gebhart/patrepeval huggingface dataset:
Functional and immunophenotypic modifications induced by interleukin-2 did not predict response to therapy in patients with renal cell carcinoma. (1990)

Twenty-five patients with renal cell carcinoma were treated with continuous infusion of IL-2 (3 x 10(6) units/m2/day) with or without lymphokine-activated killer (LAK) cells; 5 responded to therapy. Functional and immunophenotypic modifications of the peripheral blood lymphocytes (PBLs) did not predict response to therapy. Systemic administration of interleukin-2 (IL-2) during 5 days caused a preferential proliferation of natural killer (NK) cells, although CD4+ T cells remained the predominant circulating population, in particular in three of the five responding patients. The IL-2 low-affinity receptor was induced only on CD4+ T cells. B cells did not proliferate and immunoglobulin levels were not modified by IL-2. In the peripheral blood, the NK function increased but the LAK function in vivo remained low. The T-cell proliferative response in mixed lymphocyte cultures (MLCs) decreased after therapy. Four days of ex vivo culture of PBLs with IL-2 did not modify T and NK distributions, but increased the coexpression of CD8 on NK cells and NKH1 density; it decreased the coexpression of CD16 and induced LAK cell function. Three weeks after the end of the first course of therapy and before the second course was started, all immunological parameters returned to baseline levels, except the T-cell proliferative response in MLCs. The second course of IL-2 therapy induced the same modifications as the first one, with the exception of a higher CD4+ T-cell proliferation.
Modeling competition among autoreactive CD8+ T cells in autoimmune diabetes: implications for antigen-specific therapy (2006)

Antigen therapy remains a promising strategy for prevention and treatment of autoimmune diseases, but translating this strategy to clinical therapy has been largely unsuccessful. We have shown that development of autoimmune diabetes in non-obese diabetic (NOD) mice involves prevalent recruitment of CD8+ T cells recognizing epitopes of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP). Administration of peptide analogs of IGRP206-214, the dominant epitope, reduced disease incidence but only under conditions that led to selective deletion of high-avidity T-cell clones. Peptide types or doses that resulted in elimination of all IGRP206-214-reactive T cells, regardless of avidity, promoted the recruitment of sub-dominant epitope-specific T cells and failed to prevent disease development. Here, we mathematically model competition of IGRP-reactive T-cell clones during spontaneous disease, and in response to peptide treatment. Based on realistic T-cell activation, proliferation and differentiation parameter values, our model shows that progression of spontaneous disease is characterized by (i) initial expansion of all IGRP206-214-reactive T-cell clones (irrespective of avidity) and (ii) slow replacement of T-cell clones recognizing peptide/MHC with low avidity by their high-avidity counterparts. This model helps understand the paradoxical outcomes of IGRP-based peptide treatment experiments. Furthermore, it predicts that slight deviations in dose or peptide affinity can lead to treatment failure or disease progression. This will occur if the treatment (i) increases the imbalance between competing IGRP206-214-reactive T-cell clones such that it favors rapid takeover of high-avidity clones or (ii) deletes all IGRP206-214-reactive clones, thereby creating a vacuum that promotes the recruitment of pathogenic sub-dominant specificities. Our data and model urge caution in the application of peptide therapy in autoimmunity.
Signals for transcription initiation and termination in the Saccharomyces cerevisiae plasmid 2 micron circle. (1985)

By S1 nuclease protection experiments and primer extension analysis, we determined precisely the cap and polyadenylation sites of transcripts from the four genes of the yeast 2 micron circle plasmid, as well as those of other plasmid transcripts of unknown function. In addition, we used deletion analysis to identify sequences necessary for polyadenylation in plasmid transcripts. Our results indicate that plasmid genes constitute independent transcription units and that plasmid mRNAs are not derived by extensive processing of precursor transcripts. In addition, we found that the D coding region of 2 micron circle is precisely encompassed by a polyadenylated transcript, suggesting that this coding region constitutes a functional plasmid gene. Our identification of the position of plasmid polyadenylation sites and of sequences necessary for polyadenylation provides support for a tripartite signal for polyadenylation as proposed by Zaret and Sherman (K.S. Zaret and F. Sherman, Cell 28:563-573, 1982). Finally, these data highlight salient features of the transcriptional regulatory circuitry that underlies the control of plasmid maintenance in the cell.
Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. (1998)

Polymeric interstitial chemotherapy increases survival of humans with recurrent gliomas and animals with transplanted tumors in the brain, but the relationship between rates of drug release from polymer implants and drug concentration in brain tissue is unknown. This work presents a pharmacokinetic framework for application of this new modality of chemotherapy delivery in primates. Either [3H]carmustine, 4-hydroperoxycyclophosphamide (4-HC), or paclitaxel was encapsulated in a polyanhydride pellet (28-41 microCi/animal, 40 mg/animal), which was implanted intracranially in cynomolgus monkeys (Macaca fascicularis); (n = 17) for up to 30 days. Drug concentrations in the brain, blood, and cerebrospinal fluid were measured by quantitative autoradiography, TLC, and scintillation counting. High drug concentrations (0.5-3.5 mM for carmustine, 0.3-0.4 mM for 4-HC, and 0.2-1.0 mM for paclitaxel) were measured within the first 3 mm from the polymer implant; significant (0.4 microM for carmustine, 3 microM for 4-HC, and 0.6 microM for paclitaxel) concentrations were measured up to approximately 5 cm from the implant as long as 30 days after implantation. Pharmacokinetic analysis indicated that tissue exposure to carmustine area under concentration-time curve achieved by polymeric delivery was 4-1200 times higher than that produced by i.v. administration of a higher dose.
1  ×  8 Supergrating wavelength-division demultiplexer in a silica planar waveguide (1997)

Wavelength-division demultiplexing by superimposed gratings (supergrating) in a planar waveguide is modeled, accounting for intergrating coupling, and a theoretical decoupling criterion that serves as a guideline for practical design is presented. Superimposed gratings were formed by direct photoinscription in a photosensitive silica planar waveguide, which is a promising method for practical optical circuit applications. A 1x8 channel wavelength-division multiplexer is demonstrated experimentally as a proof-of-concept study. The effects on experimental performance of wavelength-selectivity broadening and finite photosensitive index-modulation depth are discussed.
Targeting Foxo1 in Mice Using Antisense Oligonucleotide Improves Hepatic and Peripheral Insulin Action (2006)

Fasting hyperglycemia, a prominent finding in diabetes, is primarily due to increased gluconeogenesis. The transcription factor Foxo1 links insulin signaling to decreased transcription of PEPCK and glucose-6-phosphatase (G6Pase) and provides a possible therapeutic target in insulin-resistant states. Synthetic, optimized antisense oligonucleotides (ASOs) specifically inhibit Foxo1 expression. Here we show the effect of such therapy on insulin resistance in mice with diet-induced obesity (DIO). Reducing Foxo1 mRNA expression with ASO therapy in mouse hepatocytes decreased levels of Foxo1 protein and mRNA expression of PEPCK by 48 +/- 4% and G6Pase by 64 +/- 3%. In mice with DIO and insulin resistance, Foxo1 ASO therapy lowered plasma glucose concentration and the rate of basal endogenous glucose production. In addition, Foxo1 ASO therapy lowered both hepatic triglyceride and diacylglycerol content and improved hepatic insulin sensitivity. Foxo1 ASO also improved adipocyte insulin action. At a tissue-specific level, this manifested as improved insulin-mediated 2-deoxyglucose uptake and suppression of lipolysis. On a whole-body level, the result was improved glucose tolerance after an intraperitoneal glucose load and increased insulin-stimulated whole-body glucose disposal during a hyperinsulinemic-euglycemic clamp. In conclusion, Foxo1 ASO therapy improved both hepatic insulin and peripheral insulin action. Foxo1 is a potential therapeutic target for improving insulin resistance.
Adeno-Associated Virus RNAs Appear in a Temporal Order and Their Splicing Is Stimulated during Coinfection with Adenovirus (2000)

We have used a quantitative RNase protection assay to characterize the relative accumulation and abundance of individual adeno-associated virus type 2 (AAV) RNAs throughout the course of AAV-adenovirus coinfections and preinfections. We have demonstrated that there is a previously unrecognized temporal order to the appearance of AAV RNAs. First, unspliced P5-generated transcripts, which encode Rep78, were detectable prior to the significant accumulation of other AAV RNAs. Ultimately, as previously demonstrated, P19-generated products accumulated to levels greater than those generated from P5, and P40-generated transcripts predominated in the total RNA pool. Second, the percentage of each class of AAV RNA that was spliced increased during infection, and the degree of this increase was different for the P5/P19 products than for those generated by P40. At late times postcoinfection, approximately 90% of P40 products, but only approximately 50% of RNAs generated by P5 and P19, were seen to be spliced; thus, the AAV intron was removed to different final levels from these different RNA species. We have shown that each of the AAV RNAs is quite stable; the majority of each RNA species persisted 6 h after treatment with actinomycin D. Quantification of the accumulation of individual AAV RNAs, over intervals during which degradation was negligible, allowed us to infer that at late times during infection the relative strength of P5, P19, and P40 was approximately 1:3:18, respectively, consistent with the steady-state accumulated levels of the RNAs generated by each promoter. All AAV RNAs exited to the cytoplasm with similar efficiencies in the presence or absence of adenovirus; however, adenovirus coinfection appeared to stimulate total splicing of AAV RNAs and the relative use of the downstream intron acceptor. Our results confirm and extend previous observations concerning the appearance and processing of AAV-generated RNAs.
Wavelength locking of multiple diode lasers by multiplexed gratings in a photorefractive crystal (2000)

We propose a technique to simultaneously stabilize relative wavelengths among multiple diode lasers by using multiplexed photorefractive gratings. Each grating is designed to be Bragg matched for the counter-propagating reflection at a specific diode laser wavelength. Experimental results from stabilization of two diode laser wavelengths by using two photorefractive gratings exhibit excellent short- and long-term wavelength stability. We show that this technique can be extended to stabilize relative wavelengths of many diode lasers. The thermal stability of the photorefractive gratings and the signal-to-noise ratio (or the bit-error rate) are discussed.
Advances in cell culture: anchorage dependence (2014)

Anchorage-dependent cells are of great interest for various biotechnological applications. (i) They represent a formidable production means of viruses for vaccination purposes at very large scales (in 1000-6000 l reactors) using microcarriers, and in the last decade many more novel viral vaccines have been developed using this production technology. (ii) With the advent of stem cells and their use/potential use in clinics for cell therapy and regenerative medicine purposes, the development of novel culture devices and technologies for adherent cells has accelerated greatly with a view to the large-scale expansion of these cells. Presently, the really scalable systems--microcarrier/microcarrier-clump cultures using stirred-tank reactors--for the expansion of stem cells are still in their infancy. Only laboratory scale reactors of maximally 2.5 l working volume have been evaluated because thorough knowledge and basic understanding of critical issues with respect to cell expansion while retaining pluripotency and differentiation potential, and the impact of the culture environment on stem cell fate, etc., are still lacking and require further studies. This article gives an overview on critical issues common to all cell culture systems for adherent cells as well as specifics for different types of stem cells in view of small- and large-scale cell expansion and production processes.
NKp44, A Triggering Receptor Involved in Tumor Cell Lysis by Activated Human Natural Killer Cells, Is a Novel Member of the Immunoglobulin Superfamily (1999)

Surface receptors involved in natural killer (NK) cell triggering during the process of tumor cell lysis have recently been identified. Of these receptors, NKp44 is selectively expressed by IL-2- activated NK cells and may contribute to the increased efficiency of activated NK cells to mediate tumor cell lysis. Here we describe the molecular cloning of NKp44. Analysis of the cloned cDNA indicated that NKp44 is a novel transmembrane glycoprotein belonging to the Immunoglobulin superfamily characterized by a single extracellular V-type domain. The charged amino acid lysine in the transmembrane region may be involved in the association of NKp44 with the signal transducing molecule killer activating receptor-associated polypeptide (KARAP)/DAP12. These molecules were found to be crucial for the surface expression of NKp44. In agreement with data of NKp44 surface expression, the NKp44 transcripts were strictly confined to activated NK cells and to a minor subset of TCR-gamma/delta+ T lymphocytes. Unlike genes coding for other receptors involved in NK cell triggering or inhibition, the NKp44 gene is on human chromosome 6.
Leupaxin Negatively Regulates B Cell Receptor Signaling (2007)

The role of the paxillin superfamily of adaptor proteins in B cell antigen receptor (BCR) signaling has not been studied previously. We show here that leupaxin (LPXN), a member of this family, was tyrosine-phosphorylated and recruited to the plasma membrane of human BJAB lymphoma cells upon BCR stimulation and that it interacted with Lyn (a critical Src family tyrosine kinase in BCR signaling) in a BCR-induced manner. LPXN contains four leucine-rich sequences termed LD motifs, and serial truncation and specific domain deletion of LPXN indicated that its LD3 domain is involved in the binding of Lyn. Of a total of 11 tyrosine sites in LPXN, we mutated Tyr(22), Tyr(72), Tyr(198), and Tyr(257) to phenylalanine and demonstrated that LPXN was phosphorylated by Lyn only at Tyr(72) and that this tyrosine site is proximal to the LD3 domain. The overexpression of LPXN in mouse A20 B lymphoma cells led to the suppression of BCR-induced activation of JNK, p38 MAPK, and, to a lesser extent, Akt, but not ERK and NFkappaB, suggesting that LPXN can selectively repress BCR signaling. We further show that LPXN suppressed the secretion of interleukin-2 by BCR-activated A20 B cells and that this inhibition was abrogated in the Y72F LPXN mutant, indicating that the phosphorylation of Tyr(72) is critical for the biological function of LPXN. Thus, LPXN plays an inhibitory role in BCR signaling and B cell function.
Decreased mTOR signaling pathway in human idiopathic autism and in rats exposed to valproic acid (2015)

In contrast to some monogenic disorders with high rates of autism, our data demonstrate down-regulation of the Akt/mTOR pathway, specifically via p70S6K/eIF4B, in idiopathic autism. These findings suggest that disruption of this pathway in either direction is widespread in autism and can have adverse consequences for synaptic function. The use of valproic acid, a histone deacetylase inhibitor, in rats successfully modeled these changes, implicating an epigenetic mechanism in these pathway disruptions.
New catalysis for fast bulk ring‐opening polymerization of lactide monomers (1999)

Abstract The ring‐opening polymerization of lactides has been studied in bulk using either 2‐ethylhexanoic acid tin(II) salt, Sn(Oct) 2 , or aluminum triisopropoxide, Al(OiPr) 3 , as the initiator over a wide range of temperature and monomer‐to‐initiator molar ratio. A high increase in the bulk polymerization rate has been observed when the initiator was added with an equimolar amount of a Lewis base, such as triphenylphosphine (P(φ) 3 ) and 4‐picoline (C 6 H 7 N) added to Sn(Oct) 2 and Al(OiPr) 3 , respectively. Melt stable polylactides of high molecular weight and reasonably narrow molecular weight distribution have been accordingly prepared. The use of the Sn(Oct) 2 .P(φ) 3 equimolar combination has allowed for reaching an acceptable balance between propagation and depolymerization rates, so that the polymerization is fast enough to be performed through a continuous single‐stage process in a twin‐screw extruder. A global activation mechanism is proposed and discussed by comparison with both investigated initiation systems.
Epiluminescence microscopy-based classification of pigmented skin lesions using computerized image analysis and an artificial neural network (1998)

Epiluminescence microscopy (ELM) is a non-invasive technique for in vivo examination which can provide additional criteria for the clinical diagnosis of pigmented skin lesions (PSLs). In the present study we attempt to determine whether PSLs can be automatically diagnosed by an integrated computerized system. This system should recognize the PSL, automatically extract features and use these features in training an artificial neural network, which should--if sufficiently trained--be capable of recognizing and classifying a new PSL without human aid. One hundred and twenty images of randomly selected histologically proven PSLs (33 common naevi, 48 dysplastic naevi and 39 malignant melanomas) were used in this study. The images were digitally obtained and the morphological features of the PSLs were extracted electronically without human assistance. The numerical data were then divided into learning and testing cases and linked to an artificial neural network for training and for further classification of lesions that the system had not been trained on. Our results show that the computerized system was able to automatically identify 95% of the PSLs presented. The sensitivity and specificity of the computerized system were 90% and 74% respectively. In contrast, when differentiating between individual types of lesions, the system performed at true positive rates of only 38% for malignant melanoma, 62% for dysplastic naevi and 33% for common naevi. Our data indicate that (1) ELM images of PSLs provide an excellent source for digital image analysis; (2) the vast majority of PSLs can be correctly identified by a relatively simple (and thus not "intelligent") application of digital image analysis; (3) automatic feature extraction based mainly on ABCD rules provides reliable data on the distinction between benign and malignant PSLs; and (4) there is evidence that artificial neural networks can be trained to adequately discriminate between benign and malignant PSLs.
DHEA in Elderly Women and DHEA or Testosterone in Elderly Men (2006)

Neither DHEA nor low-dose testosterone replacement in elderly people has physiologically relevant beneficial effects on body composition, physical performance, insulin sensitivity, or quality of life. (ClinicalTrials.gov number, NCT00254371 [ClinicalTrials.gov].).
Looking for Chinks in the Armor of Bacterial Biofilms (2007)

Researchers are exploring various ways to control the stubborn biofilms that bacteria form on medical devices and in many persistent infections.
A prospective study of circulating mutant KRAS2 in the serum of patients with colorectal neoplasia: strong prognostic indicator in postoperative follow up (2002)

Serum mutant KRAS2 can be detected preoperatively in all stages of colorectal neoplasia. Postoperatively, serum mutant KRAS2 is a strong predictor of disease recurrence, stronger even than Dukes' stage of disease, and thus shows potential for use in clinical practice as a marker of preclinical disease recurrence.
The structural and electrical evolution of graphene by oxygen plasma-induced disorder (2009)

Evolution of a single graphene layer with disorder generated by remote oxygen plasma irradiation is investigated using atomic force microscopy, Raman spectroscopy and electrical measurement. Gradual changes of surface morphology from planar graphene to isolated granular structure associated with a decrease of transconductance are accounted for by two-dimensional percolative conduction by disorder and the oxygen plasma-induced doping effect. The corresponding evolution of Raman spectra of graphene shows several peculiarities such as a sudden appearance of a saturated D peak followed by a linear decrease in its intensity, a relatively inert characteristic of a D' peak and a monotonic increase of a G peak position as the exposure time to oxygen plasma increases. These are discussed in terms of a disorder-induced change of Raman spectra in the graphite system.