gebhart/patrepeval huggingface dataset:
Hedgehog signaling pathway and its targets for treatment in basal cell carcinoma (2012)

Basal cell carcinoma (BCC) of the skin is the most common type of cancer and accounts for up to 40% of all cancers in the US, with a growing incidence rate over recent decades in all developed countries. Surgery is curative for most patients, although it leaves unaesthetic scars, but those that develop locally advanced or metastatic BCC require different therapeutic approaches. Furthermore, patients with BCC present a high risk of developing additional tumors. The increasing economic burden and the morbidity of BCC render primary interest in the development of targeted treatments for this disease. Among the molecular signals involved in the development of BCC, the critical role of the morphogenetic Hedgehog (Hh) pathway has become evident. This pathway is found altered and activated in almost all BCCs, both sporadic and inherited. Given the centrality of the Hh pathway in the pathophysiology of BCC, the primary efforts to identify molecular targets for the topical or systemic treatment of this cancer have focused on the Hh components. Several Hh inhibitors have been so far identified - from the first identified natural cyclopamine to the recently Food and Drug Administration-approved synthetic vismodegib - most of which target the Hh receptor Smoothened (either its function or its translocation to the primary cilium). Other molecules await further characterization (bisamide compounds), while drugs currently approved for other diseases such as itraconazole (an antimicotic agent) and vitamin D3 have been tested on BCC with encouraging results. The outcomes of the numerous ongoing clinical trials are expected to expand the field in the very near future. Further research is needed to obtain drugs targeting downstream components of the Hh pathway (eg, Gli) or to exploit combinatorial therapies (eg, with phosphatidylinositol 3-kinase inhibitors or retinoids) in order to overcome potential drug resistance.
Directed and enhanced neurite growth with pulsed magnetic field stimulation (2000)

Pulsed magnetic field (PMF) stimulation was applied to mammalian neurons in vitro to influence axonal growth and to determine whether induced current would direct and enhance neurite growth in the direction of the current. Two coils were constructed from individual sheets of copper folded into a square coil. Each coil was placed in a separate water-jacketed incubator. One was energized by a waveform generator driving a power amplifier, the other was not energized. Whole dorsal root ganglia (DRG) explant cultures from 15-day Sprague-Dawley rat embryos were established in supplemented media plus nerve growth factor (NGF) at concentrations of 0-100 ng/mL on a collagen-laminin substrate. Dishes were placed at the center of the top and bottom of both coils, so that the DRG were adjacent to the current flowing in the coil. After an initial 12 h allowing DRG attachment to the substrate floor, one coil was energized for 18 h, followed by a postexposure period of 18 h. Total incubation time was 48 h for all DRG cultures. At termination, DRG were histochemically stained for visualization and quantitative analysis of neurite outgrowth. Direction and length of neurite outgrowth were recorded with respect to direction of the current. PMF exposed DRG exhibited asymmetrical growth parallel to the current direction with concomitant enhancement of neurite length. DRG cultures not PMF exposed had a characteristic radial pattern of neurite outgrowth. These results suggest that PMF may offer a noninvasive mechanism to direct and promote nerve regeneration.
Costimulation Through the CD137/4-1BB Pathway Protects Human Melanoma Tumor-infiltrating Lymphocytes From Activation-induced Cell Death and Enhances Antitumor Effector Function (2011)

Adoptive T-cell therapy (ACT) using expanded tumor-infiltrating lymphocytes (TIL) with high-dose interleukin-2 is a promising form of immunotherapy for stage IV melanoma having clinical response rates of 50% or more. One of the major problems preventing further success of this therapy is that the current protocols used to highly expand TIL for infusion drive CD8(+) T cells to differentiate into effector cells losing key costimulatory molecules such as CD28 and CD27. This has been associated with a lack of persistence in vivo for reasons not entirely clear. In this study, we demonstrate that while human melanoma CD8(+) TIL lost CD27 and CD28 expression during the rapid expansion for ACT, they gained expression of the alternative costimulatory molecule CD137/4-1BB, and to a lesser extent CD134/OX40. Postrapid expansion protocol (REP) TIL were found to be highly sensitive to activation-induced cell death when reactivated through the T-cell receptor with low levels of OKT3 antibody. However, coligation of 4-1BB using 2 different agonistic anti-4-1BB antibodies potently prevented activation-induced cell death of post-REP CD8(+) TIL, including those specific for melanoma antigen recognized by T cells, and facilitated even further cell expansion. This was correlated with increased levels of bcl-2 and bcl-xL together with decreased bim expression. 4-1BB costimulated post-REP TIL also expressed increased levels of the cytolytic granule proteins and exhibited enhanced cytotoxic T-cell activity against melanoma cells. Lastly, post-REP CD8(+) TIL were protected from cell death by anti-4-1BB ligation when exposed to human leukocyte antigen-matched melanoma cells. Our results indicate that 4-1BB costimulation may significantly improve TIL survival during melanoma ACT and boost antitumor cytolytic activity.
Universal quantum computation in a semiconductor quantum wire network (2010)

Universal quantum computation (UQC) using Majorana fermions on a two-dimensional topological superconducting (TS) medium remains an outstanding open problem. This is because the quantum gate set that can be generated by braiding of the Majorana fermions does not include any two-qubit gate and also no single-qubit $\ensuremath{\pi}/8$ phase gate. In principle, it is possible to create these crucial extra gates using quantum interference of Majorana fermion currents. However, it is not clear if the motion of the various order parameter defects (vortices, domain walls, etc.), to which the Majorana fermions are bound in a TS medium, can be quantum coherent. We show that these obstacles can be overcome using a semiconductor quantum wire network in the vicinity of an $s$-wave superconductor, by constructing topologically protected two-qubit gates and any arbitrary single-qubit phase gate in a topologically unprotected manner, which can be error corrected using magic-state distillation. Thus our strategy, using a judicious combination of topologically protected and unprotected gate operations, realizes UQC on a quantum wire network with a remarkably high error threshold of $0.14$ as compared to ${10}^{\ensuremath{-}3}$ to ${10}^{\ensuremath{-}4}$ in ordinary unprotected quantum computation.
A feather-weight virtual machine for windows applications (2006)

Many fault-tolerant and intrusion-tolerant systems require the ability to execute unsafe programs in a realistic environment without leaving permanent damages. Virtual machine technology meets this requirement perfectly because it provides an execution environment that is both realistic and isolated. In this paper, we introduce an OS level virtual machine architecture for Windows applications called Feather-weight Virtual Machine (FVM), under which virtual machines share as many resources of the host machine as possible while still isolated from one another and from the host machine. The key technique behind FVM is namespace virtualization, which isolates virtual machines by renaming resources at the OS system call interface. Through a copy-on-write scheme, FVM allows multiple virtual machines to physically share resources but logically isolate their resources from each other. A main technical challenge in FVM is how to achieve strong isolation among different virtual machines and the host machine, due to numerous namespaces and interprocess communication mechanisms on Windows. Experimental results demonstrate that FVM is more flexible and scalable, requires less system resource, incurs lower start-up and run-time performance overhead than existing hardware-level virtual machine technologies, and thus makes a compelling building block for security and fault-tolerant applications.
Twists and Turns of the Cation-dependent Mannose 6-Phosphate Receptor (2002)

Mannose 6-phosphate receptors (MPRs) participate in the biogenesis of lysosomes in higher eukaryotes by transporting soluble acid hydrolases from the trans-Golgi network to late endosomal compartments. The receptors release their ligands into the acidic environment of the late endosome and then return to the trans-Golgi network to repeat the process. However, the mechanism that facilitates ligand binding and dissociation upon changes in pH is not known. We report the crystal structure of the extracytoplasmic domain of the homodimeric cation-dependent MPR in a ligand-free form at pH 6.5. A comparison of the ligand-bound and ligand-free structures reveals a significant change in quaternary structure as well as a reorganization of the binding pocket, with the most prominent change being the relocation of a loop (residues Glu(134)-Cys(141)). The movements involved in the bound-to-free transition of the cation-dependent MPR are reminiscent of those of the oxy-to-deoxy hemoglobin transition. These results allow us to propose a mechanism by which the receptor regulates its ligand binding upon changes in pH; the pK(a) of Glu(133) appears to be responsible for ligand release in the acidic environment of the late endosomal compartment, and the pK(a) values of the sugar phosphate and His(105) are accountable for its inability to bind ligand at the cell surface where the pH is about 7.4.
Identification of Novel TSH Interaction Sites by Systematic Binding Analysis of the TSHR Hinge Region (2011)

In which ways the binding of the thyroid stimulating hormone to the extracellular domain of its receptor leads to activation of the thyroid-stimulating hormone receptor (TSHR) is currently only incompletely understood. It is known that TSH binding to the TSHR depends on the interaction with the leucine-rich repeat and sulfation at Y385 of the hinge region. Recently it was also shown that electrostatic interactions between positive charges of bovine (b) TSH and the residues E297, E303, and D382 of the hinge region contribute to hormone-TSHR binding. After the identification of these first TSH binding sites in the hinge region, it was apparent that multiple positions in this region remained to be characterized for their roles in hormone binding. The goal of this study was therefore to clarify whether further contact points of TSH exist in the structurally undefined hinge region. Therefore, we systematically analyzed 41 uncharacterized residues of the TSHR hinge region as single mutants regarding differences between cell surface expression and bTSH binding. Indeed, we identified further amino acids of the hinge region with influence on bTSH binding. Some of these contribute to a new binding domain from human TSHR position F381 to D386. These hinge mutants with influence on bTSH binding were also analyzed for binding of the superagonistic human TSH analog TR1401 demonstrating that these positions also have an impact on TR1401 binding. Moreover, side chain variations revealed that different amino acid properties like the negative charge, aromatic as well as hydrophilic characteristics, contribute to maintain the hormone-TSHR hinge interaction.
Induction and Isolation of Vascular Cells From Human Induced Pluripotent Stem Cells—Brief Report (2009)

We succeeded in inducing and isolating human vascular cells from iPS cells and indicate that the properties of human iPS cell differentiation into vascular cells are nearly identical to those of hES cells. This work will contribute to our understanding of human vascular differentiation/development and to the development of vascular regenerative medicine.
Reduction in faecal excretion ofSalmonella typhimuriumstrain F98 in chickens vaccinated with live and killedS. typhimuriumorganisms (1990)

SUMMARY Chickens given orally at 4 days of age a smooth spectinomycin resistant mutant (Spc r ) of Salmonella typhimurium strain F98 excreted the organism in their faeces for approximately 4 weeks. Following oral administration of a nalidixic acid resistant (Nal r ) mutant of the same strain 4 weeks later when later when the chickens had virtually cleared themselves of the first infection, these chickens excreted far fewer salmonella organisms and for a shorter time than did a previously uninfected control group of chickens which were infected at the same time with the Nal r mutant. Chickens inoculated intramuscularly at 4 days developed a similar immunity to challenge and also excreted the immunizing strain in their faeces. In contrast intramuscular inoculation or incorporation into the food of formalin-killed S. typhimurium organisms had little lasting effect on the faecal excretion of the challenge strain. Two attenuated mutants of strain F98 Nal r were produced: one was a rough strain produced by lytic bacteriophage and the other was an aro A auxotrophic mutant which had been cured of the 85 kilobase–pair virulence–associated plasmid. These mutants were avirulent for chickens, mice, calves and man and when ingested by human volunteers did not persist in the faeces. When inoculated intramuscularly into chickens they produced an early reduction in faecal excretion of the challenge strain (Spc r ) which was not maintained. Oral administration of both strains produced reductions in faecal excretion of the challenge strain. This was much more noticeable with the rough strain which was itself excreted for a much longer period than the parent strain.
SEQUENTIAL MECHANISMS IN THE ENHANCED ABSORPTION OF VITAMIN B12 BY INTRINSIC FACTOR IN THE RAT* (1960)

Pernicious anemia, a clinical state of vitamin B12 deficiency, is characterized by a virtually complete absence of gastric intrinsic factor secretion, result- ing in marked inability of the patient to absorb the low concentrations of vitamin B12 present in usual dietary sources. Intrinsic factor deficiency is also produced by total gastrectomy in the rat and, as in the patient, can be temporarily abolished by the oral administration of intrinsic factor. A number of facts concerning the nature and function of in- trinsic factor have been discovered by observations on patients (1-2) and, recently, on gastrectomized rats (3-5).
Mechanisms of photophysical processes and photochemical reactions in polymers: Theory and applications (1987)

Electronically Excited States Electronic Energy Transfer Processes Excimers and Exciplexes Application of Luminescence Spectroscopy in Polymers Photoinitiated Polymerizations Photochemistry of Solvents Photochemistry of Photoinitiators and Photosensitizers Photomodification of Polymer Surfaces Photocycloaddition Reactions Photochromic Polymers Photocrosslinking of Polymers Photoreactive Polymers in Image Formation Photocuring Photodegradation of Polymers Photostabilization of Polymers Polymeric Systems in Solar Energy Conversion.
Nanoliposomal irinotecan and metronomic temozolomide for patients with recurrent glioblastoma: BrUOG329, a phase IB/IIA Brown University Oncology Research Group (BrUOG) trial. (2020)

e14548 Background: Nanoliposomal irinotecan (nal-IRI)) is a novel formulation of irinotecan, encapsulating drug molecules within long-circulating liposome-based nanoparticles with resulting favorable pharmacokinetic and biodistribution properties. Nanoliposomes improve the solubility and bioavailability of drugs and potentially increase their ability to cross the blood brain barrier. We performed a phase I study to determine the maximum tolerated dose (MTD) and preliminary efficacy of nal-IRI in combination with metronomic temozolomide (TMZ) in patients with recurrent glioblastoma. Methods: Patients with recurrent glioblastoma who had progressed after at least 1 line of therapy with a KPS of &gt; 60 were eligible. All patients received TMZ 50 mg/m 2 PO daily with nal-IRI IV every 2 weeks until disease progression. Three dose levels of nal-IRI were planned, 50 mg/m 2 , 70 mg/m 2 and 80 mg/m 2 . Dose limiting toxicities (DLTs) were defined as those occurring during the first 2 cycles (28 days) of treatment. Patients were accrued in a 3+3 design. Accrual at the MTD level was to be expanded to 25 patients, unless the study was terminated early if 0-1 responses were observed in the first 13 evaluable patients. Results: Twelve patients were treated over 2 dose levels (nal-IRI 50-70 mg/m 2 ). At dose level 2, nal-IRI 70mg/m 2 , 2 of 3 patients developed DLTs, including one patient who developed grade 4 neutropenia, grade 2 diarrhea and grade 3 anorexia and one patient with grade 3 diarrhea, grade 3 hypokalemia and grade 3 anorexia. Accrual at nal-IRI 50 mg/m 2 , defined as the MTD, was expanded to 9 patients. Treatment-related toxicities at this dose level included grade 3 ALT (N = 1). As there were no responses seen in the initial 12 patients (0/12, 0%), the BrUOG Data Safety Monitoring Board terminated the study. Conclusions: The MTD of nal-IRI was 50 mg/m 2 every 2 weeks with TMZ 50mg/m 2 /day. DLTs were grade 3 diarrhea and anorexia. No antitumor activity was seen in the first 12 patients and the study was terminated. Clinical trial information: NCT03119064.
Surface Modification of Poly(methyl methacrylate) Used in the Fabrication of Microanalytical Devices (2000)

We report here the chemical modification of poly(methyl methacrylate) (PMMA) surfaces by their reaction with the monoanion of alpha,omega-diaminoalkanes (aminolysis reaction) to yield amine-terminated PMMA surfaces. It is found that the amine functionalities are tethered to the PMMA backbone through an alkane bridge to amide bonds formed during the aminolysis of the surface ester functionalities. The distribution of the amine termini is quite uniform as judged by fluorescence micrographs. It is found that the electroosmotic flow in aminated PMMA microchannels is reversed when compared to that in unmodified channels. In addition, it is demonstrated that enzymes can be immobilized onto the amine-terminated PMMA surfaces and are effective in the restriction digestion of dsDNAs. Finally, the availability of the surface amine groups is further demonstrated by their reaction with n-octadecane-1-isocyanate to form PMMA surfaces terminated with well-ordered and highly crystalline octadecane chains.
A test-bed for the dynamic adaptive streaming over HTTP featuring session mobility (2011)

In this paper, we present a multimedia test-bed enabling session mobility in the context of the emerging ISO/IEC MPEG standard, Dynamic Adaptive Streaming over HTTP (DASH). In general, session mobility is defined as the transfer of a running streaming session from one device to another device where it may need to be consumed in an adaptive way. The two main challenges are: (1) taking into account the new context of the device (e.g., capabilities) to which the session is transferred and (2) performing the actual transfer in a seamless and interoperable way. Our system addresses both challenges supported by a prototype implementation integrated into VLC. In anticipation of the results we can conclude that interoperability is achieved adopting existing standards while the performance of the system does not depend on these standards. That is, the modules responsible for the performance are usually not defined within such standards and left out for competition. However, our system is designed in an extensible way and is able to accommodate this fact.
Soporte vital avanzado en el adulto: Recomendaciones ILCOR 2010 (2ª parte) (2011)

Como comentamos en la primera parte, el Soporte Vital Avanzado (SVA) es uno de los eslabones de la cadena de supervivencia que incluye acciones encaminadas a prevenir, tratar y mejorar la supervivencia de los pacientes que sufren una Parada Cardiaca (PCR) (alrededor de 7,6% al alta hospitalaria.
The Broadly Neutralizing Anti-Human Immunodeficiency Virus Type 1 Antibody 2G12 Recognizes a Cluster of α1→2 Mannose Residues on the Outer Face of gp120 (2002)

2G12 is a broadly neutralizing human monoclonal antibody against human immunodeficiency virus type-1 (HIV-1) that has previously been shown to bind to a carbohydrate-dependent epitope on gp120. Here, site-directed mutagenesis and carbohydrate analysis were used to define further the 2G12 epitope. Extensive alanine scanning mutagenesis showed that elimination of the N-linked carbohydrate attachment sequences associated with residues N295, N332, N339, N386, and N392 by N-->A substitution produced significant decreases in 2G12 binding affinity to gp120(JR-CSF). Further mutagenesis suggested that the glycans at N339 and N386 were not critical for 2G12 binding to gp120(JR-CSF). Comparison of the sequences of isolates neutralized by 2G12 was also consistent with a lesser role for glycans attached at these positions. The mutagenesis studies provided no convincing evidence for the involvement of gp120 amino acid side chains in 2G12 binding. Antibody binding was inhibited when gp120 was treated with Aspergillus saitoi mannosidase, Jack Bean mannosidase, or endoglycosidase H, indicating that Man(alpha)1-->2Man-linked sugars of oligomannose glycans on gp120 are required for 2G12 binding. Consistent with this finding, the binding of 2G12 to gp120 could be inhibited by monomeric mannose but not by galactose, glucose, or N-acetylglucosamine. The inability of 2G12 to bind to gp120 produced in the presence of the glucose analogue N-butyl-deoxynojirimycin similarly implicated Man(alpha)1-->2Man-linked sugars in 2G12 binding. Competition experiments between 2G12 and the lectin cyanovirin for binding to gp120 showed that 2G12 only interacts with a subset of available Man(alpha)1-->2Man-linked sugars. Consideration of all the data, together with inspection of a molecular model of gp120, suggests that the most likely epitope for 2G12 is formed from mannose residues contributed by the glycans attached to N295 and N332, with the other glycans playing an indirect role in maintaining epitope conformation.
Nitric Oxide Activation of Poly(ADP-Ribose) Synthetase in Neurotoxicity (1994)

Poly(adenosine 5'-diphosphoribose) synthetase (PARS) is a nuclear enzyme which, when activated by DNA strand breaks, adds up to 100 adenosine 5'-diphosphoribose (ADP-ribose) units to nuclear proteins such as histones and PARS itself. This activation can lead to cell death through depletion of beta-nicotinamide adenine dinucleotide (the source of ADP-ribose) and adenosine triphosphate. Nitric oxide (NO) stimulated ADP-ribosylation of PARS in rat brain. Benzamide and other derivatives, which inhibit PARS, blocked N-methyl-D-aspartate- and NO-mediated neurotoxicity with relative potencies paralleling their ability to inhibit PARS. Thus, NO appeared to elicit neurotoxicity by activating PARS.
Nontumoral, benign ad malignant stages of transformation of a diploid pig cell line. A review. (1981)

The PFT cell line originated from diploid endometrial cells and was subcultured more than 500 times. Nontumoral, benign and malignant transformation appeared at different stages. Four populations (F1, F2, F3 and F4) of cells were demonstrated sequentially by chromosomes analysis. These consisted of eight phenotypes corresponding to the sequential appearance of markers which included three chromosomal aberrations. The PFT malignant transformation in vitro is a progressive process through qualitatively different stages and may reflect neoplastic development in vivo. It is suggested that the benign and malignant transformations were under separate genetic control since they occurred after two chromosomal translocations on two different chromosomes. The spontaneous expression of a pig endogenous type-C virus which occurred concomitantly with the first translocation appeared to be related to oncogenesis.