gebhart/patrepeval huggingface dataset:
Immunological Property of Antibodies against N -Glycolylneuraminic Acid Epitopes in Cytidine Monophospho– N -Acetylneuraminic Acid Hydroxylase-Deficient Mice (2010)

The generation of pigs devoid of Galalpha1,3Galbeta1,4GlcNAc (Gal) residues has stimulated interest in non-Gal Ags as potentially important targets for Ab binding leading to rejection of pig organ xenografts in humans. Although N-glycolylneuraminic acid (NeuGc) epitopes, which are widely expressed on the endothelial cells of all mammals except humans, are likely targets of anti-non-Gal Abs, this aspect has not been investigated intensively owing to the absence of an appropriate animal model. In this study, we used CMAH(-/-) mice, which are completely deficient in NeuGc and thus produce anti-NeuGc Abs. Sera obtained from CMAH(-/-) mice and healthy human volunteers having anti-NeuGc Abs initiated complement-mediated lysis against CMAH(+/+) cells in vitro. The cytotoxic activity of anti-NeuGc Abs was also determined in vivo (i.e., NeuGc-expressing CMAH(+/+) mouse splenocytes that had been i.v. injected were completely eliminated in syngeneic CMAH(-/-) mice). CMAH(-/-) mice rejected the islets transplanted from syngeneic CMAH(+/+) mice. Thus, the anti-NeuGc Ab-mediated response may be crucially involved in xenograft loss. This is the first direct demonstration of the immunogenic property of NeuGc determinants as targets of the corresponding Abs in CMAH(+/+)-to-CMAH(-/-) transplantation setting.
Growth factor requirement for survival in cell-cycle dormancy of primitive murine lymphohematopoietic progenitors (1993)

We used enriched marrow cells from mice administered three doses of 150 mg/kg 5-fluorouracil (5-FU) 1, 3 and 7 days before they were killed to study the effects of different growth factors on the survival of primitive, cell-cycle dormant progenitors in culture. This cell population yielded substantially fewer colonies in response to single growth factors than corresponding preparations from day 2 post-5-FU bone marrow samples, and the majority of progenitors were multipotential in nature. These observations were consistent with the prediction that multiple cycles of 5-FU treatment would further enrich for primitive cells. With this cell population, we found that among all the factors tested, interleukin-3 (IL-3) and steel factor (SF) as single factors are the most effective in supporting survival of dormant primitive progenitors. Interleukin-6 (IL-6), granulocyte colony- stimulating factor (G-CSF), interleukin-11 (IL-11), interleukin-4 (IL- 4), interleukin-1 alpha (IL-1 alpha), and tumor necrosis factor-alpha (TNF-alpha) also supported survival of a few progenitors, but much less effectively than either IL-3 or SF. The hematopoietic progenitors that survived for 1 week in liquid culture supplemented with either IL-3 or SF retained the capability to develop pre-B-cell colonies in secondary culture. Our results demonstrate that survival of dormant murine lymphohematopoietic cells in culture is dependent on the presence of specific growth factors, and that this growth factor requirement can be satisfied well by SF or IL-3.
HotSpot Wizard: a web server for identification of hot spots in protein engineering (2009)

HotSpot Wizard is a web server for automatic identification of 'hot spots' for engineering of substrate specificity, activity or enantioselectivity of enzymes and for annotation of protein structures. The web server implements the protein engineering protocol, which targets evolutionarily variable amino acid positions located in the active site or lining the access tunnels. The 'hot spots' for mutagenesis are selected through the integration of structural, functional and evolutionary information obtained from: (i) the databases RCSB PDB, UniProt, PDBSWS, Catalytic Site Atlas and nr NCBI and (ii) the tools CASTp, CAVER, BLAST, CD-HIT, MUSCLE and Rate4Site. The protein structure and e-mail address are the only obligatory inputs for the calculation. In the output, HotSpot Wizard lists annotated residues ordered by estimated mutability. The results of the analysis are mapped on the enzyme structure and visualized in the web browser using Jmol. The HotSpot Wizard server should be useful for protein engineers interested in exploring the structure of their favourite protein and for the design of mutations in site-directed mutagenesis and focused directed evolution experiments. HotSpot Wizard is available at http://loschmidt.chemi.muni.cz/hotspotwizard/.
Comprehensive follow-up of the first genome-wide association study of multiple sclerosis identifies KIF21B and TMEM39A as susceptibility loci (2009)

Genome-wide association studies (GWASs) have proven highly effective, identifying hundreds of associations across numerous complex diseases. These studies typically test hundreds of thousands of variations and identify hundreds of potential associations. However, to date, follow-up attempts have generally only concentrated on just the few most significant initial associations, leaving the majority of true associations in any GWAS study without replication. Here, we present a substantially more comprehensive follow-up of the first genome-wide association screen performed in multiple sclerosis (MS), a complex genetic disease with central nervous system inflammation. We genotyped approximately 30 000 single-nucleotide polymorphisms (SNPs) that demonstrated mild-to-moderate levels of significance (P < or = 0.10) in the initial GWAS in an independent set of 1343 MS cases and 1379 controls. We further replicated several of the most significant findings in another independent data set of 2164 MS cases and 2016 controls. We find considerable evidence for a number of novel susceptibility loci including KIF21B [rs12122721, combined P = 6.56 x 10(-10), odds ratio (OR) = 1.22] and TMEM39A (rs1132200, P = 3.09 x 10(-8), OR = 1.24), both of which meet genome-wide significance. Both of these loci were overlooked in the initial replication, despite being among the top 3000 ( approximately 1%) SNP hits in the original screen.
Serum microRNA expression profile: miR-1246 as a novel diagnostic and prognostic biomarker for oesophageal squamous cell carcinoma (2013)

These data support our contention that serum miR-1246 has strong potential as a novel diagnostic and prognostic biomarker in ESCC, and its releasing mechanism is selective and independent of tissue miRNA abundance.
Development of Regenerative Cardiomyocytes from Mesenchymal Stem Cells for Cardiovascular Tissue Engineering (2001)

We have isolated a cardiomyogenic (CMG) cell line from murine bone marrow stroma. Stromal cells were immortalized, treated with 5-azacytidine, and spontaneous beating cells were repeatedly screened for. The cells showed a fibroblast-like morphology. However, this morphology changed after 5-azacytidine treatment in about 30% of the cells, which connected with adjoining cells after 1 week, formed myotube-like structures and began spontaneous beating after 2 weeks, and beat synchronously after 3 weeks. These cells expressed atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Electron microscopy revealed a cardiomyocyte-like ultrastructure including typical sarcomeres and atrial granules. They had sinus node-like or ventricular cell-like action potentials. Analysis of the isoform of contractile protein genes, such as myosin and alpha-actin, indicated that their phenotype was similar to fetal ventricular cardiomyocytes. These cells expressed Nkx2.5, GATA4, TEF-1, and MEF2-C mRNA before 5-azacytidine treatment, and expressed MEF2-A and MEF2-D after treatment. This new cell line provides a powerful model for the study of cardiomyocyte transplantation.
ICONIC: Biologic and clinical activity of first in class ICOS agonist antibody JTX-2011 +/- nivolumab (nivo) in patients (pts) with advanced cancers. (2018)

3000 Background: ICOS is a costimulatory molecule expressed on the surface of activated T cells. JTX-2011 is an ICOS agonist designed to stimulate CD4 T effector (T eff) cells and deplete intratumoral T regulatory (Treg) cells. Preclinical efficacy was seen with mouse JTX-2011 monotherapy (mono) and combination (combo) with anti-PD-1 in ICOS+ tumors. Methods: Relapsed/refractory cancer pts received escalating doses of JTX-2011 mono or combo with nivo in Phase 1 (P1), and the recommended P2 dose (RP2D) in P2, based on safety, target engagement (TE), immunophenotyping and cytokines. P2 gastric (GC) and triple negative breast (TNBC) combo cohorts completed enrollment. ICOS was assessed by IHC in archival (arch) and fresh pre-treatment tumor biopsies (bx) or by flow in peripheral blood. Results: 164 pts had ≥1 dose of JTX-2011; 71 P1 (40 mono, 31 combo); 93 P2 (25 mono, 68 combo) including 7 GC mono, 24 GC and 16 TNBC combo. Pts ≥3 prior therapies: 57% GC mono, 48% GC combo, 56% TNBC combo. JTX-2011 RP2D: 0.3mg/kg q3w mono and combo with nivo 240 mg q3w. DLTs: raised AST/ALT and pleural effusion at 1 mg/kg mono. At 0.3mg/kg: TE > 70% sustained through 3wks; no substantial change in # of peripheral T eff or Tregs; dose dependent increase in IFN-γ at 1-6 hrs. P2 adverse events (AEs): drug-related G3-4 8% mono, 13% combo; immune-related 4% mono, 21% combo; infusion related 12% mono, 19% combo. Of 13 GC combo pts with paired arch and fresh bx, 6 were ICOS hi on both, 5 changed from low to hi. Of 7 TNBC combo pts with paired bx, 5/7 archival were ICOS hi, 4/7 fresh were ICOS hi. RECIST antitumor activity: JTX-2011 mono: 1/7 partial response (PR) in GC; 2/5 stable disease (SD) in P1 TNBC. JTX-2011 combo: 2 PRs (0.1, 0.3mg/kg) and 2 ongoing SD in 19 P1/2 GC; 1 PR in 15 P2 TNBC. Of 17 evaluable pts, 4 had emergence of peripheral CD4 T cell ICOS hi subsets during JTX-2011 therapy, including 1 PR mono, 2 PR combo and 1 SD; none were seen in pts with progressive disease. Conclusions: JTX-2011 mono and combo with nivo were well tolerated with antitumor responses in heavily pre-treated GC and TNBC pts. Emergence of peripheral blood CD4 ICOS hi T cell subsets may be a surrogate biomarker of response. Further trials of JTX-2011 are planned. Clinical trial information: NCT02904226.
Acid‐catalyzed condensation of oleic acid into estolides and polyestolides (1994)

Abstract Oleic acid, when treated with 1.0 equivalent of perchloric acid at 50°C, produced a 76% yield of polyestolide. The concentration of mineral acid greatly affected the rate of estolide formation, with increased rates under high acid concentrations. Over a range of temperatures from room temperature to 100°C, reaction rates increased at higher temperatures. However, high acid concentrations and temperatures produced undesirable side products, primarily lactones. Other acids catalyze the condensation of oleic acid to form estolide with the following relative rates: HClO 4 &gt;H 2 SO 4 &gt; p ‐toluenesulfonic&gt;BF 3 ·Et 2 O&gt; montmorillonite K‐10&gt;HCl&gt;H 3 PO 4 , HNO 3 . Addition of water impedes the formation of estolide.
Cancer Genome Sequencing and Its Implications for Personalized Cancer Vaccines (2011)

New DNA sequencing platforms have revolutionized human genome sequencing. The dramatic advances in genome sequencing technologies predict that the $1,000 genome will become a reality within the next few years. Applied to cancer, the availability of cancer genome sequences permits real-time decision-making with the potential to affect diagnosis, prognosis, and treatment, and has opened the door towards personalized medicine. A promising strategy is the identification of mutated tumor antigens, and the design of personalized cancer vaccines. Supporting this notion are preliminary analyses of the epitope landscape in breast cancer suggesting that individual tumors express significant numbers of novel antigens to the immune system that can be specifically targeted through cancer vaccines.
Cytotoxic activity of lymphocytes. VII. cellular origin of alpha-lymphotoxin. (1978)

To detect the cellular origins of alpha-lymphotoxin (alpha-LT), we cultured various subpopulations of human blood lymphocytes separated by erythrocyte-rosetting techniques with various mitogens. T cell-enriched subpopulations responded to PHA by increased 3H-thymidine uptake into DNA and large amounts of alpha-LT production. SPL and Con A-Sepharose stimulated DNA synthesis in T cell-enriched cultures if the macrophage content was greater than 1.5%; however, alpha-LT production was not induced by these two mitogens even when reconstituted with 10% macrophages. B and/or null cell-enriched populations severely depleted of T cells (less than 0.7% did not respond to PHA, SPL, or Con A-Sepharose. However, reconstitution to 5 or more percent in E-RFC allowed all three mitogens to stimulate DNA synthesis and alpha-LT production. The LT made by all cell populations 5 and 7 days after stimulation were equally neutralized by a heterologous antiserum to alpha-LT. These results show that human T and B and/or null cells, when appropriately stimulated, can produce alpha-LT.
Quantitative Evaluation of Experimental Results an the Heterogeneous Freezing Nucleation of Supercooled Liquids (1971)

Freezing experiments using large numbers of small drops are frequently used for the study of both homogeneous and heterogeneous nucleation of water and of other substances. For heterogeneous nucleation, the spread in the observed freezing temperatures of drops has been shown to arise from the presence of nuclei of different activities in the sample. In the past no quantitative assessment of the nucleus content could be given independent of the drop sizes used. It is shown in this paper that from the observed freezing temperatures of the drops one can derive both a differential and a cumulative nucleus spectrum. The differential spectrum represents the concentrations of nuclei which are active at specific temperatures and the cumulative spectrum represents the concentrations of nuclei active at all temperatures warmer than the selected temperature. The accuracies of the derived spectra were examined by Monte Carlo simulation and are shown to be such that the concentrations are reliable to within factors of 2–4. The dependence of the average freezing temperature on drop volume is shown in general to be determined by the shape of the nucleus spectrum but is approximately exponential for many spectra.
Covalent Attachment of Poly(ethylene glycol) to Surfaces, Critical for Reducing Bacterial Adhesion (2003)

The effects of different poly(ethylene glycol) (PEG) attachment strategies upon the adhesion of a Gram-negative bacteria (Pseudomonas sp.) was tested. PEG was covalently immobilized, at the lower critical solution temperature of PEG, to a layer of branched poly(ethylenimine) (PEI). PEI was both physically adsorbed to a stainless-steel (SS) substrate and covalently immobilized to a carboxylated poly(ethylene terephthalate) (PET-COOH) surface, On both substrates, the PEI and PEG grafting conditions were optimized so that the levels of surface coverage after each step were maximized and were the same on both substrates, as judged by X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry (ToF-SIMS). Also, ToF-SIMS imaging showed that both substrates were chemically uniform after each surface modification step. Thus, the two surfaces differ only in the mode of attachment of PEI to the substrate. In bacterial adhesion experiments, the optimal SS-PEG surface was not capable of reducing the number of adherent Pseudomonas sp. when compared to the controls. However, the PET-PEG surface reduced the level of adhesion by between 2 and 4 orders of magnitude for up to 5 h. ToF-SIMS analysis showed that both PEG surfaces adsorbed low but comparable levels of proteinaceous growth medium components (tryptic soy broth), as indicated by the addition of unique amino acid fragment ions in the spectra, most likely small peptides. Thus, bacterial adhesion was strongly dependent on the PEG immobilization strategy and not on the extent of peptide/protein adsorption. However, for the best PEG surfaces the residual bacterial adhesion is most likely from recognition of the small amount of adsorbed peptides. This highlights the necessity for preventing the adsorption of small biological species that can even penetrate PEG layers of high graft density, in the quest for the ultimate 'nonfouling' surface.
Spike-Timing Theory of Working Memory (2010)

Working memory (WM) is the part of the brain's memory system that provides temporary storage and manipulation of information necessary for cognition. Although WM has limited capacity at any given time, it has vast memory content in the sense that it acts on the brain's nearly infinite repertoire of lifetime long-term memories. Using simulations, we show that large memory content and WM functionality emerge spontaneously if we take the spike-timing nature of neuronal processing into account. Here, memories are represented by extensively overlapping groups of neurons that exhibit stereotypical time-locked spatiotemporal spike-timing patterns, called polychronous patterns; and synapses forming such polychronous neuronal groups (PNGs) are subject to associative synaptic plasticity in the form of both long-term and short-term spike-timing dependent plasticity. While long-term potentiation is essential in PNG formation, we show how short-term plasticity can temporarily strengthen the synapses of selected PNGs and lead to an increase in the spontaneous reactivation rate of these PNGs. This increased reactivation rate, consistent with in vivo recordings during WM tasks, results in high interspike interval variability and irregular, yet systematically changing, elevated firing rate profiles within the neurons of the selected PNGs. Additionally, our theory explains the relationship between such slowly changing firing rates and precisely timed spikes, and it reveals a novel relationship between WM and the perception of time on the order of seconds.
Recent findings on laser treatment of twin-to-twin transfusion syndrome (2006)

Purpose of review Despite the recent demonstration of the benefit of the primary laser over amnioreduction, overall survival is far from optimal (70–80%), and therefore diagnosis and management of early and late complications following placental surgery became of great importance. Recent findings Laser therapy has proven to be better than amnioreduction in treating twin-to-twin transfusion syndrome. Miscarriage, preterm premature rupture of the membranes and preterm delivery account for more than 20% of perinatal mortality after treatment. In those who die despite treatment, recurrence of twin-to-twin transfusion syndrome, placental insufficiency or feto-fetal hemorrhage with anemia/polycythemia are complications that have to be managed with different secondary therapeutic options, such as amnioreduction, cord coagulation, intrauterine transfusion or repeat fetoscopy-guided laser. Ex-vivo placental angiography has confirmed that these complications occur when anastomoses are missed. Early predictors of laser efficacy in twin-to-twin transfusion syndrome treatment, such as improvement in the umbilical vein flow imbalance and urine production, are being evaluated, because they are earlier predictors of outcome than amniotic fluid discordance. Summary Optimization of laser treatment of twin-to-twin transfusion syndrome and new insight into the follow-up are likely to become the key to a better prognosis, and they are therefore important issues that have to be addressed in forthcoming studies.
Abnormal 24-hr mean plasma concentrations of dehydroisoandrosterone and dehydroisoandrosterone sulfate in women with primary operable breast cancer. (1981)

The 24-hr mean plasma concentrations of dehydroisoandrosterone (DHA) and dehydroisoandrosterone sulfate were measured in 11 women with primary operable breast cancer, ages 31 to 78 years, and in 37 normal women, ages 21 to 75 years. In contrast to the marked and progressive decline of DHA and dehydroisoandrosterone sulfate concentration with age in the normal women, the concentrations of both steroids were age invariant in the cancer patients. The premenopausal patients had subnormal plasma DHA and dehydroisoandrosterone sulfate levels, while the post menopausal patients had supranormal levels. Since the plasma DHA/androsterone ratio was normal in the premenopausal patients and significantly elevated in the postmenopausal patients, it is postulated that the subnormal plasma adrenal androgen levels in the premenopausal patients were due principally to diminished production of these steroids, while the elevated plasma levels in the postmenopausal patients were due principally to slowed metabolic removal. Reports in the literature that DHA inhibits the development of breast cancer in mice suggest that the subnormal plasma DHA levels in premenopausal breast cancer may have clinical significance.
Cost/benefit analysis for incorporating human factors in the software lifecycle (1988)

New software engineering techniques and the necessity to improve the user interface in increasingly interactive software environments have led to a change in traditional software development methods. Methodologies for improvement of the interface design, an overview of the human factors element, and cost/benefit aspects are explored.
Structure of the human ghicagon gene (1986)

A clone containing the complete human glucagon gene was isolated and sequenced. The gene is approximately 9.4 kilobases in length and comprises six exons and five introns. The putative preproglucagon encoded by this gene, 180 amino acids in length and containing glucagon and two glucagon-like peptides, is very similar to that of other mammalian species (greater than 90% amino acid sequence homology). There is 88% nucleotide sequence homology between the proximal 130 base pairs of the 5' flanking regions of the human and rat glucagon genes. These sequences, highly conserved throughout evolution, are likely involved in the regulation of glucagon gene transcription.
T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer (2016)

We identified a polyclonal CD8+ T-cell response against mutant KRAS G12D in tumor-infiltrating lymphocytes obtained from a patient with metastatic colorectal cancer. We observed objective regression of all seven lung metastases after the infusion of approximately 1.11×10<sup>11</sup> HLA-C*08:02-restricted tumor-infiltrating lymphocytes that were composed of four different T-cell clonotypes that specifically targeted KRAS G12D. However, one of these lesions had progressed on evaluation 9 months after therapy. The lesion was resected and found to have lost the chromosome 6 haplotype encoding the HLA-C*08:02 class I major histocompatibility complex (MHC) molecule. The loss of expression of this molecule provided a direct mechanism of tumor immune evasion. Thus, the infusion of CD8+ cells targeting mutant KRAS mediated effective antitumor immunotherapy against a cancer that expressed mutant KRAS G12D and HLA-C*08:02.
Infant Parenteral Nutrition Remains a Significant Source for Aluminum Toxicity (2016)

Aluminum contamination in infant PN remains almost 3 times higher than the advised maximum exposure (<5 mcg/kg/d, Food and Drug Administration 2004). Unexpectedly, an association between infant weight and aluminum exposure was not apparent, likely due to the homogeneity of our population. Isolating the source of aluminum contamination is difficult, as multiple components appear to be involved. Calcium gluconate is likely still a major contributor, but further investigations into individual components are warranted to promote the reduction of aluminum in infant PN.