gebhart/patrepeval huggingface dataset:
Why Your New Cancer Biomarker May Never Work: Recurrent Patterns and Remarkable Diversity in Biomarker Failures (2012)

Less than 1% of published cancer biomarkers actually enter clinical practice. Although best practices for biomarker development are published, optimistic investigators may not appreciate the statistical near-certainty and diverse modes by which the other 99% (likely including your favorite new marker) do indeed fail. Here, patterns of failure were abstracted for classification from publications and an online database detailing marker failures. Failure patterns formed a hierarchical logical structure, or outline, of an emerging, deeply complex, and arguably fascinating science of biomarker failure. A new cancer biomarker under development is likely to have already encountered one or more of the following fatal features encountered by prior markers: lack of clinical significance, hidden structure in the source data, a technically inadequate assay, inappropriate statistical methods, unmanageable domination of the data by normal variation, implausibility, deficiencies in the studied population or in the investigator system, and its disproof or abandonment for cause by others. A greater recognition of the science of biomarker failure and its near-complete ubiquity is constructive and celebrates a seemingly perpetual richness of biologic, technical, and philosophical complexity, the full appreciation of which could improve the management of scarce research resources.
A critical review of clinical trials in systemic lupus erythematosus (2016)

One challenge in caring for patients with systemic lupus erythematosus (SLE) is a paucity of approved therapeutics for treatment of the diverse disease manifestations. In the last 60 years, only one drug, belimumab, has been approved for SLE treatment. Critical evaluation of investigator initiated and pharma-sponsored randomized controlled trials (RCTs) highlights barriers to successful drug development in SLE, including disease heterogeneity, inadequate trial size or duration, insufficient dose finding before initiation of large trials, handling of background medications, and choice of primary endpoint. Herein we examine lessons learned from landmark SLE RCTs and subsequent advances in trial design, as well as discuss efforts to address limitations in current SLE outcome measures that will improve detection of true therapeutic responses in future RCTs.
Structure and Function of Natural Killer Cell Surface Receptors (2003)

Since mid-1990, with cloning and identification of several families of natural killer (NK) receptors, research on NK cells began to receive appreciable attention. Determination of structures of NK cell surface receptors and their ligand complexes led to a fast growth in our understanding of the activation and ligand recognition by these receptors as well as their function in innate immunity. Functionally, NK cell surface receptors are divided into two groups, the inhibitory and the activating receptors. Structurally, they belong to either the immunoglobulin (Ig)-like receptor superfamily or the C-type lectin-like receptor (CTLR) superfamily. Their ligands are either members of class I major histocompatibility complexes (MHC) or homologs of class I MHC molecules. The inhibitory form of NK receptors provides the protective immunity through recognizing class I MHC molecules with self-peptides on healthy host cells. The activating, or the noninhibitory, NK receptors mediate the killing of tumor or virally infected cells through their specific ligand recognition. The structures of activating and inhibitory NK cell surface receptors and their complexes with the ligands determined to date, including killer immunoglobulin-like receptors (KIRs) and their complexes with HLA molecules, CD94, Ly49A, and its complex with H-2Dd, and NKG2D receptors and their complexes with class I MHC homologs, are reviewed here.
Frequency dependence of the structure and electrical behaviour of carbon nanotube networks assembled by dielectrophoresis (2005)

The statistical variations in the properties of carbon nanotubes and their contacts to metallic electrodes can be averaged by using networks of single-walled carbon nanotubes as sensing devices. Carbon nanotube networks have been assembled on microstructures with dielectrophoresis, using an inhomogeneous alternating electric field to attract carbon nanotubes onto the microelectrodes. The networks were assembled on identical microstructures using four different frequencies in the range 10 kHz–10 MHz. From structural and electrical characterization of the assembled structures, we found that at higher frequencies the assembled nanotubes align better with the electric field and are more free of impurities. We also found consistently lower resistances for networks assembled at higher frequencies, suggesting that a high assembly frequency may lead to better quality networks with low contact resistances.
In vivo system for the detection of low level activity barnase mutants (1995)

We report the design of a new tightly controlled barnase system which allows the existence of the barnase gene in host cells without a signal sequence. When expression of barnase is turned on by gene inversion in vivo, the lethal effect of barnase (or its mutants) is not compromised either by coexpression of its polypeptide inhibitor (barstar), or by extracellular secretion. This serves as a rapid, sensitive in vivo test for the detection of any very low residual activity of the barnase mutants. Active-site mutants His102Lys, Glu73Asp and Arg87Lys, and a mutant which greatly reduces the stability and yield of protein, Arg83Lys, produce enough activity to be detectable by this test. In contrast, when expressed on a secretion vector, these mutants do not yield detectable activity in a solution assay. Truly inactive mutants, such as those of His102 to Gly, Ala or Leu, were completely harmless when expressed in this system.
Testing a tripartite model: I. Evaluating the convergent and discriminant validity of anxiety and depression symptom scales. (1995)

L.A. Clark and D. Watson (1991) proposed a tripartite model that groups symptoms of depression and anxiety into 3 subtypes: symptoms of general distress that are largely nonspecific, manifestations of somatic tension and arousal that are relatively unique to anxiety, and symptoms of anhedonia and low Positive Affect that are specific to depression. This model was tested in 5 samples (3 student, 1 adult, and 1 patient sample) using the Mood and Anxiety Symptom Questionnaire (MASQ; D. Watson & L. A. Clark, 1991), which was designed to assess the hypothesized symptom groups, together with other symptom and cognition measures. Consistent with the tripartite model, the MASQ Anxious Arousal and Anhedonic Depression scales both differentiated anxiety and depression well and also showed excellent convergent validity. Thus, differentiation of these constructs can be improved by focusing on symptoms that are relatively unique to each.
A Mining-Based System Framework for Deploying Knowledge Maps of Composite E-Services (2005)

Providing e-services and composite e-services on the Internet is an important trend of e-business. Composite e-services are complex processes which consist of various e-services provided by different e-service providers. In such complex environments, the flexibility and success of e-business depend on effective knowledge supports to access related information and resources of composite e-services. This work proposes a knowledge map platform to provide an effective knowledge support for utilizing composite e-services. A mining-based system framework is proposed to construct the knowledge map. Moreover, the proposed knowledge map is integrated with recommendation capability to provide users customized decision support in utilizing composite e-services.
Histogenesis of the papillary Clara cell adenoma. (1981)

Mouse lung adenomas have two characteristic histologic patterns, alveolar and bronchiolar or papillary. Differences in biologic behavior have been noted in tumors of different histologic form, in that papillary tumors were said to grow faster and become larger and possibly malignant. Progressive development from the alveolar to the papillary tumors has been proposed, involving a step-wise transformation from benign to malignant tumors. The author recently presented evidence from ultrastructural studies that the different histologic patterns were related to the cell of origin; the bronchiolar tumors consisted of Clara cells, while the alveolar tumors were made up of Type II alveolar epithelium. In the present study, designed to evaluate the histologic patterns of tumors during their development, multiple lung adenomas were induced in fetal Bagg-Webster mice on the sixteenth day of gestation by a single transplacental exposure to ethyl-nitrosourea. The animals were killed from the seventh postnatal day to 185 days of age; their tumors were counted and categorized histologically. Analysis of serial-step sections of the right lower lobes of young postnatal mice showed tumors with either an alveolar (37%) or a bronchiolar pattern (63%). Two forms of the latter were recognized, tubular and papillary. Between Day 80 and Day 186 papillary adenomas increased, tubular tumors decreased, and alveolar adenomas remained relatively constant in number. At the end of the 6-month observation period the overall proportion of alveolar and Clara cell tumors was similar to that found in the first 3 weeks of life. These data support the concept that alveolar and papillary tumors arise from different cell lines, the papillary tumors exclusively from Clara cells.
TIR-containing Adapter Molecule (TICAM)-2, a Bridging Adapter Recruiting to Toll-like Receptor 4 TICAM-1 That Induces Interferon-β (2003)

Lipopolysaccharide (LPS) is an agonist for Toll-like receptor (TLR) 4 and expresses many genes including NF-kappaB- and interferon regulatory factor (IRF)-3/IFN-inducible genes in macrophages and dendritic cells (DCs). TICAM-1/TRIF was identified as an adapter that facilitates activation of IRF-3 followed by expression of interferon (IFN)-beta genes in TLR3 signaling, but TICAM-1 does not directly bind TLR4. Although MyD88 and Mal/TIRAP adapters functions downstream of TLR4, DC maturation and IFN-beta induction are independent of MyD88 and Mal/TIRAP. In this investigation, we report the identification of a novel adapter, TICAM-2, that physically bridges TLR4 and TICAM-1 and functionally transmits LPS-TLR4 signaling to TICAM-1, which in turn activates IRF-3. In its structural features, TICAM-2 resembled Mal/TIRAP, an adapter that links TLR2/4 and MyD88. However, TICAM-2 per se exhibited minimal ability to activate NF-kappaB and the IFN-beta promoter. Hence, in LPS signaling TLR4 recruits two types of adapters, TIRAP and TICAM-2, to its cytoplasmic domain that are indirectly connected to two effective adapters, MyD88 and TICAM-1, respectively. We conclude that for LPS-TLR4-mediated activation of IFN-beta, the adapter complex of TICAM-2 and TICAM-1 plays a crucial role. This results in the construction of MyD88-dependent and -independent pathways separately downstream of the two distinct adapters.
Fast Nonnegative Matrix Factorization: An Active-Set-Like Method and Comparisons (2011)

Nonnegative matrix factorization (NMF) is a dimension reduction method that has been widely used for numerous applications, including text mining, computer vision, pattern discovery, and bioinformatics. A mathematical formulation for NMF appears as a nonconvex optimization problem, and various types of algorithms have been devised to solve the problem. The alternating nonnegative least squares (ANLS) framework is a block coordinate descent approach for solving NMF, which was recently shown to be theoretically sound and empirically efficient. In this paper, we present a novel algorithm for NMF based on the ANLS framework. Our new algorithm builds upon the block principal pivoting method for the nonnegativity-constrained least squares problem that overcomes a limitation of the active set method. We introduce ideas that efficiently extend the block principal pivoting method within the context of NMF computation. Our algorithm inherits the convergence property of the ANLS framework and can easily be extended to other constrained NMF formulations. Extensive computational comparisons using data sets that are from real life applications as well as those artificially generated show that the proposed algorithm provides state-of-the-art performance in terms of computational speed.
Short chain fatty acid distributions of enema samples from a sigmoidoscopy population: an association of high acetate and low butyrate ratios with adenomatous polyps and colon cancer. (1988)

We investigated the distribution of short chain fatty acids (SCFA) in enema samples taken from subjects before sigmoidoscopy as an indicator of possible microbial community differences between subjects subsequently diagnosed as normal or having colonic disorders. The major SCFA in all groups were acetic, propionic, and butyric acids. A significantly higher ratio of acetate to total SCFA and lower ratio of butyrate to total SCFA was found for polyp-colon cancer subjects than for normal subjects. There were no significant differences in the ratios of acetate, propionate, or butyrate between the diverticulosis or inflammatory bowel groups and the normal group. There were no significant sex differences nor were there correlations with the ratios of acetate, propionate or butyrate and age, subject weight, or dry weights of samples. Significant differences in concentrations of individual acids were found between normal and certain diagnostic groups. The difference in proportions of individual SCFA between groups suggest differences in fermentation patterns of the colonic microflora.
BsiY I, a novel thermophilic restriction endonuclease that recognizes 5′ CCNNNNNNNGG 3′ and the discovery of a wrongly sequenced site in pACYC177 (1991)

A new type II restriction endonuclease designated BsiY I has been purified from a thermophilic soil Bacillus stearothermophilus strain. This enzyme recognizes and cleaves the highly degenerate sequence 5' CCNNNNN!NNGG 3'. During the identification of the recognition sequence of BsiY I, we discovered that there should be five G nucleotides instead of four at position 1227-1230 of the plasmid pACYC177.
Detection of deep venous thrombi and pulmonary embolus with technetium-99m-DD-3B6/22 anti-fibrin monoclonal antibody Fab' fragment. (1994)

The results indicate that 99mTc-DD-3B6/22 Fab' has potential for noninvasive detection of deep-vein thrombosis and pulmonary embolism.
Depression – emerging insights from neurobiology (2001)

An emerging hypothesis suggests that the pathogenesis and treatment of depression is likely to involve a plasticity of neuronal pathways. The inability of neuronal systems to exhibit appropriate, adaptive plasticity could contribute to the pathogenesis of depression. Antidepressant treatments may exert their therapeutic effects by stimulating appropriate adaptive changes in neuronal systems. Recent studies have demonstrated that chronic antidepressant administration up-regulates the cAMP signal transduction cascade resulting in an increased expression and function of the transcription factor CREB. Enhanced CREB expression leads to an up-regulation of specific target genes, including the neurotrophin BDNF. Chronic antidepressant treatments enhance BDNF expression within hippocampal and cortical neurons and can prevent the stress-induced decrease in BDNF expression. Stress has been shown to: (i) induce neuronal atrophy/death; and (ii) decrease neurogenesis of hippocampal neurons. Clinical studies indicate significant hippocampal damage in cases of major, recurrent depression. It is possible that antidepressant treatments through enhanced expression of growth and survival promoting factors like BDNF may prevent or reverse the atrophy and damage of hippocampal neurons. Indeed, studies have indicated that chronic antidepressant treatments enhance hippocampal neurogenesis, promote neuronal sprouting and prevent atrophy. The molecular mechanisms underlying the effects of antidepressant treatments including adaptations in the cAMP transduction cascade, CREB and BDNF gene expression, and structural neuronal plasticity are discussed.
Insulin-Like Growth Factor-I Receptors in Human Glial Tumors (1990)

Insulin and insulin-like growth factors (IGFs) are anabolic effectors in many tissues and cultured cells, including astrocytes and neurons. Receptors for insulin and IGFs are found throughout the human brain. We examined the level of insulin and IGF receptors on membranes prepared from surgical specimens of tumor (astrocytomas and glioblastomas) and normal human brain. Specific binding (per 100 micrograms membrane protein) of insulin was less than 5% in all normal and tumor samples. Specific binding of IGF-I to 12 normal brain specimens ranged from 1-8%. IGF-I binding to 18 glioma specimens ranged from 2-25%. Scatchard analyses of IGF-I binding confirmed increased IGF-I-binding sites in some glial tumors vs. normal brain, but detected no difference in affinity characteristics. Cross-linking of [125I]IGF-I demonstrated that glioma tissue expressed the same lower mol wt (approximately 118 kDa) alpha-subunit as the normal brain confirming the neural origin of the cells expressing the IGF-I receptor. IGF-binding proteins (approximately 40 kDa) were also found in the membranes of some of the glioma but none of the normal brain specimens. In cell lines derived from glioma specimens, IGF binding was readily detectable (4-10% specific binding), but insulin binding was barely detectable (0-03%) in every line examined. The size of the IGF-I alpha-subunit in the cultured cells was larger (approximately 133 kDa) than that in the original tissue. Most glioma cell lines exhibited an IGF-I dose-dependent stimulation of thymidine incorporation into DNA, and partially purified IGF-I receptors from these cells exhibited a dose-dependent stimulation of the autophosphorylation of the beta-subunit. We conclude that human glioma cells have functional IGF-I receptors and suggest a role for this receptor in glioma cell growth.
Challenges and Opportunities in the Design of TRILL: A Routed Layer 2 Technology (2009)

This paper describes some of the interesting technical issues that arose in the design of TRILL (TRansparent Interconnection of Lots of Links), a technology being standardized in IETF, that combines the ease of configuration usually associated with layer 2, with the flexibility, robustness, and route optimizations usually associated with layer 3. In addition to describing the issues, we describe the alternative proposals, and the rationale behind the resolutions.
Biliverdin Reductase Mediates Hypoxia-Induced EMT via PI3-Kinase and Akt (2008)

Chronic hypoxia in the renal parenchyma is thought to induce epithelial-to-mesenchymal transition (EMT), leading to fibrogenesis and ultimately end-stage renal failure. Biliverdin reductase, recently identified as a serine/threonine/tyrosine kinase that may activate phosphatidylinositol 3-kinase (PI3K) and Akt, is upregulated in response to reactive oxygen species that may accompany hypoxia. We investigated this potential role of biliverdin reductase in hypoxia-induced renal tubular EMT. Expression of biliverdin reductase was upregulated in a human proximal tubule cell line (HK-2) cultured in hypoxic conditions (1% O2), and this was accompanied by reduced expression of E-cadherin and increased expression of the mesenchymal marker vimentin. Inhibiting PI3K reversed these changes, consistent with EMT. In normoxic conditions, overexpression of biliverdin reductase promoted similar characteristics of EMT, which were also reversed by inhibiting PI3K. Furthermore, using small interfering RNA (siRNA) to knockdown biliverdin reductase, we demonstrated that the enzyme associates with phosphorylated Akt and mediates the hypoxia-induced EMT phenotype. In vivo, expression of biliverdin reductase increased in the tubular epithelia of 5/6-nephrectomized rats, and immunohistochemistry of serial sections demonstrated similar localization of phosphorylated Akt and biliverdin reductase. In conclusion, biliverdin reductase mediates hypoxia-induced EMT through a PI3K/Akt-dependent pathway.
Approximate and probabilistic algorithms for shading and rendering structured particle systems (1985)

Detail enhances the visual richness and realism of computer-generated images. Our stochastic modelling approach, called particle systems , builds complex pictures from sets of simple, volume-filling primitives. For example, structured particle systems have been used to generate trees and a grass-covered forest floor. Particle systems can produce so much irregular, three-dimensional detail that exact shading and visible surface calculations become infeasible. We describe approximate and probabilistic algorithms for shading and the visible surface problem. Because particle systems algorithms generate richly-detailed images, it is hard to detect any deviation from an exact rendering. Recent work in stochastic modelling also enables us to model complex motions with random variation, such as a field of grass blowing in the breeze. We analyze the performance of our current algorithms to understand the costs of our stochastic modelling approach.
Expression Profile Matrix of Arabidopsis Transcription Factor Genes Suggests Their Putative Functions in Response to Environmental Stresses[W] (2002)

Numerous studies have shown that transcription factors are important in regulating plant responses to environmental stress. However, specific functions for most of the genes encoding transcription factors are unclear. In this study, we used mRNA profiles generated from microarray experiments to deduce the functions of genes encoding known and putative Arabidopsis transcription factors. The mRNA levels of 402 distinct transcription factor genes were examined at different developmental stages and under various stress conditions. Transcription factors potentially controlling downstream gene expression in stress signal transduction pathways were identified by observed activation and repression of the genes after certain stress treatments. The mRNA levels of a number of previously characterized transcription factor genes were changed significantly in connection with other regulatory pathways, suggesting their multifunctional nature. The expression of 74 transcription factor genes responsive to bacterial pathogen infection was reduced or abolished in mutants that have defects in salicylic acid, jasmonic acid, or ethylene signaling. This observation indicates that the regulation of these genes is mediated at least partly by these plant hormones and suggests that the transcription factor genes are involved in the regulation of additional downstream responses mediated by these hormones. Among the 43 transcription factor genes that are induced during senescence, 28 of them also are induced by stress treatment, suggesting extensive overlap responses to these stresses. Statistical analysis of the promoter regions of the genes responsive to cold stress indicated unambiguous enrichment of known conserved transcription factor binding sites for the responses. A highly conserved novel promoter motif was identified in genes responding to a broad set of pathogen infection treatments. This observation strongly suggests that the corresponding transcription factors play general and crucial roles in the coordinated regulation of these specific regulons. Although further validation is needed, these correlative results provide a vast amount of information that can guide hypothesis-driven research to elucidate the molecular mechanisms involved in transcriptional regulation and signaling networks in plants.