gebhart/patrepeval huggingface dataset:
Targeting the EWSR1-FLI1 Oncogene-Induced Protein Kinase PKC-β Abolishes Ewing Sarcoma Growth (2012)

Ewing sarcoma is a rare but aggressive disease most common in young adults. This cancer is driven by a unique chimeric fusion oncogene but targeted strategies have been elusive. Here we report the identification of the protein kinase PKC-ß (PRKCB) as a disease-specific druggable target for treatment of Ewing sarcoma. We found that transcriptional activation of PRKCB was directly regulated by the chimeric fusion oncogene EWSR1-FLI1 that drives this cancer. PRKCB phosphorylated histone H3T6 to permit global maintenance of H3K4 trimethylation at a variety of gene promoters. PRKCB loss induced apoptosis in vitro and prevented tumor growth in vivo. Gene expression profiling revealed a strong overlap between genes modulated by EWSR1-FLI1 and PRKCB in regulating crucial signaling pathways. Taken together, our findings offer a preclinical proof-of-concept for PRKCB as a promising therapeutic target in Ewing sarcoma.
Imbalance towards Th1 predominance is associated with acceleration of lupus-like autoimmune syndrome in MRL mice. (1996)

To investigate the respective roles of Th1 and Th2 cells in the pathogenesis of lupus-like autoimmune disease, we have analyzed the spontaneous and antigen-induced productions of IgG1 vs IgG2a and IgG3 subclasses in relation to the mRNA expression of INF-gamma (Th1 cytokine promoting IgG2a and IgG3 production), IL-4 (Th2 cytokine promoting IgG1 production), and IL-10 (Th2 cytokine) in CD4+ T cells from lupus-prone MRL mice. For this purpose, two paired sets of MRL mice were chosen for the comparison of these parameters: (a) MRL-lpr/lpr (lpr for lymphoproliferation) and its recently described substrain with a prolonged survival, termed MRL-lpr/lpr.ll (ll for long lived) and (b) MRL male mice bearing the Yaa (Y-linked autoimmune acceleration) gene (MRL.Yaa) with an accelerated disease and their male counterparts lacking the Yaa gene. We demonstrate herein that the accelerated development of lupus-like autoimmune disease in MRL-lpr/lpr and MRL.Yaa mice, as compared with MRL-lpr/lpr.ll and MRL-+/+ mice, respectively, was correlated with an enhanced expression of IFN-gamma vs IL-4 and IL-10 mRNA in CD4+ T cells, which paralleled with an increase of spontaneous and foreign T cell-dependent antigen-induced productions of IgG2a and IgG3 vs IgG1 antibodies. These data suggest that an imbalance towards Th1 predominance may play a significant role in the acceleration of lupus-like autoimmune disease in MRL mice.
Determinants of prescribing of second-choice antibiotics for upper and lower respiratory tract episodes in Dutch general practice (2005)

Given the growing number of prescriptions of second-choice antibiotics, it is important to implement professional guidelines in daily practice, while training in being reluctant to prescribe new drugs and being alert to the marketing activities of pharmaceutical companies should be started in the medical curriculum.
Enhanced Immunity and Protective Efficacy against SIV mac251 Intrarectal Challenge Following Ad-SIV Priming by Multiple Mucosal Routes and gp120 Boosting in MPL-SE (2005)

Previously, 39% of rhesus macaques primed orally, intranasally, and intratracheally with adenovirus (Ad)-simian immunodeficiency virus (SIV) recombinants and boosted with gp120 in monophosphoryl lipid A-stable emulsion (MPL-SE) remained aviremic or cleared or controlled viremia at the threshold of detection following SIV(mac251) intrarectal challenge (Study B). In contrast, no macaques primed orally and intranasally with Ad-SIV recombinants and boosted with gp120 in Quillaja Saponaria-21 exhibited undetectable viremia post-challenge (Study A). We conducted a detailed comparison of the studies to elucidate the effect of different vaccine regimens on induced immunity associated with the different challenge outcomes. Quantitative viral load comparisons were statistically analyzed. All immune responses were assessed at identical timepoints post-immunization, and cellular immunity was re-evaluated on cryopreserved cells from Study B macaques to match Study A data acquired with frozen cells. Study B exhibited greater protective efficacy, increased levels of p11C and p54m tetramer positive cells and a trend toward enhanced interferon-gamma secreting cells in response to Env and Gag peptides, modestly enhanced serum neutralizing antibodies, and greater positivity in anti-gp120 rectal IgA and IgG antibodies. Study A macaques exhibited greater positivity in salivary IgA anti-gp120 antibodies. Thus, the vaccine regimen using oral-intranasal-intratracheal priming and protein boosting in MPL-SE was superior, eliciting greater protective efficacy against pathogenic SIV(mac251) and enhanced SIV-specific immunity, systemically and at rectal sites. The mechanism(s) by which binding antibodies, lacking neutralizing activity against the primary challenge virus, may contribute to protection requires further study.
Cyclic AMP response element-binding protein, CRE-BP1, mediates the E1A-induced but not the Tax-induced trans-activation. (1991)

The adenovirus E1A protein and tax protein (Tax) of human T-cell leukemia virus-1 (HTLV-1) are transcriptional regulators that do not bind to DNA directly. The ATF sites/CRE (cyclic AMP response element) of the adenovirus E4 promoter and the long terminal repeat of HTLV-1 have been shown to be required for E1A and Tax inducibility, respectively. Using the c-Myb-CRE-BP1 fusion protein, it was shown that CRE-BP1, which could bind to the ATF sites/CRE, mediated the E1A-induced trans-activation. For this activation, the N-terminal portion of CRE-BP1, which contained the putative metal finger structure, was essential but not sufficient. In contrast, the trans-activation induced by HTLV-1 Tax was not mediated by CRE-BP1. These results strongly suggested that E1A activates transcription through interaction with CRE-BP1, but another CRE-binding protein participates in the Tax-induced trans-activation.
Anaplastic lymphoma kinase-positive squamous cell carcinoma of the lung: A case report (2016)

It is widely known that echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) rearrangement mostly occurs in the adenocarcinoma subtype of non-small-cell lung cancer (NSCLC). Patients with squamous cell carcinoma harboring the ALK rearrangement are extremely rare. This is a case report of a squamous cell carcinoma patient with EML4-ALK rearrangement. An elderly man with a heavy smoking history presented with a mass lesion in the right main bronchus. Bronchoscopic biopsy of the tumor confirmed a diagnosis of squamous cell carcinoma, and it was proven to harbor ALK rearrangement, based on fluorescence <i>in situ</i> hybridization, but not epidermal growth factor receptor mutations. The patient underwent radiation therapy, with a markedly favorable response. ALK-targeted treatment may be a viable option if disease progression occurs in such a case in the future.
Ring-Field EUVL Camera with Large Etendu (1996)

These scanning cameras with large instantaneous fields make efficient use of the new, 300-μm diameter, debris-less laser-plasma sources while printing 100-nm features.
Treatment of Rheumatoid Arthritis with Methotrexate Alone, Sulfasalazine and Hydroxychloroquine, or a Combination of All Three Medications (1996)

In patients with rheumatoid arthritis, combination therapy with methotrexate, sulfasalazine, and hydroxychloroquine is more effective than either methotrexate alone or a combination of sulfasalazine, and hydroxychloroquine.
Crystal Structure of Human Frataxin (2000)

Friedreich's ataxia, an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia, cardiomyopathy, and diabetes mellitus, is caused by decreased frataxin production or function. The structure of human frataxin, which we have determined at 1.8-A resolution, reveals a novel protein fold. A five-stranded, antiparallel beta sheet provides a flat platform, which supports a pair of parallel alpha helices, to form a compact alphabeta sandwich. A cluster of 12 acidic residues from the first helix and the first strand of the large sheet form a contiguous anionic surface on the protein. The overall protein structure and the anionic patch are conserved in eukaryotes, including animals, plants, and yeast, and in prokaryotes. Additional conserved residues create an extended 1008-A(2) patch on a distinct surface of the protein. Side chains of disease-associated mutations either contribute to the anionic patch, help create the second conserved surface, or point toward frataxin's hydrophobic core. These structural findings predict potential modes of protein-protein and protein-iron binding.
Gambogic acid‐induced degradation of mutant p53 is mediated by proteasome and related to CHIP (2010)

As an oncoprotein, mutant p53 is a potential tumor-specific target for cancer therapy. Most mutated forms of the protein are largely accumulated in cancer cells due to their increased stability. In the present study, we demonstrate that mutant p53 protein stability is regulated by gambogic acid (GA). Following GA exposure, protein levels of mutant p53 decreased while the mRNA levels were not affected in MDA-MB-435 cells, which indicate that GA down-regulates mutant p53 at post-transcription level. Co-treatment with GA and cycloheximide, a protein synthesis inhibitor, induced a decrease of half-life of mutant p53 protein. These findings indicated that the reduction of mutant p53 by GA was due to the destabilization and degradation of the protein. Furthermore, inhibition of proteasome activity by MG132 blocked GA-induced down-regulation of mutant p53, causing mutant p53 accumulation in detergent-insoluble cellular fractions. Further studies revealed that mutant p53 was ubiquitinated and it was chaperones related ubiquitin ligase carboxy terminus of Hsp70-interacting protein (CHIP) rather than MDM2 involved in the degradation of mutant p53. In addition, GA prevented Hsp90/mutant p53 complex formation and enhanced interaction of mutant p53 with Hsp70. Depletion of CHIP stabilized mutant p53 in GA treated cells. In conclusion, mutant p53 may be down-regulated by GA through chaperones-assisted ubiquitin/proteasome degradation pathway in cancer cells.
Direct sequencing of the HA gene of influenza (H3N2) virus in original clinical samples reveals sequence identity with mammalian cell-grown virus (1990)

When influenza (H3N2) viruses from infected individuals are grown in embryonated chicken eggs, viruses are isolated which differ antigenically and structurally from viruses grown in mammalian Madin-Darby canine kidney (MDCK) cell culture [G.C. Schild, J.S. Oxford, J.C. de Jong, and R.G. Webster, Nature (London) 303:706-709, 1983]. To determine which of these viruses is most representative of virus replicating in the infected individual, a region of the HA gene of virus present in original clinical samples was amplified by using the polymerase chain reaction and sequenced directly. Comparison of 170 amino acid residues of HA1 flanking and containing the receptor-binding site and antigenic sites indicated that over this region, the HA of virus replicating in the infected individual was identical to that of virus after growth in MDCK cells and was distinct from the HA of viruses grown in eggs. Therefore, cultivation of human influenza H3N2 virus in mammalian MDCK cells results in a virus similar to the predominant population of virus found in the infected individual.
Unilateral Abscence Of Nose With Proboscis (1991)

Abstract A case of unilateral absence of nose with nasal proboscis and microphthalmia is being reported for its rarity along with proposed surgical procedure and review of literature. Unilateral absence of nose is a rare disorder which is often associated with unilateral arhencephaly or unilateral proboscis which hangs down from the medical canthus. The case is being reported for its rarity.
A Review of Where Medicine Went Wrong: Rediscovering the Path to Complexity (2009)

A Review of Where Medicine Went Wrong: Rediscovering the Path to Complexity written by Bruce J. West reviewed by Jack Cohen published by World Scientific Publishing Company ISBN 9789812568830 (2006) This is a wonderful book, marred by the virtual absence of copy-editing. There are more than twenty errors, spelling and stylistic, in the first ten pages, making it annoying to read; this is very odd, as West is himself the editor of the series. story it tells is a familiar one to this E:CO authence. medical profession has put all its money on bell-shaped - Gaussian - curves and linear mathematical argument, and has missed the (mostly nonlinear because nearly all mathematics is nonlinear) contexts for physiology. Missed it partly because it isn't physics: West himself started as a physicist, and the tear marks where he had to completely revise his assumptions are still visible; he has been singing this song for a long time (since the early 1980s), and the story is nearly complete. What a pity it isn't more elegantly put. He starts by showing how the law tried to treat farmers and city gents similarly ('feudal' and 'agrarian'), and how this led to 'egalitarian' philosophies that in turn led inexorably to Gaussian - bell-shaped - curves. From de Moivre and Bernoulli he distils that radical difference of philosophy that predicts, from that which aggregates: he uses the vaccination procedure, its odds on individual death from vaccination compared to the vaccination of the populace, to make this point. (And I can make the copy-editing point: The Turkish method was to impregnate the skin with puss from live smallpox putules from which most recipients would subsequently become immune to the disease. Apart from puss, putule, recipient, impregnate is the wrong word and subsequently is unnecessary!) difference is less important now than it was to the physicist that he was in the 1980s. He describes a variety of clinical systems - heart, locomotion, gut etc. and makes the point that homeostasis, even cybernetics, isn't enough to handle the contextual feedback in these systems. He goes on to elaborate four ways in which science (at least his science) has changed: firstly, all science was quantitative (he quotes Rutherford that if it's not, it's just stampcollecting) - but from D'Arcy Thompson to Thorn, from embryology to psychology, that can't be carried: qualitative is at least as important. Secondly, explanation came from natural via essentially linear functions - but we now realize that nearly all 'real' maths is nonlinear, and complexity studies break the links between laws and events, not least by changing scale. …
<title>0.35-micron DUV lithography for poly gate layer</title> (1994)

The evaluation of processes for 0.35 micron poly gate patterning using DUV negative resist is described. The advantages and drawbacks of negative versus positive resist, for linewidth control, are outlined. The necessity of using top or bottom anti-reflective coatings is examined. The performance of the different process schemes is compared, with regard to linewidth control over isolation topography, reflective notching control, line edge roughness, and line length control. Although the negative tone resist showed good process latitude and performed well, with regard to notching behavior, the high transmission of the resist led to unacceptable linewidth variations unless a bottom anti-reflective coating was used.
Improved hydrogeophysical characterization and monitoring through parallel modeling and inversion of time-domain resistivity andinduced-polarization data (2010)

Abstract Electrical geophysical methods have found wide use in the growing discipline of hydrogeophysics for characterizing the electrical properties of the subsurface and for monitoring subsurface processes in terms of the spatiotemporal changes in subsurface conductivity, chargeability, and source currents they govern. Presently, multichannel and multielectrode data collections systems can collect large data sets in relatively short periods of time. Practitioners, however, often are unable to fully utilize these large data sets and the information they contain because of standard desktop-computer processing limitations. These limitations can be addressed by utilizing the storage and processing capabilities of parallel computing environments. We have developed a parallel distributed-memory forward and inverse modeling algorithm for analyzing resistivity and time-domain induced polar-ization (IP) data. The primary components of the parallel computations include distributed computation of the pole solutions in forward mode, distributed storage and computation of the Jacobian matrix in inverse mode, and parallel execution of the inverse equation solver. We have tested the corresponding parallel code in three efforts: (1) resistivity characterization of the Hanford 300 Area Integrated Field Research Challenge site in Hanford, Washington, U.S.A., (2) resistivity characterization of a volcanic island in the southern Tyrrhenian Sea in Italy, and (3) resistivity and IP monitoring of biostimulation at a Superfund site in Brandywine, Maryland, U.S.A. Inverse analysis of each of these data sets would be limited or impossible in a standard serial computing environment, which underscores the need for parallel high-performance computing to fully utilize the potential of electrical geophysical methods in hydrogeophysical applications.
Distortion in Current Commutating Passive CMOS Downconversion Mixers (2009)

CMOS passive mixer linearity is analyzed using a Volterra-series analysis and closed-form expressions for IIP <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> , two-tone IIP <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sub> , and cross-modulation IIP <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sub> are presented, exhibiting dependence upon the mixer source and load impedances. Design guidelines are suggested for improving the mixer linearity performance. Accurate expressions are presented for the input impedance of an ideal passive mixer with an arbitrary load impedance. The calculations are in close agreement with the measured results and the simulated response.
Single‐Dose Administration of MK‐0657, an NR2B‐Selective NMDA Antagonist, Does Not Result in Clinically Meaningful Improvement in Motor Function in Patients With Moderate Parkinson's Disease (2009)

The glutamatergic system is thought to contribute to the motor disturbances observed in Parkinson's disease. Blockade of glutamatergic activity by a selective antagonist of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor is associated with improvement in motor symptoms in a preclinical model of Parkinson's disease. A randomized, double-blind, double-dummy, placebo-controlled, 3-period crossover study was conducted in patients with moderate Parkinson's disease to evaluate the pharmacologic activity of MK-0657, an NR2B-selective NMDA receptor antagonist. Patients (n=16) received single oral doses of MK-0657 7 mg, carbidopa/levodopa 25/250 mg (LD) as a positive control, and placebo, after which motor function was serially evaluated by means of the Unified Parkinson's Disease Rating Scale-Motor Examination (UPDRS-ME). LD administration resulted in significant improvement in the UPDRS-ME relative to placebo (P=.025), confirming the sensitivity of the test paradigm; however, the UPDRS-ME change following MK-0657 administration showed no improvement compared with placebo (P=.110) despite exceeding the target MK-0657 plasma concentration of 400 nM. Although the administration of MK-0657 was generally well tolerated, it was associated with increases in systolic and diastolic blood pressure relative to placebo. The results of this study do not support ongoing clinical development of MK-0657 as a novel monotherapy for Parkinson's disease.
Possible therapeutic reversal of immune suppression in patients with metastatic melanoma by timed delivery of temozolomide chemotherapy: A pilot study (2009)

e20013 Background: Recent evidence suggests that patients with advanced cancer exhibit an underlying anti-tumor immune response that is continuously attenuated by regulatory T cells (Treg). Depletion of Treg using conventional chemotherapy may be feasible and clinically beneficial. C-reactive protein (CRP) is reported to rise/fall with initiation/termination of the immune response, and may be a surrogate for the periodicity of Treg proliferation that could be utilized for timing of anti-proliferative therapy. Timed delivery of chemotherapy therapy based on CRP cycling may deplete Treg and yield clinical benefit. Methods: We conducted a pilot clinical for 12 patients with metastatic melanoma who underwent serial CRP measurements (every 2–3 days) for 2 weeks. The CRP oscillation cycle was identified and chemotherapy with temozolomide (200mg/m 2 for 5 days, every 28 days) was initiated at the estimated peak of plasma CRP. Patients were evaluated for clinical and immune response endpoints every 8 weeks until progression. Results: All 12 patients (median age 61; 4 female; 7 with M1c disease) exhibited oscillating CRP levels with an average periodicity of 7.8 days. Only 11 patients were treated (1 patient had rapid tumor progression). The two patients who remain progression-free for &gt;2 years (1 PR, 1 CR), were treated in the pre-peak section of the CRP cycle, distinctly separate from the other patients treated post CRP-peak (all progressed &lt;5 months). Presented are peripheral blood immunological laboratory correlates (cellular and cytokine) to CRP oscillation. Conclusions: These data suggest that patient clinical outcome may be dependent on the timing of therapy relative to an individual patient's immune response cycle and outline the dynamic equilibrium of systemic immune homeostasis in patients with advanced melanoma. Further investigations of these observations are under way. [Table: see text]
An improved picture display for NMR imaging (1976)

A display system is described which allows NMR images to be viewed on a monitor oscilloscope. Density variations in the image are displayed as intensity variations with good linearity using a new technique of Z axis time modulation.
Dietary hydrated sodium calcium aluminosilicate reduction of aflatoxin M1 residue in dairy goat milk and effects on milk production and components1 (1994)

Lactating dairy goats were exposed to aflatoxin (100 and 200 ppb) and hydrated sodium calcium aluminosilicate at 1, 2, and 4% in two separate experiments. Naturally occurring low levels of aflatoxin M1 (.009 ppb) were found in the milk of the control diet, whereas there were no detectable levels of aflatoxin M1 in the milk of diets containing hydrated sodium calcium aluminosilicate in both experiments. In Exp. 1, no treatment-related differences in clinical behavior or significant difference in the feed intake, milk production, or milk component analyses were observed with 200 ppb of aflatoxin and 4% hydrated sodium calcium aluminosilicate. However, 4% hydrated sodium calcium aluminosilicate was responsible for an 86.9% reduction of aflatoxin M1 residue in the milk of diary goats. In Exp. 2, the combination of 1% hydrated sodium calcium aluminosilicate and aflatoxin at 100 ppb resulted in an overall reduction of aflatoxin M1 residue by 51.9%, which represented a mean change of aflatoxin M1 from .553 to .266 ppb of aflatoxin M1 in the milk. The diet that contained 2% hydrated sodium calcium aluminosilicate and 100 ppb of aflatoxin further reduced aflatoxin residue by a mean change from .553 to .098 of ppb aflatoxin M1, which represents an 82.2% reduction of aflatoxin M1 residue in the milk. Analysis of the data by time indicated that there were no statistical differences between days of sampling. Information regarding the ability of hydrated sodium calcium aluminosilicate to prevent or reduce the level of aflatoxin M1 residues in milk is critically needed.(ABSTRACT TRUNCATED AT 250 WORDS)