gebhart/patrepeval huggingface dataset:
Clonogenic and nonclonogenic in vitro chemosensitivity assays. (1985)

We need practical laboratory methods for predicting the chemosensitivity of human neoplasms. Over the past 20 years, numerous investigators have implied or stated with increasing certitude that clonogenic assays are the most valid (or only valid) approach to predictive chemosensitivity testing. We feel that this point of view may have insufficient scientific validity and may be harmful to progress in this area. In addition to well-known technical problems, there are serious theoretical problems with clonogenic assays. These include the disruption of normal cell-to-cell interactions, the possibility that true tumor stem cells may be largely nondividing (G0) cells, while cells forming colonies are exclusively dividing cells, the possibility that clonogenic cells may largely represent cells which are not true stem cells, and the fact that clonogenic assays have the ability to measure cell kill over a narrow log range, while meaningful clinical responses require a multiple-log cell kill. This latter fact mandates the use of unrealistically low drug concentrations to avoid excessive false-positive results. Neither theoretical concepts, direct experimental data, nor clinical correlations support the alleged superiority of clonogenic assays. Clonogenic assays may not be advantageous compared to other more practical methods of estimating the general chemosensitivity of proliferating cells. In contrast, there is a growing body of literature which indicates that early evidence of cell damage in the entire tumor cell population may accurately predict for a multiple-log stem cell kill and meaningful clinical response. Future studies should continue to develop and test assays based on alternative methods for detecting cell kill in the proliferating and total tumor cell populations.
50-nm x-ray lithography using synchrotron radiation (1994)

A technology of proximity x-ray lithography has been developed to replicate patterns of sub-100-nm feature size using synchrotron radiation. Process modeling has been done in advance in order to optimize the mask absorber thickness. It is shown that with tungsten absorber, a 0.3 μm thickness is the most desirable for 50 nm linewidth processing. Masks compatible with a Karl Suss stepper have been fabricated using 50 keV electron-beam lithography and reactive ion etching techniques. As a result, well-defined 50-nm-wide isolated W lines and small gratings of period down to 100 nm have been fabricated. Then they have been replicated under proximity condition using Super ACO synchrotron radiation. We present details of a replication procedure with gap settings down to 5 μm and show how sub-100 nm structures can be 1:1 printed into both poly (methylmethacrylate) (PMMA) and (8.5%) MAA/PMMA resists. Finally, the results are analyzed in terms of a scaling rule to evaluate the resolution limit as a function of proximity gap using a synchrotron source.
Computer Analyses of EEG-Sleep in the Neonate (1990)

Neonatal EEG interpretation can aid in the estimation of central nervous system maturation, as well as provide diagnostic and prognostic information of the high-risk infant. However, one cannot easily visualize the complex interrelationships coupling EEG and polysomnographic components of the EEG-sleep rhythm. This is particularly relevant for the preterm neonate, in whom a rudimentary sleep cycle has not yet been clearly delineated. Computer analysis can augment the information derived from the visual interpretation of scalp-generated EEG activity. Automated techniques for EEG-sleep analysis have only recently been applied to a neonatal population. Such studies have been limited to full-term rather than preterm infants and rely on conventional methods that assume stationarity of neurophysiologic signals. We describe a computer system that simultaneously compares behavioral and electrographic components of EEG-sleep in a manner that preserves the integrity of the signals over time, while investigating the time- and frequency-dependent relationships among signals. Strategies for on-line and off-line editing, data storage, and off-line signal processing are described. Computational algorithms regarding analyses of EEG power, motility, and cardiorespiratory data are being used to study the ontogeny of EEG-sleep in asymptomatic preterm and full-term neonates. Computer strategies are based on both principles of stationarity and nonstationarity of physiologic signals and are applied depending on the temporal resolution required for specific signal processing needs.
GENETICS OF SOMATIC MAMMALIAN CELLS (1958)

A methodology designed to eliminate mitotic inhibitor action and involving use of pretested fetal calf serum and careful pH and temperature control has been described by which cells from normal human and animal tissue can be maintained in active growth for long periods in vitro without development of aneuploidy. By means of this procedure, it is possible reliably to establish cell cultures from minute skin biopsies which can be taken from any individual. Clones of mammalian cells with chromosomal markers have been isolated by this means from x-irradiated non-irradiated cell cultures. Application of these techniques to chromosome delineation in large numbers of human subjects; determination of chromosomal sex in patients; spontaneuos and induced genetic changes in somatic mammalian cells in vivo and in vitro; comparison of metabolic differences between normal and cancerous cells and other problems have been indicated.
Permanent inactivation of Huntington's disease mutation by personalized allele-specific CRISPR/Cas9 (2016)

A comprehensive genetics-based precision medicine strategy to selectively and permanently inactivate only mutant, not normal allele, could benefit many dominantly inherited disorders. Here, we demonstrate the power of our novel strategy of inactivating the mutant allele using haplotype-specific CRISPR/Cas9 target sites in Huntington's disease (HD), a late-onset neurodegenerative disorder due to a toxic dominant gain-of-function CAG expansion mutation. Focusing on improving allele specificity, we combined extensive knowledge of huntingtin (HTT) gene haplotype structure with a novel personalized allele-selective CRISPR/Cas9 strategy based on Protospacer Adjacent Motif (PAM)-altering SNPs to target patient-specific CRISPR/Cas9 sites, aiming at the mutant HTT allele-specific inactivation for a given diplotype. As proof-of-principle, simultaneously using two CRISPR/Cas9 guide RNAs (gRNAs) that depend on PAM sites generated by SNP alleles on the mutant chromosome, we selectively excised ∼44 kb DNA spanning promoter region, transcription start site, and the CAG expansion mutation of the mutant HTT gene, resulting in complete inactivation of the mutant allele without impacting the normal allele. This excision on the disease chromosome completely prevented the generation of mutant HTT mRNA and protein, unequivocally indicating permanent mutant allele-specific inactivation of the HD mutant allele. The perfect allele selectivity with broad applicability of our strategy in disorders with diverse disease haplotypes should also support precision medicine through inactivation of many other gain-of-function mutations.
Mode scanning: Heating pattern synthesis with ultrasound phased arrays (1994)

Modes, the characteristic symmetric focal patterns of an ultrasound phased array, prove especially useful for hyperthermia. Modes cancel the complex pressure fields exactly along the central axis, eliminating axial constructive interference both proximal and distal to the treatment volume. A simple calculation exploits planar or rotational array symmetry and produces the driving signals which generate modal focal patterns. Results show that temporal mode scanning improves heating patterns considerably, expanding the maximum treatable size of the tumour volume.
INTERLEUKIN-1 IS A CRITICAL EFFECTOR MOLECULE DURING CYTOKINE DYSREGULATION IN GRAFT VERSUS HOST DISEASE TO MINOR HISTOCOMPATIBILITY ANTIGENS1 (1993)

Cytokines are believed to cause a number of inflammatory diseases. We have investigated the role of 3 inflammatory cytokines, IL-1, IL-2, and TNF alpha, during graft-versus-host disease (GVHD), a paradigm disease of cytokine dysregulation in vivo. Measuring cytokine mRNA transcripts with a quantitative polymerase chain reaction technique, we demonstrate that IL-1 transcript levels are increased several hundred-fold in GVHD target organs, whereas TNF alpha transcripts increase only 4- to 6-fold. Kinetic studies during the first month after transplant unexpectedly show that GVHD never induces IL-2 transcripts in the skin and only induces IL-2 transcripts in the spleen during the first week, whereas levels of IL-1 transcripts continue to increase throughout the entire 4 weeks. Administration of an IL-1 receptor antagonist after the termination of the IL-2 response and after the establishment of GVHD significantly increases long-term survival, confirming the central role of IL-1 as an effector molecule of GVHD and suggesting new therapeutic strategies for this disorder.
Empirical Strength Criterion for Rock Masses (1980)

An empirical strength criterion for rocks and rock masses is proposed. The nonlinear criterion includes the uniaxial compressive strength of the intact rock material and introduces two dimensionless parameters, m and s. The parameter m varies with rock type, the angle of interblock or interparticle friction and the degree of block or particle interlock. The parameter s varies from 1.0 for intact rock material to zero for granular aggregates and depends on the interparticle tensile strength and the degree of interlock within the rock mass. For anisotropic rock, both m and s vary with the orientations of the planes of weakness to the principal stress directions. Approximate relationships between rock type, rock mass quality indices, and the rock mass strength parameters m and s, are presented. These relationships have been found useful in preliminary design calculations for slopes and underground excavations in jointed rock.
Making greed work in networks (1994)

This paper discusses congestion control from a game-theoretic perspective. There are two basic premises: (1) users are assumed to be independent and selfish, and (2) central administrative control is exercised only at the network switches. The operating points resulting from selfish user behavior depend crucially on the service disciplines implemented in network switches. This effect is investigated in a simple model consisting of a single exponential server shared by many Poisson sources. We discuss the extent to which one can guarantee, through the choice of switch service disciplines, that these selfish operating points will be efficient and fair. We also discuss to what extent the choice of switch service disciplines can ensure that these selfish operating points are unique and are easily and rapidly accessible by simple self-optimization techniques. We show that no service discipline can guarantee optimal efficiency. As for the other properties, we show that the traditional FIFO service discipline guarantees none of these properties, but that a service discipline called Fair Share guarantees all of them. While the treatment utilizes game-theoretic concepts, no previous knowledge of game theory is assumed.
Lens arrays for a three-dimensional imaging system (2002)

This paper describes optical components developed for a three-dimensional imaging system based on integral photography. A variety of lens arrays with differing specifications were required and, by suitable choices and refinements to manufacturing techniques, lens arrays were developed specifically for various stages of the imaging system. Major achievements include an image transfer screen 300 mm × 300 mm with 125 µm pitch lenses formed in photoresist and high-quality replica arrays with a 100% fill factor and pitch value of 850 µm moulded from diamond-machined masters.
Discovery of Potent and Selective Inhibitors of Trypanosoma brucei Ornithine Decarboxylase (2010)

Human African trypanosomiasis, caused by the eukaryotic parasite Trypanosoma brucei, is a serious health problem in much of central Africa. The only validated molecular target for treatment of human African trypanosomiasis is ornithine decarboxylase (ODC), which catalyzes the first step in polyamine metabolism. Here, we describe the use of an enzymatic high throughput screen of 316,114 unique molecules to identify potent and selective inhibitors of ODC. This screen identified four novel families of ODC inhibitors, including the first inhibitors selective for the parasitic enzyme. These compounds display unique binding modes, suggesting the presence of allosteric regulatory sites on the enzyme. Docking of a subset of these inhibitors, coupled with mutagenesis, also supports the existence of these allosteric sites.
Staging prostate cancer (1995)

Prostate-specific antigen is now one of the most valuable tumor markers with regard to the diagnosis of prostate cancer, the monitoring of patients after definitive therapy, and in determining the extent of disease after establishing the diagnosis of prostate cancer. Prostate-specific antigen, when combined with a local clinical stage from the digital rectal examination and the tumor grade from the biopsy specimen, has excellent ability for predicting regional lymph node involvement. As a result, many patients can be spared a staging bilateral pelvic lymphadenectomy prior to definitive treatment with either radical prostatectomy or radiation therapy. It is also clear that serum prostate-specific antigen is an excellent predictor of bone scan findings. Based on two studies involving more than 2500 patients, it appears that men, with newly diagnosed, untreated prostate cancer who have no skeletal symptoms and a serum prostate-specific antigen value less than or equal to 10ng/ml, have an extremely low probability of having a positive bone scan. For these men, approximately 40% of those presenting with newly diagnosed prostate cancer, a staging radionuclide bone scan is not necessary. Eliminating the staging radionuclide bone scan would result in huge annual economic savings in the LJS alone. As urologists and nonurologists alike attempt to reduce health-care costs, innovative use of the prostate-specific antigen test based on scientifically and statistically correct investigations will be most important. With this approach, many patients can be spared unnecessary staging studies, such as the bilateral pelvic lymphadenectomy and radionuclide bone scan.
Detection of reactive oxygen and reactive nitrogen species in skeletal muscle (2001)

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are usually identified with pathological states and mediators of cellular injury. However, over the last decade ROS and RNS have been identified in skeletal muscle under physiological conditions. Detection of ROS and RNS production by skeletal muscle cells is fundamental to the problem of differentiating between physiological and pathological levels. The goal of this paper is to review the techniques that have been used to detect ROS and RNS in skeletal muscle. Electron spin resonance, fluorescent assays, cyotchrome c reduction, chemiluminescence, hydroxylation of salicylate, and nitration of phenylalanine are some of the assay systems that have been used thus far. A large body of evidence now indicates that ROS and RNS are continually produced by many different skeletal muscle types studied in vivo, in situ, and in vitro. Under resting conditions, ROS and RNS are detectable in both intracellular and extracellular compartments. Production increases during both non-fatiguing and fatiguing muscle contractions. In the absence of disease, the individual molecular species detected in skeletal muscle include parent radicals for the ROS and RNS cascades: superoxide anions and nitric oxide. Both are generated at rates estimated to range from pmol-to-nmol/mg muscle/minute. Evidence indicates that hydrogen peroxide, hydroxyl radicals, and peroxynitrite are also present under physiological conditions. However, the molecular species that mediate specific biological effects remains largely undetermined, as do the sources of ROS and RNS within muscle fibers. Eventual delineation of the mechanisms whereby ROS and RNS regulate cellular function will hinge on our understanding of the production and distribution of ROS and RNS within skeletal muscle.
THE RELATIONSHIP OF GRANZYME A AND PERFORIN EXPRESSION TO CARDIAC ALLOGRAFT REJECTION AND DYSFUNCTION1 (1995)

The mechanisms underlying contractile dysfunction following heart transplantation are poorly defined. To investigate the role of cytotoxic T cells (CTL) in cardiac transplant rejection, and during episodic contractile dysfunction, we performed a prospective study analyzing the expression of granzyme A and perforin, two functional markers of activated CTL. Sixteen consecutive patients were analyzed during the first year posttransplantation. All patients received induction therapy with OKT-3 and received standard three-drug immunosuppression therapy. Rejection status was monitored using routine surveillance endomyocardial biopsy and graded according to the ISHLT scale. Granzyme A and perforin mRNA were detected by reverse transcription PCR at the time of each routine biopsy. A total of 64/123 biopsies were positive for granzyme expression, while 38/123 samples were positive for perforin expression. LV function was monitored using M-mode derived fractional shortening and Doppler assessment of diastolic function (isovolumic relaxation time [IVRT] and pressure half-time [P1/2]). As expected, the presence of granzyme A message was associated with rejection score (ANOVA, P = 0.001). In addition, granzyme A expression was correlated with a decrease in diastolic function (chi 2 = 6.4, P < 0.02), but was not associated with systolic function. The presence of perforin message was not correlated with functional changes or with rejection grade, but was associated with granzyme expression (chi 2 = 9.11, P = 0.0025). These studies suggest that the presence of granzyme A message may be an important predictor of graft function.
Anti‐parasitic effector mechanisms in human brain tumor cells: Role of interferon‐γ and tumor necrosis factor‐α (1996)

Toxoplasma gondii, an obligate intracellular parasite, is able to replicate in human brain cells. We recently showed that interferon (IFN)-gamma-activated cells from glioblastoma line 86HG39 were able to restrict Toxoplasma growth. The effector mechanism responsible for this toxoplasmostatic effect was shown by us to be the IFN-gamma-mediated activation of indolamine 2,3-dioxygenase (IDO), resulting in the degradation of the essential amino acid tryptophan. In contrast, glioblastoma 87HG31 was unable to restrict Toxoplasma growth after IFN-gamma activation, and IFN-gamma-mediated IDO activation was weak. We observed that tumor necrosis factor (TNF)-alpha alone is unable to activate IDO or to induce toxoplasmostasis in any glioblastoma cell line tested. Interestingly, we found that TNF-alpha and IFN-gamma were synergistic in the activation of IDO in glioblastoma cells 87HG31, 86HG39 and U373MG and in native astrocytes. This was shown by the measurement of enzyme activity as well as by the detection of IDO mRNA in TNF-alpha + IFN-gamma activated cells. This IDO activity results in a strong toxoplasmostatic effect mediated by glioblastoma cells activated simultaneously by both cytokines. Antibodies directed against TNF-alpha or IFN-gamma were able to inhibit IDO activity as well as the induction of toxoplasmostasis in glioblastoma cells stimulated with both cytokines. Furthermore, it was found that the addition of L-tryptophan to the culture medium completely blocks the antiparasitic effect. We therefore conclude that both TNF-alpha and IFN-gamma may be involved in the defense against cerebral toxoplasmosis by inducing IDO activity as an antiparasitic effector mechanism in brain cells.
Tumor induction by the c-Myc target genes rcl and lactate dehydrogenase A. (2000)

The characterization of c-Myc target genes, such as rcl and lactate dehydrogenase A (LDH-A), is critical for understanding the mechanisms of c-Myc-induced cell transformation and tumorigenesis. We have previously demonstrated that Rcl induces anchorage-independent growth in Ratla fibroblasts and that LDH-A is required for cell transformation by c-Myc. In this study, we report that Rcl and LDH-A act synergistically to induce anchorage-independent growth. Cells expressing both Rcl and LDH-A form tumors after s.c. injection into nude mice, although neither Rcl or LDH-A overexpression alone induces tumorigenesis. The inability of Rcl and LDH-A to fully recapitulate c-Myc activity, however, indicates that other c-Myc target genes participate in tumorigenesis. In addition, cells that coexpress Rcl and vascular endothelial growth factor are more comparable with c-Myc overexpressing cells in their ability to form tumors in nude mice. These findings confirm Rcl and LDH-A as critical components of the cell transformation program induced by c-Myc and suggest that Rcl is tumorigenic in cells that are provided with a permissive metabolic milieu.
The Attention System of the Human Brain: 20 Years After (2012)

Here, we update our 1990 Annual Review of Neuroscience article, "The Attention System of the Human Brain." The framework presented in the original article has helped to integrate behavioral, systems, cellular, and molecular approaches to common problems in attention research. Our framework has been both elaborated and expanded in subsequent years. Research on orienting and executive functions has supported the addition of new networks of brain regions. Developmental studies have shown important changes in control systems between infancy and childhood. In some cases, evidence has supported the role of specific genetic variations, often in conjunction with experience, that account for some of the individual differences in the efficiency of attentional networks. The findings have led to increased understanding of aspects of pathology and to some new interventions.
Microarray Bioinformatics (2003)

This book is a comprehensive guide to all of the mathematics, statistics and computing you will need to successfully operate DNA microarray experiments. It is written for researchers, clinicians, laboratory heads and managers, from both biology and bioinformatics backgrounds, who work with, or who intend to work with microarrays. The book covers all aspects of microarray bioinformatics, giving you the tools to design arrays and experiments, to analyze your data, and to share your results with your organisation or with the international community. There are chapters covering sequence databases, oligonucleotide design, experimental design, image processing, normalisation, identifying differentially expressed genes, clustering, classification and data standards. The book is based on the highly successful Microarray Bioinformatics course at Oxford University, and therefore is ideally suited for teaching the subject at postgraduate or professional level.