gebhart/patrepeval huggingface dataset:
Chicken or Egg: Is Clonal Hematopoiesis Primarily Caused by Genetic or Epigenetic Aberrations? (2019)

Hematopoietic malignancies, including multiple myeloma, are associated with characteristic mutations and genetic instabilities that drive malignant transformation. On the other hand, tumor formation is also associated with drastic epigenetic aberrations, which can impact on the genetic sequence. Therefore, the question arises if malignant transformation is primarily caused by genetic or epigenetic events. The tight connection of these processes becomes obvious by the fact that in several malignancies, as well as in age-related clonal hematopoiesis, mutations are particularly observed in epigenetic writers such as DNMT3A and TET2. On the other hand, specific epigenetic aberrations, so called “epimutations”, can mimic genomic mutations. In contrast to the genetic sequence, which remains relatively stable throughout life, the epigenome notoriously undergoes drastic changes in normal hematopoietic development and aging. It is conceivable that such epigenetic reorganization, e.g. in 3D chromatin conformation, paves the way for secondary chromosomal instabilities, which then result in tumor-specific genomic changes that further trigger disease progression. This scenario might explain occurrence of tumor-specific mutations particularly in the elderly. Taken together, the causality dilemma is difficult to solve because genetic and epigenetic aberrations are interlinked during disease development. A better understanding of how the chromatin structure or 3D nuclear organization can evoke specific mutations might provide new perspectives for prevention, early diagnostics, and targeted therapy.
Non-Sampled Anti-Aliasing (2013)

In this paper we present a parallel method for high-quality edge anti-aliasing in rasterization. In contrast to traditional graphics hardware methods, which rely on massive oversampling to combat aliasing issues, we evaluate a closed-form solution of the associated prefilter convolution. This enables the use of a wide range of filter functions with arbitrary kernel sizes, as well as general shading methods such as texture mapping or complex illumination models. Due to the use of analytic solutions, our results are exact in the mathematical sense and provide objective ground-truth for other anti-aliasing methods and enable the rigorous comparison of different models and filters. An efficient implementation on general purpose graphics hardware is discussed and several comparisons to existing techniques and of various filter functions are given.
Comparison of Two Corticosteroid Pre-Infusion Regimens for Pegloticase in the United States: A Retrospective Analysis in Community Rheumatology Practices (2019)

In this retrospective chart-review project, patients were able to have a longer duration of pegloticase therapy, received a significantly greater number of infusions, and experienced fewer infusion reactions when methylprednisolone was used as the corticosteroid for pre-infusion prophylaxis compared with hydrocortisone.
Lipid-mediated resistance of Gram-negative bacteria against various pore-forming antimicrobial peptides (2005)

Lipopolysaccharides (LPSs) play a dual role as target and as effector molecules. The knowledge of the LPS-induced activation of human immune cells is increasing; however, surprisingly, much less effort seems to be directed towards the understanding of the mechanisms leading to the killing of the bacterial organisms, which eventually results in the release of LPS from the bacterial surface into the blood circulation. We demonstrate mechanisms of interaction of peptides of the innate immune system (e.g. defensins and cathelicidins) as well as of externally administered antibiotics (e.g. Polymyxin B) with Gram-negative bacteria. The main focus is directed on data derived from electrical measurements on a reconstitution system of the outer membrane as an asymmetric bilayer composed on one side of LPS and on the other of phospholipids. All these antimicrobial peptides (AMPs) are membrane-active and induce the permeabilization of the reconstituted membranes by the formation of lesions. We found that differences in the activity of the AMPs against various sensitive and resistant Gram-negative bacteria can be explained solely by variations in the chemical structure of LPS, e.g. in the composition of the sugar head group. A reduction of the net negative charge of LPS is responsible for a reduced interaction with the polycationic AMPs and thus for resistance. A most important side effect of positively charged AMPs is the neutralization of the negatively charged LPS released from the bacterial surface as a consequence of AMP-induced killing.
Toll-interacting protein down-regulates src family tyrosine kinases fyn expression in human esophageal squamous cell carcinoma (2011)

Objective To determine the relationship between Src family tyrosine kinases Fyn ex- pression and Toll-interacting protein （Tollip） in human esophageal squamous cell carcinoma （ESCC）. Methods The Tollip expression was detected in 3 cases of ESCC and compared to the unremarkable epi- thelium by Western blotting. Tollip plasmid DNA （ 1 μg） was transfected into TEl cells and the Fyn/Tollip expression was examined by Western blotting. Results The Tollip expression level was lower in ESCC group than in UNR group. Tollip decreased Fyn protein expression in TEl cells. Conclusion ToUip may act as a negative regulator of Fyn in human ESCC, and play an important role in human ESCC progress.

Key words: 
Esophageal/neoplasms ;  Carcinoma, squamous cell;  Fyn ;  Tollip
New Experimental Drugs for the Treatment of Tuberculosis (1989)

New antitubercular agents are needed for two main purposes: to further simplify therapy (through reductions in the number of medicaments used, the number of doses administered, and the duration of treatment required), thus facilitating supervision and improving compliance, and to combat resistant mycobacteria. Reduction in the number of medicaments has been achieved by combining two or more drugs in a single tablet while retaining a degree of bioavailability similar to that of the single components. The adverse effects observed with once-weekly high doses of rifampin have limited the development of widely spaced intermittent regimens of treatment. For this reason new rifamycins have been developed that are as active as rifampin against mycobacteria but that also offer the advantage of high and prolonged serum levels and thus have the potential for once-weekly administration. The in vitro and in vivo properties of these drugs have been studied. Three classes of drugs show promise for the treatment of drug-resistant tuberculosis: spiropiperidyl rifamycin, the fluoroquinolones, and combinations of beta-lactam agents and beta-lactamase inhibitors.
Epithelial-to-Mesenchymal Transition and MicroRNAs in Lung Cancer (2017)

Despite major advances, non-small cell lung cancer (NSCLC) remains the major cause of cancer-related death in developed countries. Metastasis and drug resistance are the main factors contributing to relapse and death. Epithelial-to-mesenchymal transition (EMT) is a complex molecular and cellular process involved in tissue remodelling that was extensively studied as an actor of tumour progression, metastasis and drug resistance in many cancer types and in lung cancers. Here we described with an emphasis on NSCLC how the changes in signalling pathways, transcription factors expression or microRNAs that occur in cancer promote EMT. Understanding the biology of EMT will help to define reversing process and treatment strategies. We will see that this complex mechanism is related to inflammation, cell mobility and stem cell features and that it is a dynamic process. The existence of intermediate phenotypes and tumour heterogeneity may be debated in the literature concerning EMT markers, EMT signatures and clinical consequences in NSCLC. However, given the role of EMT in metastasis and in drug resistance the development of EMT inhibitors is an interesting approach to counteract tumour progression and drug resistance. This review describes EMT involvement in cancer with an emphasis on NSCLC and microRNA regulation.
General Method for Synthesis of Bipyridines: Palladium Catalyzed Cross-coupling Reaction of Trimethylstannyl-pyridines with Bromopyridines (1986)

Trimethylstannylpyridines 1 were treated with bromopyridines 2 in the presence of catalytic amount of tetrakis(triphenylphosphine)palladium to give the corresponding bipyridines 3 in moderate to good yields. Nicotelline (6) was similarly synthesized from 2, 4-bis(trimethylstannyl)pyridine (5) and 3-bromo-pyridine (2b).
A novel sensor‐regulator protein that belongs to the homologous family of signal‐transduction proteins involved in adaptive responses in Escherichia coli (1992)

Expression of the Escherichia coli outer membrane porins, OmpC and OmpF, is regulated in response to changes in the medium osmolarity through the functions of the regulatory factors, EnvZ and OmpR. A 3.0 kilobase pair DNA fragment cloned from E. coli is able phenotypically to suppress the defect in ompC and ompF expression caused by an envZ deletion mutation, provided that a certain gene located in this fragment is expressed on a high copy-number plasmid. Nucleotide sequencing revealed that the putative gene encodes a protein of 102,452 Da. The deduced amino acid sequence of the protein shows a high degree of homology to those of both EnvZ and OmpR, i.e. it contains both a 'sensory kinase domain' and a 'response regulator domain' in its primary amino acid sequence. The protein identified in this study is probably a novel member of the homologous family of proteins involved in bacterial adaptive responses. Hence, the gene encoding this novel sensor-regulator protein was designated as barA (bacterial adaptive responses) and mapped at 60 min on the E. coli genetic map. The BarA protein in isolated membranes was demonstrated in vitro to undergo phosphorylation in the presence of ATP.
Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer (2020)

Adoptive T cell therapy (ACT) using ex vivo-expanded autologous tumor-infiltrating lymphocytes (TILs) can mediate complete regression of certain human cancers. The impact of TIL phenotypes on clinical success of TIL-ACT is currently unclear. Using high-dimensional analysis of human ACT products, we identified a memory-progenitor CD39-negative stem-like phenotype (CD39<sup>-</sup>CD69<sup>-</sup>) associated with complete cancer regression and TIL persistence and a terminally differentiated CD39-positive state (CD39<sup>+</sup>CD69<sup>+</sup>) associated with poor TIL persistence. Most antitumor neoantigen-reactive TILs were found in the differentiated CD39<sup>+</sup> state. However, ACT responders retained a pool of CD39<sup>-</sup> stem-like neoantigen-specific TILs that was lacking in ACT nonresponders. Tumor-reactive stem-like TILs were capable of self-renewal, expansion, persistence, and superior antitumor response in vivo. These data suggest that TIL subsets mediating ACT response are distinct from TIL subsets enriched for antitumor reactivity.
The identification of hepatitis B virus X gene responsive elements reveals functional similarity of X and HTLV-I tax. (1990)

The human hepatitis B virus (HBV) X gene encodes a general transactivator which was suggested to be a potential factor in viral hepatocarcinogenesis. We show here that this protein transactivates the HBV enhancer linked either to the X gene promoter or heterologous promoters. Analysis of individual elements of the HBV enhancer revealed that the E element is sufficient to respond to X and is termed hence the X responsive element (XRE). Interestingly, XRE shares sequence similarity with the HTLV-I taxI responsive element (21 bp repeat or taxRE), and both elements bind similar nuclear proteins. The functional significance of this sequence similarity was demonstrated by the ability of XRE to respond to taxI. We also show that both X and taxI have the capacity to activate transcription through a second cis element, the NF-kappa B binding site. The response pattern of these viral regulators is also similar and both act in a concentration dependent manner. They are very active in low amounts, but almost inactive at high concentrations. Based on these observations, we suggest a common mechanism of action by regulator genes of distinct viruses.
Aglycosylation of human IgG1 and IgG3 monoclonal antibodies can eliminate recognition by human cells expressing FcγRI and/or FcγRII receptors (1989)

Aglycosylated human IgG1 and IgG3 monoclonal anti-D (Rh) and human IgG1 and IgG3 chimaeric anti-5-iodo-4-hydroxy-3-nitrophenacetyl (anti-NIP) monoclonal antibodies produced in the presence of tunicamycin have been compared with the native glycosylated proteins with respect to recognition by human Fc gamma RI and/or Fc gamma RII receptors on U937, Daudi or K562 cells. Human red cells sensitized with glycosylated IgG3 form rosettes via Fc gamma RI with 60% of U937 cells. Inhibition of rosette formation required greater than 35-fold concentrated more aglycosylated than glycosylated human monoclonal anti-D (Rh) antibody. Unlabelled polyclonal human IgG and glycosylated monoclonal IgG1 and anti-D (Rh) antibody inhibited the binding of 125I-labelled monomeric human IgG binding by U937 Fc gamma RI at concentrations greater than 50-fold lower than the aglycosylated monoclonal IgG1 anti-D (Rh) (K50 approximately 3 x 10(-9) M and approximately 6 x 10(-7) M respectively). Similar results were obtained using glycosylated and aglycosylated monoclonal human IgG1 or IgG3 chimaeric anti-NIP antibody-sensitized red cells rosetting with Fc gamma RI-/Fc gamma RII+ Daudi and K562 cells. Rosette formation could be inhibited by the glycosylated form (at greater than 10(-6) M) but not by the aglycosylated form. Haemagglutination analysis using a panel of murine monoclonal antibodies specific for epitopes located on C gamma 2, C gamma 3 or C gamma 2/C gamma 3 interface regions did not demonstrate differences in Fc conformation between the glycosylated or aglycosylated human monoclonal antibodies. These data suggest that the Fc gamma RI and Fc gamma RII sites on human IgG are highly conformation-dependent and that the carbohydrate moiety serves to stabilize the Fc structure rather than interacting directly with Fc receptors.
High-Resolution Solution Structure of the β Chemokine hMIP-1β by Multidimensional NMR (1994)

The three-dimensional structure of a member of the beta subfamily of chemokines, human macrophage inflammatory protein-1 beta (hMIP-1 beta), has been determined with the use of solution multidimensional heteronuclear magnetic resonance spectroscopy. Human MIP-1 beta is a symmetric homodimer with a relative molecular mass of approximately 16 kilodaltons. The structure of the hMIP-1 beta monomer is similar to that of the related alpha chemokine interleukin-8 (IL-8). However, the quaternary structures of the two proteins are entirely distinct, and the dimer interface is formed by a completely different set of residues. Whereas the IL-8 dimer is globular, the hMIP-1 beta dimer is elongated and cylindrical. This provides a rational explanation for the absence of cross-binding and reactivity between the alpha and beta chemokine subfamilies. Calculation of the solvation free energies of dimerization suggests that the formation and stabilization of the two different types of dimers arise from the burial of hydrophobic residues.
Metal-enhanced fluorescence from copper substrates (2007)

In this letter, the authors report the observation of metal-enhanced fluorescence emission from fluorophores deposited on copper (Cu) substrates. Different thicknesses of Cu particulate films (from 1 to 5nm) were deposited onto glass slides using thermal vapor deposition. Fluorophores positioned in close proximity to the Cu films show fluorescence enhancement as a function of the Cu thickness increases, reaching a maximum (2.5-fold) at ≈3nm. The findings strongly suggest that surface plasmons from Cu can radiate and therefore enhance a fluorophore’s spectral properties, similar to observations reported for both silver and gold nanoparticle deposited substrates.
METHYLATION PHARMACOGENETICS: Catechol O-Methyltransferase, Thiopurine Methyltransferase, and Histamine N-Methyltransferase (1999)

Methyl conjugation is an important pathway in the biotransformation of many exogenous and endogenous compounds. Pharmacogenetic studies of methyltransferase enzymes have resulted in the identification and characterization of functionally important common genetic polymorphisms for catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. In recent years, characterization of these genetic polymorphisms has been extended to include the cloning of cDNAs and genes, as well as a determination of the molecular basis for the effects of inheritance on these methyltransferase enzymes. The thiopurine methyltransferase genetic polymorphism is responsible for clinically significant individual variations in the toxicity and therapeutic efficacy of thiopurine drugs such as 6-mercaptopurine. Phenotyping for the thiopurine methyltransferase genetic polymorphism represents one of the first examples in which testing for a pharmacogenetic variant has entered standard clinical practice. The full functional implications of pharmacogenetic variation in the activities of catechol O-methyltransferase and histamine N-methyltransferase remain to be determined. Finally, experimental strategies used to study methylation pharmacogenetics illustrate the rapid evolution of biochemical, pharmacologic, molecular, and genomic approaches that have been used to determine the role of inheritance in variation in drug metabolism, effect, and toxicity.
Flatly broadened, wideband and low noise supercontinuum generation in highly nonlinear hybrid fiber (2004)

We present wideband of 1180-2100 nm, flatly broadened supercontinuum (SC) generation using highly nonlinear hybrid fibers and femtosecond fiber laser. Stable and smooth spectra without fine structure are demonstrated. The hybrid fibers are constructed by fusion splicing fibers with different properties. The SC spectra can be properly controlled by the optimal design of the hybrid fiber based on the numerical analysis. The generated SC pulse shows the low relative intensity noise (RIN).
Quantitative phosphoproteomics revealed interplay between Syk and Lyn in the resistance to nilotinib in chronic myeloid leukemia cells (2011)

In this study, we have addressed how Lyn kinase signaling mediates nilotinib-resistance by quantitative phospho-proteomics using Stable Isotope Labeling with Amino acid in Cell culture. We have found an increased tyrosine phosphorylation of 2 additional tyrosine kinases in nilotinib-resistant cells: the spleen tyrosine kinase Syk and the UFO family receptor tyrosine kinase Axl. This increased tyrosine phosphorylation involved an interaction of these tyrosine kinases with Lyn. Inhibition of Syk by the inhibitors R406 or BAY 61-3606 or by RNA interference restored the capacity of nilotinib to inhibit cell proliferation. Conversely, coexpression of Lyn and Syk were required to fully induce resistance to nilotinib in drug-sensitive cells. Surprisingly, the knockdown of Syk also strongly decreased tyrosine phosphorylation of Lyn and Axl, thus uncovering interplay between Syk and Lyn. We have shown the involvement of the adaptor protein CDCP-1 in resistance to nilotinib. Interestingly, the expression of Axl and CDCP1 were found increased both in a nilotinib-resistant cell line and in nilotinib-resistant CML patients. We conclude that an oncogenic signaling mediated by Lyn and Syk can bypass the need of Bcr-Abl in CML cells. Thus, targeting these kinases may be of therapeutic value to override imatinib or nilotinib resistance in CML.
Electrokinetic concentration enrichment within a microfluidic device using a hydrogel microplug (2005)

A simple and efficient approach for concentration of charged molecules in microfluidic devices is described. The functional component of the system is a hydrogel microplug photopolymerized within the main channel of a microfluidic device. When an appropriately biased voltage is applied across the hydrogel, charged analyte molecules move from the source well toward the hydrogel. Transport of the analyte through the hydrogel is slow compared to its velocity in the microfluidic channel, however, and therefore it concentrates at the hydrogel/solution interface. For an uncharged hydrogel, a bias of 100 V leads to a approximately 500-fold enrichment of the DNA concentration within 150 s, while the same conditions result in an enrichment of only 50-fold for fluorescein. Somewhat lower enrichment factors are observed when a negatively charged hydrogel is used. A qualitative model is proposed to account for the observed behavior.
Recombinant Vesicular Stomatitis Virus (VSV) and Other Strategies in HCV Vaccine Designs and Immunotherapy (2006)

Several vaccine strategies have been attempted in chimpanzee and smaller animal models to generate immune responses to hepatitis C virus (HCV). While neutralizing antibody may play a role in preventing HCV infection, studies in chimpanzees and humans during rare cases of acute resolving HCV infection indicate that, HCV immunity appears to be associated with vigorous, sustained and multi-specific Th1 intra hepatic CD8+ and CD4+ T cell responses. Several new promising technologies utilizing viral based vaccine approaches that appear to generate both antibody and cell mediated immune responses have recently been reported. These include viral vectors that express HCV products and non-replicating viral like particles (VLPs) that appear to induce T-helper type 1 (Th1) immune responses considered important in resolving HCV infection. In addition, viral vectors based on recombinant vesicular stomatitis virus (rVSV) may offer safe yet potent stimulation of both innate and adaptive immune responses. Here, we review the successful application of viral based vaccines, including VSV in generating viral immunity in animal models and describe the potential usefulness of this technology as a strategy for HCV vaccine design and immunotherapy.
Deep learning via Hessian-free optimization (2010)

We develop a 2 nd-order optimization method based on the “Hessian-free ” approach, and apply it to training deep auto-encoders. Without using pre-training, we obtain results superior to those reported by Hinton &amp;amp; Salakhutdinov (2006) on the same tasks they considered. Our method is practical, easy to use, scales nicely to very large datasets, and isn’t limited in applicability to autoencoders, or any specific model class. We also discuss the issue of “pathological curvature ” as a possible explanation for the difficulty of deeplearning and how 2 nd-order optimization, and our method in particular, effectively deals with it. 1.
MicroRNA 29b functions in acute myeloid leukemia (2009)

MicroRNAs (miRNAs) are associated with cytogenetics and molecular subtypes of acute myelogeneous leukemia (AML), but their impact on AML pathogenesis is poorly understood. We have previously shown that miR-29b expression is deregulated in primary AML blasts. In this work, we investigated the functional role of miR-29b in leukemogenesis. Restoration of miR-29b in AML cell lines and primary samples induces apoptosis and dramatically reduces tumorigenicity in a xenograft leukemia model. Transcriptome analysis after ectopic transfection of synthetic miR-29b into leukemia cells indicates that miR-29b target apoptosis, cell cycle, and proliferation pathways. A significant enrichment for apoptosis genes, including MCL-1, was found among the mRNAs inversely correlated with miR-29b expression in 45 primary AML samples. Together, the data support a tumor suppressor role for miR-29 and provide a rationale for the use of synthetic miR-29b oligonucleotides as a novel strategy to improve treatment response in AML.