gebhart/patrepeval huggingface dataset:
Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti–PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells (2015)

Several anti-PD-1/PD-L1 monoclonal antibodies (mAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these mAbs is to inhibit PD-1 on immune cells interacting with PD-L1 on tumor cells. These mAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective mAb-mediated cancer therapies. A fully human anti-PD-L1 mAb would potentially be able to block PD-1/PD-L1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 mAb. The studies reported here demonstrate (i) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (ii) IFNγ can enhance tumor cell PD-L1 expression and, in some cases, enhance ADCC tumor cell lysis; (iii) purified NK cells are potent effectors for avelumab; (iv) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (v) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (vi) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 mAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity.
Synthesis of New Bioactive Sulfur Compounds Bearing Heterocyclic Moiety and Their Analytical Applications (2011)

Some new bioactive sulfur compounds bearing heterocyclic nitrogen moieties such as 3- imino–2-thioxo-4,5-dihydro- thiazolidin – 4-one (3), 3-imino – 2-thioxo -3,4,5,6-tetrahydro-1, 3-thiazine-4, 6- (2 H)dione(4), N- substituted – pyrazol -3,5-dione (10) , 1,3 –disubstituted -2-thioxo-pyrimidin-4,6 –dione (11) and di –(3,5-diaminopyrazolin-1-yl)thioketone (13) derived from dithioc formic acid hydrazide (1) and thiocarbohydrazide (7)were prepared via condensation of compound 1 or 7 with acyclic and cyclic oxo compounds (e.g. aldehydes andketones) in 1:1 and 1:2 molar ratios, and addition of iso thiocyanate or treatment with active methylene compoundsfollowed by ring closing reactions in different media (Schemes I & II). The biocidal effect of some compoundstowards some bacteria and fungi was evaluated. Compound 4 was used as selective chelating agent forspectrophotometric determination of mercury (II) ions. The limit of detection (LOD) and quantification (LOQ) ofthe developed spectrophotometric method were found to be equal to 0.16 and 0.52 ?g mL-1 mercury (II),respectively. Compound 4 was also physically immobilized onto polyurethane foam (PUFs) and was successfullyused as solid sorbent in packed column for removal of mercury (II) ions from wastewater.
The endothelin receptor B (EDNRB) promoter displays heterogeneous, site specific methylation patterns in normal and tumor cells (2001)

The 5' region for the endothelin receptor B (EDNRB) gene is a complex CpG island giving rise to four individual transcripts initiating within the island. Here, for the first time, we analyze the relationship between methylation and gene expression in a CpG island located in the 5' region of a gene with multiple transcription start sites. The CpG island was unmethylated in normal prostate and bladder tissue, whereas it became methylated in apparently normal colonic epithelium. Tumors derived from these tissues were frequently hypermethylated relative to the respective normal tissues. Analysis of 11 individual CpG sites located throughout the CpG island showed that specific sites with high methylation levels in several tumors were also methylated in normal tissues, suggesting that they might serve as foci for further de novo methylation. This region also had high levels of methylation in several cancer cell lines, and we found that a low methylation level in a small region within the 5' region correlated with expression of the 5'-most transcript. Interestingly, almost complete methylation 200-1000 bp downstream of the transcriptional start site did not block expression of this transcript. Finally, we show that treatment with 5-aza-2'-deoxycytidine can induce transcriptional activation of the four EDNRB transcripts. Our results show the existence of differential, tissue-dependent methylation at the EDNRB 5' region, suggest the existence of a spreading mechanism for de novo methylation, starting from methylation hotspots, and show that hypermethylation immediately 3' to a transcriptional start site does not prevent initiation.
Cytokines in rheumatoid arthritis: is it all TNF-alpha? (2001)

Anti-TNF-alpha therapy has shown clear efficacy in the treatment of rheumatoid arthritis (RA). Since some patients do not respond and the treatment is suspensive, combination therapy may be of interest. Other cytokines produced by monocytes such as IL-1, IL-12, IL-18 are also involved. The secretion of these cytokines is regulated by subsets of T-lymphocytes. Among these, IL-17 producing Th1 cells appear to contribute directly to the destructive process. Furthermore, this T-cell contribution enhances the action of monocyte derived proinflammatory cytokines. Using models of human RA synovium inflammation and bone resorption, ex vivo results suggest that combination therapy may be of interest. Acting on more than one cytokine may increase the percentage of responding RA patients as well as the degree of individual patient response.
A Receptor for Tumor Necrosis Factor Defines an Unusual Family of Cellular and Viral Proteins (1990)

Tumor necrosis factor alpha and beta (TNF-alpha and TNF-beta) bind surface receptors on a variety of cell types to mediate a wide range of immunological responses, inflammatory reactions, and anti-tumor effects. A cDNA clone encoding an integral membrane protein of 461 amino acids was isolated from a human lung fibroblast library by direct expression screening with radiolabeled TNF-alpha. The encoded receptor was also able to bind TNF-beta. The predicted cysteine-rich extracellular domain has extensive sequence similarity with five proteins, including nerve growth factor receptor and a transcriptionally active open reading frame from Shope fibroma virus, and thus defines a family of receptors.
Electrical stimulation for the treatment of bladder dysfunction: Current status and future possibilities (2002)

Electrical stimulation of peripheral nerves can be used to cause muscle contraction, to activate reflexes, and to modulate some functions of the central nervous system (neuromodulation). If applied to the spinal cord or nerves controlling the lower urinary tract, electrical stimulation can produce bladder or sphincter contraction, produce micturition, and can be applied as a medical treatment in cases of incontinence and urinary retention. This article first reviews the history of electrical stimulation applied for treatment of bladder dysfunction and then focuses on the implantable Finetech-Brindley stimulator to produce bladder emptying, and on external and implantable neuromodulation systems for treatment of incontinence. We conclude by summarizing some recent research efforts including: (a) combined sacral posterior and anterior sacral root stimulator implant (SPARSI), (b) selective stimulation of nerve fibers for selective detrusor activation by sacral ventral root stimulation, (c) microstimulation of the spinal cord, and (d) a newly proposed closed-loop bladder neuroprosthesis to treat incontinence caused by bladder overactivity.
Linkage analysis of the nevoid basal cell carcinoma syndrome (1968)

Summary Twelve pedigrees were informative for linkage between the gene locus for the nevoid basal cell carcinoma syndrome and the ABO, MNS, Rh, P, Kell, Lewis, Ddy, and Kidd blood group marker loci. Linkage with a recombination fraction less than θ = 0.1 was unlikely for any marker locus. The most favourable of the possible loose linkages, that between the syndrome locus and Rh locus, showed a 12% probability of linkage when the prior odds against two autosomel loci being on the same chromosome were taken into account. The other marker loci manifested probabilities averaging about 3%.
Ensuring Confidentiality of Geocoded Health Data: Assessing Geographic Masking Strategies for Individual-Level Data (2014)

Public health datasets increasingly use geographic identifiers such as an individual's address. Geocoding these addresses often provides new insights since it becomes possible to examine spatial patterns and associations. Address information is typically considered confidential and is therefore not released or shared with others. Publishing maps with the locations of individuals, however, may also breach confidentiality since addresses and associated identities can be discovered through reverse geocoding. One commonly used technique to protect confidentiality when releasing individual-level geocoded data is geographic masking. This typically consists of applying a certain amount of random perturbation in a systematic manner to reduce the risk of reidentification. A number of geographic masking techniques have been developed as well as methods to quantity the risk of reidentification associated with a particular masking method. This paper presents a review of the current state-of-the-art in geographic masking, summarizing the various methods and their strengths and weaknesses. Despite recent progress, no universally accepted or endorsed geographic masking technique has emerged. Researchers on the other hand are publishing maps using geographic masking of confidential locations. Any researcher publishing such maps is advised to become familiar with the different masking techniques available and their associated reidentification risks.
Dynamic micro-magnetic resonance imaging of liver micrometastasis in mice with a novel liver macromolecular magnetic resonance contrast agent DAB-Am64-(1B4M-Gd)(64). (2001)

DAB-Am64-(1B4M-Gd)(64) is a newly synthesized macromolecular liver magnetic resonance imaging (MRI) contrast agent with a polypropylenimine diaminobutane (DAB) dendrimer conjugated with a bifunctional diethylenetriaminepentaacetic acid (DTPA) derivative for complexing Gd(III) atoms. The characteristics of DAB-Am64-(1B4M-Gd)(64), which quickly accumulated in the liver, have been reported recently. In the present study, the dynamic micro-MRI with DAB-Am64-(1B4M-Gd)(64) was obtained in the mouse liver metastasis model using colon carcinoma cells to evaluate the ability to visualize the micrometastatic tumors compared with that using Gd-DTPA. The dynamic micro-MRI with DAB-Am64-(1B4M-Gd)(64) was able to homogeneously enhance the normal liver parenchyma and visualize micrometastatic tumors of 0.3-mm diameter in the liver of the mice with better contrast than that with Gd-DTPA. In conclusion, DAB-Am64-(1B4M-Gd)(64) is a new liver MRI contrast agent potentially useful for diagnosis of micrometastasis in the liver.
An Intense Light Source (1998)

background. Up to now, vascular diseases were treated with various lasers, such as argon, pulsed dye, and copper vapor lasers, which can lead to side effects like hypopigmentations, hyperpigmentations, and scarring. We treated patients with vascular lesions with an incoherent intense light source, the PhotoDerm VL-flashlamp. objective. The aim of the study was to test the effectiveness and safety of the PhotoDerm VL for vascular skin lesions. methods. One hundred and twenty patients with facial or leg telangiectasias, spider nevi, erythrosis interfollicularis, and senile angiomas were treated with the PhotoDerm VL. results. In 73.6% of patients there was an immediate clearing, and in 84.3% a clearing after 1 month was found of leg telangiectasias up to 1 mm in diameter. Facial telangiectasias and erythrosis interfollicularis colli showed clearance up to 90%. Spider nevi and senile angiomas often only needed to be treated once. conclusion. From our experience we conclude that the PhotoDerm VL is an excellent device to treat vascular lesions as there were hardly any side effects seen, however, the user needs a sufficient experience to get good results.© 1998 by the American Society for Dermatologic Surgery, Inc.
Refolding and aggregation of bovine carbonic anhydrase B: quasi-elastic light scattering analysis (1990)

Bovine carbonic anhydrase B (CAB) is chosen as the model protein to study the phenomenon of protein aggregation, which often occurs during the refolding process. Refolding of CAB from 5 M GuHCl has been observed by quasi-elastic light scattering (QLS), which confirms the formation of a molten globular protein structure as reported previously [Semisotnov, G. V., Rodionova, N. A., Kutyshenko, V. P., Ebert, B., Blanck, J., & Ptitsyn, O. B. (1987) FEBS Lett. 224, 9-13]. QLS analysis reveals the formation of multimeric species prior to precipitation. Activity and cross-linking studies have confirmed the presence of inactive multimeric protein species. The dimer formation has been determined to be the initiating step in the aggregation of CAB during refolding. Activity studies have indicated that the first intermediate observed in the refolding pathway of CAB aggregates to form the inactive dimer. The rate of formation of the dimer has a stoichiometric dependence on the final protein concentration. The dimer formation rate is a function of the final guanidine hydrochloride (GuHCl) concentration to the inverse 6.7 power, which correlates well with the binding of GuHCl to the native protein in 0.60-0.80 M GuHCl. These rate dependencies require the refolding of CAB to be performed at high GuHCl concentrations (1 M GuHCl) and low protein concentrations (less than 1 mg/mL) to avoid the formation of aggregates. Alternatively, refolding can be performed by allowing the first intermediate to form the second intermediate prior to further dilution or dialysis. The aggregation of a hydrophobic first intermediate species is likely to be common to the refolding of other molten globular proteins.
Construction of an inducible cell‐communication system that amplifies Salmonella gene expression in tumor tissue (2012)

Bacterial therapies have the potential to overcome resistances that cause chemotherapies to fail. When using bacteria to produce anticancer agents in tumors, triggering gene expression is necessary to prevent systemic toxicity. The use of chemical triggers, however, is hampered by poor delivery of inducing molecules, which reduces the number of activated bacteria. To solve this problem, we created a cell-communication system that enables activated bacteria to induce inactive neighbors. We hypothesized that introducing cell communication into Salmonella would improve direct triggering strategies by increasing protein production, increasing sensitivity to inducer molecules, and enabling expression in tumor tissue. To test these hypotheses we integrated the PBAD promoter into the quorum-sensing machinery from Vibrio fischeri. The expression of a fluorescent reporter gene was compared to expression from non-communicating controls. Function in three-dimensional tissue was tested in a tumor-on-a-chip device. Bacterial communication increased fluorescence 40-fold and increased sensitivity to inducer molecules more than 10,000-fold. The system enabled bacteria to activate neighbors and increased the time-scale of protein production. Gene expression was controllable and tightly regulated. At the optimal inducing signal, communicating bacteria produced 350 times more protein than non-communicating bacteria. The cell-communication system created in this study has uses beyond cancer therapy, including protein manufacturing, bioremediation and biosensing. It would enable amplified induction of gene expression in any environment that limits availability of inducer molecules. Ultimately, because inducible cellular communication enables gene expression in tissue, it will be a critical component of bacterial anticancer therapies.
When Pages Collide: Dissecting the Words of Mormon (2012)

Careful readers of the Book of Mormon have probably found verses 12-18 of the Words of Mormon to be a bit of a puzzle. For stylistic and other reasons, they do not really fit with verses 1-11, so commentators have tried to explain their presence as a sort of "bridge" or "transition" that Mormon wrote to connect the record of the small plates with his abridgment from the large plates. This paper proposes a different explanation: Rather than being a bridge into the book of Mosiah, these verses were originally part of the book of Mosiah and should be included with it. This article presents both documentary and textual evidence to show that (1) Joseph Smith had translated some text that he did not give to Martin Harris (the lost 116 pages), (2) Oliver Cowdery, Joseph's scribe, copied from the original manuscript onto the printer's manuscript at the beginning of the book of Mosiah the chapter designation "Chapter III," (3) verses 12-18 of Words of Mormon do not use the first-person pronoun "I" and do not speak of the small plates, as verses 1-11 do, and (4) the book of Mosiah begins abruptly, without an introductory heading and without any mention of the person for whom the book was likely named (Benjamin's father, Mosiah). These and other pieces of evidence support the idea that the last seven verse in Words of Mormon were actually the last verses of what should have been Mosiah chapter 2, but chapter 1 and most of chapter 2 must have been part of the 116 pages lost by Martin Harris.
The Nature of the Interatomic Forces in Metals (1938)

It has been generally assumed that in the transition elements (Fe, Co, Ni, Cu, etc.) the $3d$ shell is filled with ten electrons or is nearly filled, and that the $d$ electrons make no significant contribution to the cohesive forces in metals. Evidence is presented here to show that about half of the $d$ orbitals (2.56 of the total of 5) are involved in bond formation, through hybridization with the $4s$ and $4p$ orbitals, and that the number of covalent bonds resonating among the available interatomic positions increases from one to nearly six in the sequence K, Ca, Sc, Ti, V, Cr, remains nearly constant from Cr to Ni, and begins to decrease with Cu. The remaining 2.44 $d$ orbitals, with very small interatomic overlapping, are occupied by nonbonding electrons which are mainly responsible for the ferromagnetic and paramagnetic properties of the metals. This point of view provides a qualitative explanation of many properties of the transition metals (including those of the palladium and platinum groups), such as interatomic distance, characteristic, temperature, hardness, compressibility, and coefficient of thermal expansion, and it accounts satisfactorily for the observed values of the atomic saturation magnetic moments of the ferromagnetic elements iron, cobalt, and nickel and their alloys. It is also shown to provide a reason for the occurrence of the positive exchange integrals which give rise to ferromagnetism.
Nonsteroidal Anti-inflammatory Drugs Induce Colorectal Cancer Cell Apoptosis by Suppressing 14-3-3ε (2007)

To determine the role of 14-3-3 in colorectal cancer apoptosis induced by nonsteroidal anti-inflammatory drugs (NSAIDs), we evaluated the effects of sulindac on 14-3-3epsilon protein expression in colorectal cancer cells. Sulindac sulfide inhibited 14-3-3epsilon proteins in HT-29 and DLD-1 cells in a time- and concentration-dependent manner. Sulindac sulfone at 600 mumol/L inhibited 14-3-3epsilon protein expression in HT-29. Indomethacin and SC-236, a selective cyclooxygenase-2 (COX-2) inhibitor, exerted a similar effect as sulindac. Sulindac suppressed 14-3-3epsilon promoter activity. As 14-3-3epsilon promoter activation is mediated by peroxisome proliferator-activated receptor delta (PPARdelta), we determined the correlation between 14-3-3epsilon inhibition and PPARdelta suppression by NSAIDs. Sulindac sulfide inhibited PPARdelta protein expression and PPARdelta transcriptional activity. Overexpression of PPARdelta by adenoviral transfer rescued 14-3-3epsilon proteins from elimination by sulindac or indomethacin. NSAID-induced 14-3-3epsilon suppression was associated with reduced cytosolic Bad with elevation of mitochondrial Bad and increase in apoptosis which was rescued by Ad-PPARdelta transduction. Stable expression of 14-3-3epsilon in HT-29 significantly protected cells from apoptosis. Our findings shed light on a novel mechanism by which NSAIDs induce colorectal cancer apoptosis via the PPARdelta/14-3-3epsilon transcriptional pathway. These results suggest that 14-3-3epsilon is a target for the prevention and therapy of colorectal cancer.
Single enantiomer drugs: should they be developed? (2006)

Biological interactions are stereoselective; thus the interactions of drugs with corresponding biological targets must also be stereoselective. However, many drugs used today are racemic mixtures. For example, approximately 25% or 1 in 4 marketed drugs are mixtures of agents (racemates) rather than single chemical entities (enantiomers). One of these enantiomers can be inactive or even counterproductive to the therapeutic use of the drug: either by reducing the efficacy of the active enantiomer or by causing unnecessary tolerability problems or even toxicity through differential pharmacodynamics. The presence of a therapeutically inactive or counterproductive enantiomer can also complicate the pharmacokinetics of the active enantiomer and the interpretation of the therapeutic drug monitoring (e.g., plasma levels) if the assay is not capable of separately quantitating the two enantiomers. This article reviews the history of stereoisomers and the relevant pharmacological principles, then discusses recent changes in rules governing drug approval and the potential advantages to the patient and the manufacturer of developing single enantiomers.
A Mechanistic Investigation of Gelation. The Sol-Gel Polymerization of Bridged Silsesquioxane Monomers (2000)

The study of a homologous series of silsesquioxane monomers has uncovered striking discontinuities in gelation behavior. An investigation of the chemistry during the early stages of the polymerization has provided a molecular basis for these observations. Monomers containing from one to four carbon atoms exhibit a pronounced tendency to undergo inter or intramolecular cyclization. The cyclic intermediates have been characterized by {sup 29}Si NMR, chemical ionization mass spectrometry and isolation from the reaction solution. These carbosiloxanes are local thermodynamic sinks that produce kinetic bottlenecks in the production of high molecular weight silsesquioxanes. The formation of cyclics results in slowing down or in some cases completely shutting down gelation. An additional finding is that the cyclic structures are incorporated intact into the final xerogel. Since cyclization alters the structure of the building block that eventually makes up the xerogel network, it is expected that this will contribute importantly to the bulk properties of the xerogel as well.