants, animals and humans. These peptides, which now number more than 100, with proven microbicidal activity against a variety of micro-organisms, share certain properties, such as their small size and cationic charge. The latter allows them to bind preferentially to a broad spectrum of micro-organisms. We have recently demonstrated that radiolabelled human defensins allow the rapid visualization of bacterial infections in mice. Furthermore, binding of this antimicrobial peptide to bacteria is the major factor contributing to the accumulation of this tracer in bacterial infections. Based on these considerations, we believe that radiolabelled antimicrobial peptides will be an important asset in the imaging of infections in patients.
Accumulation of a Lipid A Precursor Lacking the 4′-Phosphate following Inactivation of the Escherichia coli lpxKGene (1998)

The lpxK gene has been proposed to encode the lipid A 4'-kinase in Escherichia coli (Garrett, T. A., Kadrmas, J. L., and Raetz, C. R. H. (1997) J. Biol. Chem. 272, 21855-21864). In cell extracts, the kinase phosphorylates the 4'-position of a tetraacyldisaccharide 1-phosphate precursor (DS-1-P) of lipid A, but the enzyme has not yet been purified because of instability. lpxK is co-transcribed with an essential upstream gene, msbA, with strong homology to mammalian Mdr proteins and ABC transporters. msbA may be involved in the transport of newly made lipid A from the inner surface of the inner membrane to the outer membrane. Insertion of an Omega-chloramphenicol cassette into msbA also halts transcription of lpxK. We have now constructed a strain in which only the lpxK gene is inactivated by inserting a kanamycin cassette into the chromosomal copy of lpxK. This mutation is complemented at 30 degreesC by a hybrid plasmid with a temperature-sensitive origin of replication carrying lpxK+. When this strain (designated TG1/pTAG1) is grown at 44 degreesC, the plasmid bearing the lpxK+ is lost, and the phenotype of an lpxK knock-out mutation is unmasked. The growth of TG1/pTAG1 was inhibited after several hours at 44 degreesC, consistent with lpxK being an essential gene. Furthermore, 4'-kinase activity in extracts made from these cells was barely detectable. In accordance with the proposed biosynthetic pathway for lipid A, DS-1-P (the 4'-kinase substrate) accumulated in TG1/pTAG1 cells grown at 44 degreesC. The DS-1-P from TG1/pTAG1 was isolated, and its structure was verified by 1H NMR spectroscopy. DS-1-P had not been isolated previously from bacterial cells. Its accumulation in TG1/pTAG1 provides additional support for the pathway of lipid A biosynthesis in E. coli. Homologs of lpxK are present in the genomes of other Gram-negative bacteria.
Visible-light photocatalytic activity of nitrogen-doped NiTiO3 thin films prepared by a co-sputtering process (2015)

NiTiO<sub>3</sub> thin films grown using a co-sputtering process exhibited well defined structural, morphological and optical characteristics, which showed enhanced visible light photocatalytic activity.
A High IIP2 Direct-Conversion Receiver Using Even-Harmonic Reduction Technique for Cellular CDMA/PCS/GPS Applications (2008)

A high IIP2 direct-conversion receiver for cellular CDMA/PCS/GPS has been developed in a 0.35 mum SiGe BiCMOS process. This receiver consists of a RF front-end chip and a base-band chip. The RF front-end chip includes three LNAs, three mixer cores with a common output stage, and LO distribution blocks. The base-band chip includes a channel selection filter, an output buffer, and a DC calibration block. To achieve high IIP2 performance, an even-harmonic reduction technique is proposed based on a simplified analysis of second-order intermodulation. A 40-dB improvement of the IIP2 performance is accomplished by this technique, which reduces sensitivity to operating conditions and to output load mismatches. This receiver also attains high IIP3 and a low-noise figure. Measurement results show 71 dBm IIP2, -1.3 dBm IIP3, and 2.4 dB NF for Cellular CDMA; 68 dBm IIP2, - 3.7 dBm IIP3, and 2.9 dB NF for PCS; and 26 dBm IIP2 -30 dBm IIP3, and 2 dB NF for GPS.
Review article: inhibition of methanogenic archaea by statins as a targeted management strategy for constipation and related disorders (2015)

Clinical development appears promising. A phase 2 clinical trial is currently in progress that evaluates the effect of lovastatin lactone on methanogenesis and symptoms in patients with irritable bowel syndrome with constipation. The review concludes with an outlook for the future and subsequent work that needs to be done.
Structure and Function of Chitin-Binding Proteins (1993)

Crop loss due to soil salinization is an increasing threat to agriculture worldwide. This review provides an overview of cellular and physiological mechanisms in plant responses to salt. We place cellular responses in a time- and tissue-dependent context ...Read More
Engineered transfer RNAs for suppression of premature termination codons (2019)

Premature termination codons (PTCs) are responsible for 10-15% of all inherited disease. PTC suppression during translation offers a promising approach to treat a variety of genetic disorders, yet small molecules that promote PTC read-through have yielded mixed performance in clinical trials. Here we present a high-throughput, cell-based assay to identify anticodon engineered transfer RNAs (ACE-tRNA) which can effectively suppress in-frame PTCs and faithfully encode their cognate amino acid. In total, we identify ACE-tRNA with a high degree of suppression activity targeting the most common human disease-causing nonsense codons. Genome-wide transcriptome ribosome profiling of cells expressing ACE-tRNA at levels which repair PTC indicate that there are limited interactions with translation termination codons. These ACE-tRNAs display high suppression potency in mammalian cells, Xenopus oocytes and mice in vivo, producing PTC repair in multiple genes, including disease causing mutations within cystic fibrosis transmembrane conductance regulator (CFTR).
Mechanical modeling of fluid-driven polymer lenses (2008)

A finite-element model (FEM) is employed to study the pressure response of deformable elastic membranes used as tunable optical elements. The model is capable of determining in situ both the modulus and the prestrain from a measurement of peak deflection versus pressure. Given accurate values for modulus and prestrain, it is shown that the two parameters of a standard optical shape function (radius of curvature and conic constant) can be accurately predicted. The effects of prestrain in polydimethylsiloxane (PDMS) membranes are investigated in detail. It was found that prestrain reduces the sensitivity of the membrane shape to the details of the edge clamping. It also reduces the variation of the conic constant with changes in curvature. Thus the ability to control the prestrain as well as thickness and modulus is important to developing robust optical designs based on fluid-driven polymer lenses.
Genomic Organization of the Human WT1 Gene (1992)

We have analyzed the genomic structure of the human WT1 gene, one of the recessive oncogenes for Wilms' tumor at chromosome 11p13. By analyses of three cosmids covering the WT1 gene as well as products generated by polymerase chain reaction, cleavage sites for 10 restriction enzymes were mapped in a region of about 80 kb, and the positions of 10 exons were defined. We also mapped two polymorphic sites for TaqI. Our genomic map will be useful to analyze DNA abnormalities sometimes found in the tumors, as well as loss of heterozygosity.
Breast cytology and biomarkers obtained by random fine needle aspiration: Use in risk assessment and early chemoprevention trials (1997)

In a prospective pilot study, we performed breast fine needle aspirations (FNAs) on 224 high-risk and 30 low-risk women and analyzed these aspirates for cytologic changes and biomarker abnormalities of aneuploidy and overexpressed estrogen receptor (ER), epidermal growth factor receptor (EGFR), p53 and HER-2/neu. High-risk women had a first-degree relative with breast cancer (74%), prior biopsy indicating premalignant breast disease (25%), a history of breast cancer (13%), or some multiple of these risk factors (12%). Median ages of the high- and low-risk groups were 44 and 42, respectively. Seventy percent of high-risk and 17% of low-risk women had cytologic evidence of hyperplasia with or without atypia (P < .0001). Aneuploidy and overexpression of EGFR and p53 occurred in 27, 37, and 29% of high-risk subjects but only 0, 3, and 3% of low-risk subjects (P < .0023). Overexpression of ER and HER-2/neu occurred in 7 and 20% of high-risk women but in none of the low-risk subjects. Biomarker abnormalities were more frequent with increasing cytologic abnormality. Restricting the analysis to those 3 biomarkers most frequently overexpressed in the high-risk group (ploidy, EGFR, p53), 13% of high-risk women with normal cytology, 19% of high-risk women with epithelial hyperplasia, and 49% of high-risk women with hyperplasia with atypia had abnormalities of 2 or more of these 3 biomarkers (P = .00004). At a median follow-up of 32 months, four women have been diagnosed with invasive cancer and two with ductal carcinoma in situ (DCIS). Later detection of these neoplastic conditions was associated (P < or = .016) by univariate analysis with prior FNA evidence of hyperplasia with atypia; overexpression of p53 and EGFR; the modified Gail risk of breast cancer development at 10 years; and multiple biomarker abnormalities. By multivariate analysis, later detection of cancer was primarily predicted by the number of biomarker abnormalities in the 3-test battery (P = .0005) and secondarily by the Gail risk at 10 years (P = .0049). In turn, hyperplasia with atypia was associated with multiple biomarker abnormalities, particularly p53 and EGFR overexpression. Thus, hyperplasia with atypia and cytologic markers in breast FNAs have promise as risk predictors and as surrogate endpoint biomarkers for breast cancer chemoprevention trials.
Mode-partition noise and intensity correlation in a two-mode semiconductor laser (1988)

The intensity-noise characteristics of a nearly single-longitudinal-mode semiconductor laser are analyzed by adopting a two-mode model. An approximate solution of the resulting Langevin rate equations is used to obtain an analytic expression for the enhancement of the main-mode intensity noise caused by mode partition. We also obtain analytic expressions for the autocorrelation and cross-correlation functions which are used to discuss noise variances in the two modes. In particular, the cross-correlation function is related to the mode-partition coefficient, a measure of anticorrelation between the two modes that is useful to analyze the system performance. Our results show explicitly how the intensity correlation is affected by the mode-suppression ratio and other device parameters.
Recombinant Human Tumor Necrosis Factor Receptor (P75) Fc Fusion Protein (Tnfr: Fc) in Rheumatoid Arthritis (1997)

Preliminary data indicate that TNFR:Fc is an excellent candidate for future long-term studies in the treatment of rheumatoid arthritis.
Cytotoxic T cell clones isolated from ovarian tumor-infiltrating lymphocytes recognize multiple antigenic epitopes on autologous tumor cells (1991)

CTL clones were developed from tumor infiltrating lymphocytes (TIL) from the ascites of a patient with ovarian carcinoma by coculture of TIL with autologous tumor cells and subsequent cloning in the presence of autologous tumor cells. These CTL clones expressed preferential cytolytic activity against autologous tumor cells but not against allogeneic ovarian tumor cells and the NK-sensitive cell line K562. The cytolytic activity of these CTL against autologous tumors was inhibited by anti-TCR (WT31 mAb), anti-HLA class I, and anti-CD3 mAb but not by the NK function antibody Leu 11b. Cloning of the autologous tumor cells in vitro revealed that the CTL clones of the ovarian TIL expressed differential abilities to lyse autologous tumor cell clones. The specificity analysis of these autologous tumor specific CTL suggested that they recognize several antigenic determinants present on the ovarian tumor cells. Our results indicate the presence of at least three antigenic epitopes on the tumor cells (designated OVA-1A, OVA-1B, and OVA-1C), one of which (OVA-1C) is unstable. These determinants are present either simultaneously or separately, and six types of ovarian clones can be distinguished on the basis of their expression. These results indicate that CTL of the TIL detect intratumor antigenic heterogeneity. The novel heterogeneity identified within the ovarian tumor cells in this report may be of significance for understanding cellular immunity in ovarian cancer and developing adoptive specific immunotherapeutic approaches in ovarian cancer.
Intellectual property protection (2011)

In the last decade, therapeutic antibodies have become one of the commercially most successful classes of biopharmaceutical drugs. Major drug manufacturers who have successfully managed to occupy this new market, as well as biotechnology firms, some of which have experienced a quick growth and are now on par with the former, owe part of their success to suitable intellectual property strategies. This article provides an overview of the current thinking on antibody-related patents, and discusses strategies for protecting the antibody products of the future.