gebhart/patrepeval huggingface dataset:
Tumor necrosis factor, lymphotoxin and cancer (2010)

Initially TNF has been discovered as an anti-tumor factor, but it is now considered as one of the universal effectors of innate signaling implicating its key role in host defense and inflammation. Other physiological functions of TNF are primarily linked to organization of lymphoid tissues. TNF can exert deleterious effects on the organism when its local or systemic concentrations exceed certain levels. This is the main reason for the failure of TNF therapy in oncology. Moreover, in certain experimental models TNF to TNFRp55 signaling axis was found to play a pro-tumorigenic role. On the other hand, anti-TNF therapy proved to be beneficial in rheumatic and other autoimmune diseases. Taking into consideration the pivotal function of TNF in the immune system, it is obvious that such therapy cannot be entirely free of adverse effects including suppression of host defense and, possibly, predisposition to lymphomas. Lymphotoxins alpha and beta are the two related cytokines that exist in distinct trimeric forms which can signal through TNFR I and TNFR II, as well LTbetaR receptors, depending on the composition of the trimer. These signals have important functions in the development and homeostasis of the immune system. Importantly, there is a recently uncovered link between the LTalpha/LTbeta to LTbetaR signaling axis and cancer. Here we review the current status of the field with the focus on one particular issue: are TNF and lymphotoxins intrinsically anti-cancer or pro-tumorigenic.
Wetting Behavior of Block Copolymers on Self-Assembled Films of Alkylchlorosiloxanes:  Effect of Grafting Density (2000)

The wetting behavior of thin films of symmetric poly(styrene-b-methyl methacrylate) was investigated on self-assembled (SA) films of octadecyltrichlorosilane on Si/SiOx with varying grafting density. The different types of SA organic films were produced by changing the deposition times (t) in solution. Two types of wetting behavior were observed on partial self-assembled monolayers (SAMs); 8 Å < thickness < 23 Å): (1) for short deposition times with t = 1−10 h, asymmetric wetting with the poly(methyl methacrylate) block wetting the substrate, and (2) for t = 12 h, neutral wetting with lamellae oriented perpendicular to the substrate. For t = 21−24 h, the polymer films dewet complete SAMs (thickness = 26 Å (the theoretical thickness for a complete SAM)). A metastable morphology of symmetric wetting with the polystyrene block wetting the substrate was observed on SA films with long deposition times, greater than 30 h (28 Å < thickness < 36 Å). The different wetting behavior of the block copolymer films on the different types of SA films was determined to depend on the chemistry and structure of the surface. These results have important implications regarding the use of SAMs of alkylsiloxanes to control the wetting behavior of block copolymers for patterning applications.
Coordinate increase in major transcripts from the high pI alpha-amylase multigene family in barley aleurone cells stimulated with gibberellic acid. (1984)

The purpose of this study was to identify specifically genes and transcripts for the high pI isozyme of barley alpha-amylase. From hybridization of coding sequence probes to blots of genomic DNA digested with restriction enzymes that do not cut within our cloned high pI alpha-amylase cDNA, it is estimated that about 7 alpha-amylase genes or pseudogenes exist. No difference could be detected between barley aleurone cell and sprout DNAs. Experiments using probes from the 5' and 3' untranslated sequences of the high pI alpha-amylase cDNA clone identified three HindIII fragments that probably carry high pI sequences. Primer extension experiments used as a primer the terminal 5' coding sequence from our cDNA clone; this primer would not cross-hybridize to low pI alpha-amylase transcripts. Two major transcripts were identified. These shared a conserved 23-base sequence immediately 5' to the ATG start codon, although a C----G transversion and a 3-base deletion were present within this sequence. An unusual 8-base pair GC palindrome was present in the conserved region immediately preceding the ATG start codon. Distal to the conserved sequence there was no apparent homology. One transcript carrying a 97-base untranslated region was identical to our high pI cDNA clone E. The gene for the other was recovered from a lambda phage genomic library. The 5' coding sequence was very similar, but not identical to clone E, demonstrating that these transcripts arise from separate genes. The two transcripts increased coordinately in aleurone cells stimulated with gibberellic acid. These data indicate that there is a high pI alpha-amylase multigene family with at least two active members, both of which are regulated in some manner by the plant hormone gibberellic acid.
Improving InAs double heterostructure lasers with better confinement (1992)

The authors have conducted a theoretical study of InAs double heterostructure lasers. Carrier leakage due to drift current is shown to be the main mechanism of the injected carriers in lasers fabricated to date. Reduction of carrier leakage is shown to be possible by using wider bandgap lattice-matched material as the cladding layers. Increased optical confinement is also required to achieve the lowest possible threshold current, which strongly affects the highest lasing temperature achievable. An InAs double heterostructure employing AlAs/sub 0.16/Sb/sub 0.84/ as the cladding material is proposed. Simulation on this structure indicates that its threshold current density will be dominated by Auger recombination for most of the temperature range below 300 K, the estimated highest lasing temperature.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Macrophage Migration Inhibitory Factor Promotes Tumor Growth and Metastasis by Inducing Myeloid-Derived Suppressor Cells in the Tumor Microenvironment (2012)

The macrophage migration inhibitory factor (MIF), an inflammatory cytokine, is overexpressed in many solid tumors and is associated with poor prognosis. We previously identified inhibitors of MIF within a class of natural products with demonstrated anti-cancer activities. We therefore sought to determine how MIF contributes to tumor growth and progression. We show in this study that in murine tumors including the 4T1 model of aggressive, spontaneously metastatic breast cancer in immunologically intact mice, tumor-derived MIF promotes tumor growth and pulmonary metastasis through control of inflammatory cells within the tumor. Specifically, MIF increases the prevalence of a highly immune suppressive subpopulation of myeloid-derived suppressor cells (MDSCs) within the tumor. In vitro, MIF promotes differentiation of myeloid cells into the same population of MDSCs. Pharmacologic inhibition of MIF reduces MDSC accumulation in the tumor similar to MIF depletion and blocks the MIF-dependent in vitro differentiation of MDSCs. Our results demonstrate that MIF is a therapeutically targetable mechanism for control of tumor growth and metastasis through regulation of the host immune response and support the potential utility of MIF inhibitors, either alone or in combination with standard tumor-targeting therapeutic or immunotherapy approaches.
High boost converter using voltage multiplier (2005)

With the increasing demand for renewable energy, distributed power included in fuel cells have been studied and developed as a future energy source. For this system, a power conversion circuit is necessary to interface the generated power to the utility. In many cases, a high step-up DC/DC converter is needed to boost low input voltage to high voltage output. Conventional methods using cascade DC/DC converters cause extra complexity and higher cost. The conventional topologies to get high output voltage use flyback DC/DC converters. They have the leakage components that cause stress and loss of energy that results in low efficiency. This paper presents a high boost converter with a voltage multiplier and a coupled inductor. The secondary voltage of the coupled inductor is rectified using a voltage multiplier. High boost voltage is obtained with low duty cycle. Theoretical analysis and experimental results verify the proposed solutions using a 300 W prototype.
The Microbiota Mediates Pathogen Clearance from the Gut Lumen after Non-Typhoidal Salmonella Diarrhea (2010)

Many enteropathogenic bacteria target the mammalian gut. The mechanisms protecting the host from infection are poorly understood. We have studied the protective functions of secretory antibodies (sIgA) and the microbiota, using a mouse model for S. typhimurium diarrhea. This pathogen is a common cause of diarrhea in humans world-wide. S. typhimurium (S. tm(att), sseD) causes a self-limiting gut infection in streptomycin-treated mice. After 40 days, all animals had overcome the disease, developed a sIgA response, and most had cleared the pathogen from the gut lumen. sIgA limited pathogen access to the mucosal surface and protected from gut inflammation in challenge infections. This protection was O-antigen specific, as demonstrated with pathogens lacking the S. typhimurium O-antigen (wbaP, S. enteritidis) and sIgA-deficient mice (TCRβ(-/-)δ(-/-), J(H) (-/-), IgA(-/-), pIgR(-/-)). Surprisingly, sIgA-deficiency did not affect the kinetics of pathogen clearance from the gut lumen. Instead, this was mediated by the microbiota. This was confirmed using 'L-mice' which harbor a low complexity gut flora, lack colonization resistance and develop a normal sIgA response, but fail to clear S. tm(att) from the gut lumen. In these mice, pathogen clearance was achieved by transferring a normal complex microbiota. Thus, besides colonization resistance ( = pathogen blockage by an intact microbiota), the microbiota mediates a second, novel protective function, i.e. pathogen clearance. Here, the normal microbiota re-grows from a state of depletion and disturbed composition and gradually clears even very high pathogen loads from the gut lumen, a site inaccessible to most "classical" immune effector mechanisms. In conclusion, sIgA and microbiota serve complementary protective functions. The microbiota confers colonization resistance and mediates pathogen clearance in primary infections, while sIgA protects from disease if the host re-encounters the same pathogen. This has implications for curing S. typhimurium diarrhea and for preventing transmission.
"Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer (2011)

Erlotinib is effective for epidermal growth factor receptor (EGFR) mutant lung cancer, but CNS penetration at standard daily dosing is limited. We previously reported that intermittent "pulsatile" administration of high-dose (1500 mg) erlotinib once weekly was tolerable and achieved concentrations in cerebrospinal fluid exceeding the half maximal inhibitory concentration for EGFR mutant lung cancer cells in a patient with leptomeningeal metastases; we now expand this paradigm to a series of 9 patients. We retrospectively identified patients with EGFR mutant lung cancer treated with pulsatile erlotinib for CNS metastases (brain and/or leptomeningeal) that occurred despite conventional daily erlotinib or other EGFR tyrosine kinase inhibitors. Mutations in available lung and CNS tissue were correlated with efficacy. Erlotinib was administered as monotherapy at a median dose of 1500 mg weekly. Best CNS radiographic response was partial in 67% (6/9, including 2 with isolated leptomeningeal metastases), stable disease in 11% (1/9), and progressive disease in 22% (2/9). Median time to CNS progression was 2.7 months (range, 0.8-14.5 months) and median overall survival was 12 months (range, 2.5 months-not reached). Treatment was well tolerated. No acquired resistance mutations in EGFR were identified in the CNS metastases of 4 patients, including 1 harboring T790M outside the CNS. Pulsatile erlotinib can control CNS metastases from EGFR mutant lung cancer after failure of standard daily dosing. CNS disease may not harbor acquired resistance mutations that develop systemically. A prospective trial is planned.
Low-Carbohydrate Diet Versus Caloric Restriction: Effects on Weight Loss, Hormones, and Colon Tumor Growth in Obese Mice (2007)

Our objective was to compare the effects of a low-carbohydrate diet to a high-carbohydrate/calorie-restricted diet on weight loss, hormones, and transplanted colon tumor growth. Eighty male C57BL/6 mice consumed a diet-induced obesity regimen (DIO) ad libitum for 7 weeks. From Weeks 8 to 14, the mice consumed a 1) DIO diet ad libitum (HF); 2) low-carbohydrate diet ad libitum (LC); 3) high-carbohydrate diet ad libitum (HC); or 4) HC calorie restricted diet (HC-CR). MC38 cells were injected at Week 15. At the time of injection, the HC-CR group displayed the lowest body weight (25.5 +/- 0.57 g), serum insulin-like growth factor I (IGF-I; 135 +/- 56.0 ng/ml), and leptin (1.0 +/- 0.3 ng/ml) levels. This group also exhibited the longest time to palpable tumor (20.1 +/- 0.9 days). Compared to the HF group, the HC group exhibited lower body weight (39.4 +/- 1.4 vs. 32.9 +/- 0.7 g, respectively), IGF-I (604 +/- 44.2 vs. 243.4 +/- 88.9 ng/ml, respectively), and leptin (15.6 +/- 2.2 vs. 7.0 +/- 0.7 ng/ml, respectively) levels but similar tumor growth. IGF-I levels were lower in the LC group (320.0 +/- 39.9 ng/ml) than the HF group, but tumor growth did not differ. These data suggest LC diets do not slow colon tumor growth in obese mice.
In vivo growth of mouse leukemia L1210 cells with metabolic alterations in the subunits of ribonucleotide reductase. (2003)

Mouse leukemia L1210 cells selected for resistance to drugs targeted specifically at each of the protein subunits of ribonucleotide reductase were studied for their ability to grow in vivo. The life-span of the mice injected with hydroxyurea-resistant L1210 cells, which have elevated levels of the mRNA and protein for the non-heme iron (NHI, R2) subunit of ribonucleotide reductase, was approximately twice that of the mice injected with equal numbers of the parental wild-type L1210 leukemia cells. The life-span of mice injected with the L1210 cells that had alterations in the effector-binding subunit (EB, R1) was considerably shorter than the mice injected with the parental wild-type L1210 cells. These results provide direct evidence that tumor cells with alterations in the properties of ribonucleotide reductase grow differently in vivo, with defined effects on the host mouse that cause either an increased survival time or a decreased survival time compared to the effects of wild-type L1210 leukemia cells on tumor-bearing mice.
Substantial improvement of perovskite solar cells stability by pinhole-free hole transport layer with doping engineering (2015)

We fabricated perovskite solar cells using a triple-layer of n-type doped, intrinsic, and p-type doped 2,2',7,7'-tetrakis(N,N'-di-p-methoxyphenylamine)-9,9'-spirobifluorene (spiro-OMeTAD) (n-i-p) as hole transport layer (HTL) by vacuum evaporation. The doping concentration for n-type doped spiro-OMeTAD was optimized to adjust the highest occupied molecular orbital of spiro-OMeTAD to match the valence band maximum of perovskite for efficient hole extraction while maintaining a high open circuit voltage. Time-dependent solar cell performance measurements revealed significantly improved air stability for perovskite solar cells with the n-i-p structured spiro-OMeTAD HTL showing sustained efficiencies even after 840 h of air exposure.
A unified switching theory with applications to VLSI design (1982)

Classical switching theory is shown to have deficiencies when applied to the analysis and design of MOS VLSI circuits. A new logic design methodology called CSA theory is described here which overcomes many of these deficiencies. It is based on three primitive component types: connectors that perform wired-logic operations, switches representing controlled connectors, and attenuators representing resistive load devices. Four basic types of logic values are recognized: Boolean 0 and 1 values, unknown or indeterminate U values, and the high-impedance state Z. The number of logic values can be increased systematically to improve modeling accuracy using a concept of logical strength, which corresponds to current drive capability in analog circuits. It is shown that both the behavior and layout of most types of MOS logic circuits, including contact, gate, and nonclassical mixed circuits, can be treated in a uniform and rigorous manner using CSA network models with either four or seven logic values. The use of a digital charge-storage element called a well to represent sequential behavior is examined. CSA theory is applied to two VLSI design issues, inverter synthesis and fault simulation.
Solid dispersion of poorly water‐soluble drugs: Early promises, subsequent problems, and recent breakthroughs (1999)

Although there was a great interest in solid dispersion systems during the past four decades to increase dissolution rate and bioavailability of poorly water-soluble drugs, their commercial use has been very limited, primarily because of manufacturing difficulties and stability problems. Solid dispersions of drugs were generally produced by melt or solvent evaporation methods. The materials, which were usually semisolid and waxy in nature, were hardened by cooling to very low temperatures. They were then pulverized, sieved, mixed with relatively large amounts of excipients, and encapsulated into hard gelatin capsules or compressed into tablets. These operations were difficult to scale up for the manufacture of dosage forms. The situation has, however, been changing in recent years because of the availability of surface-active and self-emulsifying carriers and the development of technologies to encapsulate solid dispersions directly into hard gelatin capsules as melts. Solid plugs are formed inside the capsules when the melts are cooled to room temperature. Because of surface activity of carriers used, complete dissolution of drug from such solid dispersions can be obtained without the need for pulverization, sieving, mixing with excipients, etc. Equipment is available for large-scale manufacturing of such capsules. Some practical limitations of dosage form development might be the inadequate solubility of drugs in carriers and the instability of drugs and carriers at elevated temperatures necessary to manufacture capsules.
Design, Synthesis, and Biological Evaluation of Nonsteroidal Cycloalkane[d]isoxazole-Containing Androgen Receptor Modulators (2012)

We report here the design, preparation, and systematic evaluation of a novel cycloalkane[d]isoxazole pharmacophoric fragment-containing androgen receptor (AR) modulators. Cycloalkane[d]isoxazoles form new core structures that interact with the hydrophobic region of the AR ligand-binding domain. To systematize and rationalize the structure-activity relationship of the new fragment, we used molecular modeling to design a molecular library containing over 40 cycloalkane[d]isoxazole derivatives. The most potent compound, 4-(3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-3-yl)-2-(trifluoromethyl)benzonitrile (6a), exhibits antiandrogenic activity significantly greater than that of the most widely used antiandrogenic prostate cancer drugs bicalutamide (1) and hydroxyflutamide (2) in reporter gene assays measuring the transcriptional activity of AR (decreasing approximately 90% of the total AR activity) and in competitive AR ligand-binding assays (showing over four times higher potency to inhibit radioligand binding in comparison to bicalutamide). Notably, 6a maintains its antiandrogenic activity with AR mutants W741L and T877A commonly observed and activated by bicalutamide and hydroxyflutamide, respectively, in prostate cancer patients.
Genetic Classification of Benign and Malignant Thyroid Follicular Neoplasia Based on a Three-Gene Combination (2005)

Thyroid carcinoma is a common endocrine cancer with a favorable prognosis if subjected to timely treatment. However, the clinical identification of follicular thyroid carcinoma (FTC) among patients with benign thyroid nodules is still a challenge. Preoperative fine needle aspiration-based cytology cannot always differentiate follicular carcinomas from benign follicular neoplasias. Because current methods fail to improve preoperative diagnosis of thyroid nodules, new molecular-based diagnoses should be explored. We conducted a microarray-based study to reveal the genetic profiles unique to FTC and follicular adenomas (FAs), to identify the most parsimonious number of genes that could accurately differentiate between benign and malignant follicular thyroid neoplasia. We confirmed our data by quantitative RT-PCR and immunohistochemistry in two independent validation sets with a total of 114 samples. We were able to identify three genes, cyclin D2 (CCND2), protein convertase 2 (PCSK2), and prostate differentiation factor (PLAB), that allow the accurate molecular classification of FTC and FA. Two independent validation sets revealed that the combination of these three genes could differentiate FTC from FA with a sensitivity of 100%, specificity of 94.7%, and accuracy of 96.7%. In addition, our model allowed the identification of follicular variants of papillary thyroid carcinoma with an accuracy of 85.7%. Three-gene profiling of thyroid nodules can accurately predict the diagnosis of FTC and FA with high sensitivity and specificity, thus identifying promising targets for further investigation to ultimately improve preoperative diagnosis.
Tight Enforcement of Information-Release Policies for Dynamic Languages (2009)

This paper studies the problem of securing information release in dynamic languages. We propose (i) an intuitive framework for information-release policies expressing both what can be released by an application and where in the code this release may take place and (ii) tight and modular enforcement by hybrid mechanisms that combine monitoring with on-the-fly static analysis for a language with dynamic code evaluation and communication primitives. The policy framework and enforcement mechanisms support both termination-sensitive and insensitive security policies.
Novel Systems for Controlled Delivery of Macromolecules (1996)

Gene therapy promises new treatments for human disease by alterations in the DNA content of tissues. Methods for efficient and stable introduction of genes into target cells in the body are critically important in this effort. Researchers and physicians now have many years of experience with synthetic polymers for controlled drug delivery; many of these polymers can also be used to deliver macromolecules at controlled rates to tissues. This article reviews the use of polymers in controlled protein delivery and suggests ways that polymer delivery systems may be useful in the delivery of gene transfer agents.