gebhart/patrepeval huggingface dataset:
Activity of Entrectinib in a Patient With the First Reported NTRK Fusion in Neuroendocrine Cancer (2017)

Despite advances in genomic analysis, the molecular origin of neuroendocrine tumors (NETs) is complex and poorly explained by described oncogenes. The neurotrophic TRK family, including <i>NTRK</i>1, 2, and 3, encode the proteins TRKA, TRKB, TRKC, respectively, involved in normal nerve development. Because NETs develop from the diffuse neuroendocrine system, we sought to determine whether <i>NTRK</i> alterations occur in NETs and whether TRK-targeted therapy would be effective. A patient with metastatic well-differentiated NET, likely of the small intestine, was enrolled on the STARTRK2 trial (ClinicalTrials.gov identifier: NCT02568267) and tissue samples were analyzed using an RNA-Seq next-generation sequencing platform. An <i>ETV6:NTRK3</i> fusion was identified and therapy was initiated with the investigational agent entrectinib, a potent oral tyrosine kinase inhibitor of TRKA, TRKB, and TRKC. Upon treatment with entrectinib, the patient experienced rapid clinical improvement; his tumor response was characterized by initial tumor growth and necrosis. This is the first report of an <i>NTRK</i> fusion in NETs. Our patient's response to entrectinib suggests that <i>NTRK</i> fusions can be important in the pathogenesis of NETs. Recent DNA-based genomic analyses of NETs may have missed <i>NTRK</i> fusions due its large gene rearrangement size and multiple fusion partners. The tumor's initial pseudoprogression may represent a unique response pattern for TRK-targeted therapies. An effort to characterize the prevalence of <i>NTRK</i> fusions in NETs using optimal sequencing technology is important.
Activation of Resting Human Primary T Cells with Chimeric Receptors: Costimulation from CD28, Inducible Costimulator, CD134, and CD137 in Series with Signals from the TCRζ Chain (2004)

Chimeric receptors that include CD28 signaling in series with TCRzeta in the same receptor have been demonstrated to activate prestimulated human primary T cells more efficiently than a receptor providing TCRzeta signaling alone. We examined whether this type of receptor can also activate resting human primary T cells, and whether molecules other than CD28 could be included in a single chimeric receptor in series with TCRzeta to mediate the activation of resting human primary T cells. Human CD33-specific chimeric receptors were generated with CD28, inducible costimulator, CD134, or CD137 signaling regions in series with TCRzeta signaling region and transfected by electroporation into resting human primary T cells. Their ability to mediate Ag-specific activation was analyzed in comparison with a receptor providing TCRzeta signaling alone. Inclusion of any of the costimulatory signaling regions in series with TCRzeta enhanced the level of specific Ag-induced IL-2, IFN-gamma, TNF-alpha, and GM-CSF cytokine production and enabled resting primary T cells to survive and proliferate in response to Ag in the absence of any exogenous factors. Inclusion of CD28, inducible costimulator, or CD134 enhanced TCRzeta-mediated, Ag-specific target cell lysis. Chimeric receptors providing B7 and TNFR family costimulatory signals in series with TCRzeta in the same receptor can confer self-sufficient clonal expansion and enhanced effector function to resting human T cells. This type of chimeric receptor may now be used to discover the most potent combination of costimulatory signals that will improve current immunotherapeutic strategies.
A PRML system for digital magnetic recording (1992)

The realization of a digital recording system using partial-response class-IV signaling with maximum-likelihood sequence detection (MLSD) is described. To perform MLSD at the high data rates encountered in recording systems, a simple implementation of the Viterbi detector based on a difference-metric algorithm is developed. Decision-directed schemes for gain control and timing recovery, for tracking variations of the gain and timing phase during data readback, and for fast initial adjustment from a known preamble are presented. The dynamic behavior of the control algorithms was studied by computer simulations. Coding was used to facilitate timing recovery and gain control, to limit the path memory length of the Viterbi detector, and to allow fast and reliable startup of the receiver. The design and properties of rate 8/9 constrained codes are examined. The problem of equalization is addressed, and analog and combined analog/digital filter implementations are developed. A simple adaptive equalizer capable of compensating variations of the recording channel characteristics with track radius and/or head-to-medium distance is described.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Tuberculosis: Commentary on a Reemergent Killer (1992)

Tuberculosis remains the leading cause of death in the world from a single infectious disease, although there is little knowledge of the mechanisms of its pathogenesis and protection from it. After a century of decline in the United States, tuberculosis is increasing, and strains resistant to multiple antibiotics have emerged. This excess of cases is attributable to changes in the social structure in cities, the human immunodeficiency virus epidemic, and a failure in certain major cities to improve public treatment programs. The economic costs of not adequately addressing the problem of tuberculosis in this country are estimated from an epidemiological model.
The Experimental and Commercial Release of Transgenic Crop Plants (1993)

Abstract With advances in recombinant DNA methods and transformation procedures, it is possible to transfer genes into crop plants from unrelated plants, microbes and animals. Many of the modifications being carried out, or envisaged, are for disease and pest resistance, product quality and tolerance to environmental stress, but there are additional opportunities to modify crops to give specialized products for industrial or pharmaceutical use. Some of the characteristics of transgenic plants are considered, including: transgene copy number, position, expression, stability, pleiotropy, selectable marker genes and somaclonal variation. There have been several hundreds of field trials with transgenic plants, and the first transgenic varieties are likely to be approved for commercial production in 1993. Before releasing transgenic plants, it is necessary to carry out a risk assessment to determine whether the transgenic variety will behave differently from a conventionally bred variety. Assessment procedures are being harmonized internationally by various organizations. There is a growing commitment to apply these genetic modification methods to crops in developing countries, as genes relevant to their crops and environments become available.
Reduction in Connective Tissue Growth Factor by Antisense Treatment Ameliorates Renal Tubulointerstitial Fibrosis (2004)

Connective tissue growth factor (CTGF/CCN2) is one of the candidate factors mediating fibrogenic activity of TGF-beta. It was shown previously that the blockade of CTGF by antisense oligonucleotide (ODN) inhibits TGF-beta-induced production of fibronectin and type I collagen in cultured renal fibroblasts. The in vivo contribution of CTGF in renal interstitial fibrosis, however, remains to be clarified. With the use of a hydrodynamics-based gene transfer technique, the effects of CTGF antisense ODN are investigated in rat kidneys with unilateral ureteral obstruction (UUO). FITC-labeled ODN injection via the renal vein showed that the ODN was specifically introduced into the interstitium. At day 7 after UUO, the gene expression of CTGF, fibronectin, fibronectin ED-A, and alpha1(I) collagen in untreated or control ODN-treated obstructed kidneys was prominently upregulated. CTGF antisense ODN treatment, by contrast, markedly attenuated the induction of CTGF, fibronectin, fibronectin ED-A, and alpha1(I) collagen genes, whereas TGF-beta gene upregulation was not affected. The antisense treatment also reduced interstitial deposition of CTGF, fibronectin ED-A, and type I collagen and the interstitial fibrotic areas. The number of myofibroblasts determined by the expression of alpha-smooth muscle actin was significantly decreased as well. Proliferation of tubular and interstitial cells was not altered with the treatment. These findings indicate that CTGF expression in the interstitium plays a crucial role in the progression of interstitial fibrosis but not in the proliferation of tubular and interstitial cells during UUO. CTGF may become a potential therapeutic target against tubulointerstitial fibrosis.
Structure-Based Design of a Bispecific Receptor Mimic That Inhibits T Cell Responses to a Superantigen (2001)

Key surface proteins of pathogens and their toxins bind to the host cell receptors in a manner that is quite different from the way the natural ligands bind to the same receptors and direct normal cellular responses. Here we describe a novel strategy for "non-antibody-based" pathogen countermeasure by targeting the very same "alternative mode of host receptor binding" that the pathogen proteins exploit to cause infection and disease. We have chosen the Staphylococcus enterotoxin B (SEB) superantigen as a model pathogen protein to illustrate the principle and application of our strategy. SEB bypasses the normal route of antigen processing by binding as an intact protein to the complex formed by the MHC class II receptor on the antigen-presenting cell and the T cell receptor. This alternative mode of binding causes massive IL-2 release and T cell proliferation. A normally processed antigen requires all the domains of the receptor complex for its binding, whereas SEB requires only the alpha1 subunit (DRalpha) of the MHC class II receptor and the variable beta subunit (TCRVbeta) of the T cell receptor. This prompted us to design a bispecific chimera, DRalpha-linker-TCRVbeta, that acts as a receptor mimic and prevents the interaction of SEB with its host cell receptors. We have adopted (GSTAPPA)(2) as the linker sequence because it supports synergistic binding of DRalpha and TCRVbeta to SEB and thereby makes DRalpha-(GSTAPPA)(2)-TCRVbeta as effective an SEB binder as the native MHC class II-T cell receptor complex. Finally, we show that DRalpha-(GSTAPPA)(2)-TCRVbeta inhibits SEB-induced IL-2 release and T cell proliferation at nanomolar concentrations.
MAPbI3-xClx Mixed Halide Perovskite for Hybrid Solar Cells: The Role of Chloride as Dopant on the Transport and Structural Properties (2013)

Hybrid halide perovskites represent one of the most promising solutions toward the fabrication of all solid nanostructured solar cells, with improved efficiency and long-term stability. This article aims at investigating the structural properties of iodide/chloride mixed-halide perovskites and correlating them with their photovoltaic performances. We found out that, independent of the components ratio in the precursor solution, Cl incorporation in an iodide-based structure, is possible only at relatively low concentration levels (below 3–4%). However, even if the material band gap remains substantially unchanged, the Cl doping dramatically improves the charge transport within the perovskite layer, explaining the outstanding performances of meso-superstructured solar cells based on this material.
An interface circuit for measuring capacitance changes based upon capacitance-to-duty cycle (CDC) converter (2005)

We present a direct-to-digital capacitive sensor readout circuit that converts capacitance changes of a sensor element to changes of the duty cycle of a square-wave oscillator, which, in turn, is converted to a digital output by a counter. The readout circuit resembles a single-slope analog-to-digital converter structure. There are several advantages of this readout scheme. First, due to its simplicity and low number of components, the power consumption of the circuit is expected to be significantly smaller than in similar digital readout designs. Furthermore, linearization of the output may be achieved using an EEPROM lookup table. Another advantage is the possibility of performing adaptive measurements where the sensor resolution and bandwidth may be changed via the readout circuit software. Finally, we present a theory of the adaptive measurement and an analysis of the design tradeoffs. The capacitance-to-duty cycle readout circuit may achieve large bandwidth and high resolution in a modern low-voltage, low-power CMOS implementation. The performance of a prototype readout circuit built from discrete components is 13-bit effective resolution with a 1-kHz bandwidth.
Macrophage cytotoxicity produced by adenylate cyclase toxin from Bordetella pertussis: more than just making cyclic AMP! (2005)

The cytotoxic effect of adenylate cyclase (AC) toxin from Bordetella pertussis on host cells has been attributed to the production of supraphysiologic levels of cyclic AMP by the toxin. We have tested this hypothesis and show that at least two different mechanisms, cAMP accumulation/ATP depletion and oligomerization/pore formation, contribute, perhaps synergistically, to AC toxin-induced cytotoxicity. Wild-type (WT) AC toxin causes cell death associated with an increase in cAMP, a reduction in ATP, activation of caspases 3/7, and increased annexin V and TUNEL staining. In contrast, a non-acylated, enzymatically active, non-haemolytic form of AC toxin is able to increase cAMP, reduce ATP and elicit annexin V staining, but the decrease in ATP and the annexin staining are transient and there is minimal caspase activation, TUNEL staining and cell death. Mutant AC toxins defective in either enzymatic activity or the ability to deliver their enzymatic domain are able to kill J774 cells, without cAMP production, and with minimal caspase activation and TUNEL staining. Comparison of the potencies of WT toxin and those of mutants that only increase cAMP or only create transmembrane pores establishes that at least two mechanisms are contributory and that simply the production of cAMP is not enough to account for the cytotoxicity produced by AC toxin.
Multiplexed Illumina sequencing libraries from picogram quantities of DNA (2013)

Application of this method allows whole genome studies from samples where material or yields are limiting.
Construction of Yeast Strains with High Cell Surface Lipase Activity by Using Novel Display Systems Based on the Flo1p Flocculation Functional Domain (2002)

We constructed a novel cell-surface display system, using as a new type of cell-wall anchor 3,297 or 4,341 bp of the 3' region of the FLO1 gene (FS or FL gene, respectively), which encodes the flocculation functional domain of Flo1p. In this system, the N terminus of the target protein was fused to the FS or FL protein and the fusion proteins were expressed under the control of the inducible promoter UPR-ICL (5' upstream region of the isocitrate lyase of Candida tropicalis). Using this new system, recombinant lipase with a pro sequence from Rhizopus oryzae (rProROL), which has its active site near the C terminus, was displayed on the cell surface. Cell-surface display of the FSProROL and FLProROL fusion proteins was confirmed by immunofluorescence microscopy and immunoblotting. Lipase activity reached 145 IU/liter (61.3 IU/g [dry cell weight]) on the surface of the yeast cells, which successfully catalyzed the methanolysis reaction. Using these whole-cell biocatalysts, methylesters synthesized from triglyceride and methanol reached 78.3% after 72 h of reaction. To our knowledge, this is the first example of cell-surface display of lipase with high activity. Interestingly, the yeast cells displaying the FLProROL protein showed strong flocculation, even though the glycosylphosphatidylinositol anchor attachment signal and cell-membrane-anchoring region of Flo1p had been deleted from this gene. The cell-surface display system based on FL thus endows the yeast strain with both novel enzyme display and strong flocculation ability.
Immune Responses to Mycobacterial Antigens in the Gambian Population: Implications for Vaccines and Immunodiagnostic Test Design (2003)

Recombinant immunodominant mycobacterial antigens are needed for the development of new vaccines and immunodiagnostic tools for use against tuberculosis. Ubiquitous exposure to mycobacteria in tropical countries could influence vaccine-induced immunity and the specificity of tuberculosis immunodiagnosis. For this study conducted in The Gambia, cellular immune responses to recombinant mycobacterial antigens were characterized in Mycobacterium bovis BCG-vaccinated and nonvaccinated infants, adult community controls, household contacts, health care workers, and tuberculosis patients. Neonatal BCG vaccination induced gamma interferon (IFN-gamma) responses to Mtb8.4, Mtb32-C, Mtb39A, Mtb9.9A, and Mtb32-N, but not CFP-10 (Mtb11) and alpha-crystallin (Mtb16). Exposure to Mycobacterium tuberculosis in household contacts and health care workers was associated with high responses to CFP-10 and alpha-crystallin. Generally, low IFN-gamma responses were found in tuberculosis patients. These results suggest that Mtb8.4, Mtb32-C, Mtb39A, Mtb9.9A, and Mtb32-N may be used in a subunit vaccine to boost BCG-induced immunity. While CFP-10 and alpha-crystallin are promising candidates for the immunodiagnosis of M. tuberculosis infection or for vaccine use, disease-associated immunosuppression may prevent IFN-gamma immunodiagnosis of more advanced tuberculosis.
Lactococcus lactis: high‐level expression of tetanus toxin fragment C and protection against lethal challenge (1993)

To determine if the food-grade bacterium Lactococcus lactis holds promise as a vaccine antigen delivery vector we have investigated whether this bacterium can be made to produce high levels of a heterologous protein antigen. A regulated expression system has been developed which may be generally suitable for the expression of foreign antigens (and other proteins) in L. lactis. The system utilizes the fast-acting T7 RNA polymerase to transcribe target genes, and provides the first example of the successful use of this polymerase in a Gram-positive bacterium. When the performance of the expression system was characterized using tetanus toxin fragment C (TTFC) up to 22% of soluble cell protein was routinely obtained as TTFC. Mice immunized subcutaneously with L. lactis expressing TTFC were protected from lethal challenge with tetanus toxin. These results show for the first time that L. lactis is able to express substantial quantities of a heterologous protein antigen and that this organism can present this antigen to the immune system in an immunogenic form.
T-Cell Receptor–Transduced T Cells (2015)

The large number of T-cell epitopes that have been found to be processed and presented on human tumors, now numbering in the hundreds, provides a rich source of targets for therapeutic interventions aimed at inducing durable tumor regression. Vaccination strategies aimed at inducing responses to these antigens have been largely ineffective, and it has been challenging to generate large numbers of T cells with the functional capacity to mediate durable tumor regressions in adoptive immunotherapy strategies in patients who have common epithelial malignancies. The ability to generate T-cell receptors that recognize shared as well as unique antigens expressed in a wide variety of common tumor types that include lung, breast, ovarian, gastrointestinal, urothelial, and genitourinary cancers provides an opportunity to develop widely applicable therapies based on the adoptive transfer of autologous T cells transduced with those receptors.
Single Protein Pores Containing Molecular Adapters at High Temperatures (2005)

Hitzeresistent: Die Messung des Stroms durch einzelne Proteinporen nahe 100 °C zeigt, dass der molekulare Adapter β-Cyclodextrin (rot) auch bei hohen Temperaturen in der α-Hämolysin-Pore gebunden bleibt und seine Fähigkeit zur Bindung von Gastmolekülen (schwarz) behält. Diese Ergebnisse könnten Einzelmoleküluntersuchungen und die Entwicklung stochastischer Sensoren erleichtern.
Integrated Simulation Flow for Self-Consistent Manufacturability and Circuit Performance Evaluation (2005)

In this work we present an application of a novel DFM (Design For Manufacturability) simulation flow, which self-consistently predicts the impact of the manufacturing process on electrical circuit behavior. We apply our methodology to the design of a 2x2 AND-OR standard cell to show its effectiveness. We show that process distortions significantly impact both DC and transient circuit-behavior, and have to be considered for accurate timing analysis, prediction of IDDQ and other circuit characteristics. Intrinsic process variability and process excursions cause additional deviation from design intent and therefore performance issues and potential yield losses. This work extends and generalizes concepts introduced in [1-2] and presents an integrated implementation of a self-consistent simulation flow [3] which provides unique insight into process-design interactions.
Holographic polarization-separation elements (1994)

Volume holographic optical elements exhibit a property that we call bidiffringence, in which the diffraction efficiency of the element is strongly dependent on the polarization of the incident beam. Dualelement, volume holographic polarization separators utilizing bidiffringence can provide high extinction ratios, and they can provide greater angular separation of the polarized beams and greater flexibility in the beam-separation parameters than conventional birefringent elements. We designed and constructed holographic polarization separators using dichromated gelatin as the holographic medium. Experimental results are compared with the results predicted by the Kogelnik coupled wave theory.
Single versus Double Autologous Stem-Cell Transplantation for Multiple Myeloma (2003)

As compared with a single autologous stem-cell transplantation after high-dose chemotherapy, double transplantation improves overall survival among patients with myeloma, especially those who do not have a very good partial response after undergoing one transplantation.
δ-elimination in the repair of AP (apurinic/apyrimidinic) sites in DNA (1989)

[5'-32P]pdT8d(-)dT7, containing an AP (apurinic/apyrimidinic) site in the ninth position, and [d(-)-1',2'-3H, 5'-32P]DNA, containing AP sites labelled with 3H in the 1' and 2' positions of the base-free deoxyribose [d(-)] and with 32P 5' to this deoxyribose, were used to investigate the yields of the beta-elimination and delta-elimination reactions catalysed by spermine, and also the yield of hydrolysis, by the 3'-phosphatase activity of T4 polynucleotide kinase, of the 3'-phosphate resulting from the beta delta-elimination. Phage-phi X174 RF (replicative form)-I DNA containing AP (apurinic) sites has been repaired in five steps: beta-elimination, delta-elimination, hydrolysis of 3'-phosphate, DNA polymerization and ligation. Spermine, in one experiment, and Escherichia coli formamidopyrimidine: DNA glycosylase, in another experiment, were used to catalyse the first and second steps (beta-elimination and delta-elimination). These repair pathways, involving a delta-elimination step, may be operational not only in E. coli repairing its DNA containing a formamido-pyrimidine lesion, but also in mammalian cells repairing their nuclear DNA containing AP sites.