gebhart/patrepeval huggingface dataset:
Leukemia-Reactive Cytotoxic CD8+ and CD4+ T-Cells Specific for Novel WT-1 Epitopes Are Generated In Vitro by Sensitization with Overlapping Pentadecapeptides (15-mers) Spanning the Wilms Tumor Protein. (2007)

Abstract The Wilms Tumor protein, WT-1 is differentially expressed in 60–80% of acute leukemias and CML. Evidence also suggests WT-1 expression in clonogenic leukemia stem cells, making WT-1 an attractive target for T-cell therapy. However, to date, only a limited number of immunogenic epitopes have been identified. To address this limitation, we employed a pool of 15-mers with 10 amino acid overlaps spanning the complete sequence of WT-1 loaded on autologous monocyte derived dendritic cells or EBV transformed BLCL to sensitize T-cells from normal donors of varied HLA genotypes. Specific 15-mers eliciting WT-1 specific responses were identified by quantitating IFNγ+ CD8+ or CD4+ T-cell responses to secondary stimulation with 15-mer subpools organized in a mapping grid with single overlaps. Phenotypes of T-cells producing IFNγ+ in response to identified specific 15-mers were determined by FACS analysis. We identified the HLA class I or II allele presenting each epitope by assessing the cytolytic activity and/or cytokine production of the pooled-peptide sensitized T-cells in response to 2° stimulation with a panel of PHA blasts loaded with the identified 15-mer, each sharing a single HLA allele with the T-cell donor. T-cells from each of 15 donors tested generated WT-1 peptide reactive T-cells in response to the WT-1 peptide pool. Of 23 epitopes identified that elicited T-cell responses, 19 were heretofore unrecognized epitopes presented by HLA A0201(N=4), A0301(N=2), A2402 (N=2), B3501(N=3), B0701(N=1), B4402(N=2), B3808(N=1), DRB, 0401(N=2), DRB10402(N=1) and DRB1 0701(N=1). Each of the 15 new epitopes presented by class I alleles elicited IFNγ+ CD8+ T-cells that were also cytotoxic against leukemic blasts sharing the restricting allele. All four epitopes presented by class II HLA alleles elicited IFNγ+ CD4+ T-cell responses, of which 2 were also cytotoxic against HLADR+ leukemia blasts expressing the restricting allele. Responses to these newly identified epitopes were comparable to or exceeded those elicited by the known immunogenic peptide epitope 126–134RMFPNAPYL presented by HLAA0201. Like RMF-specific T-cells, T-cells specific for 4 of the new epitopes tested to date do not exhibit activity against normal hematopoietic progenitor cells. Thus, by sensitizing T-cells from unselected normal donors, with autologous DCs loaded with a pool of overlapping 15-mers spanning WT-1, we have generated T-cells specific for a series of new epitopes of WT-1, each, presented by a distinct class I or II HLA allele, which also exhibit HLA-restricted cytotoxic against WT-1+ leukemic cells. Clinical trials of adoptive therapy with WT-1 specific T-cells generated by this approach are being initiated for adoptive therapy.
Focus on TILs: Prognostic significanceof tumor infiltrating lymphocytes in human melanoma (2009)

Tumors contain variable numbers of lymphocytes, referred to as tumor infiltrating lymphocytes (TILs). In melanoma, the intensity of this lymphocytic infiltrate is believed to correlate with outcome, though there is some debate about the applicability of this finding for all melanomas. Much research has gone into classifying TILs with respect to antigen receptor structure and the antigen to which melanoma-specific T cells react. However, these studies for the most part did not immunophenotype TILs, and recent data has revealed that the composition of tumoral lymphocytes is not homogenous, but rather represents varying contributions from many lymphocytic subsets. Furthermore, the function of TILs is often compromised as a result of the accumulation of immunoregulatory cells and various tumor escape mechanisms. These recent insights stress the need to collect more data on the composition and function of TIL infiltrates before definitive conclusions about the prognostic significance of TILs can be drawn. Advances in immunology have also facilitated the development of immunotherapeutic strategies, examples of which will be discussed with a special emphasis on blocking antibodies against CTLA-4, which are prototypical immunotherapeutic agents. This flurry of novel biological therapies will undoubtedly complicate our already incomplete understanding of TIL immunobiology as each of these agents has the potential to uniquely distort the series of immunological events which normally occur in untreated melanoma. Therefore, considerable research is needed to better elucidate the function and prognostic significance of TILs in both untreated melanoma and tumors treated with biological therapy.
Mechanical Chest Compressions and Simultaneous Defibrillation vs Conventional Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest (2013)

clinicaltrials.gov Identifier: NCT00609778.
Design, Synthesis, and Biological Evaluation of Peptidomimetic Inhibitors of Factor XIa as Novel Anticoagulants (2006)

Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation cascade. To investigate the potential of FXIa inhibitors as safe anticoagulants, a series of potent, selective peptidomimetic inhibitors of FXIa were designed and synthesized. Some of these inhibitors showed low nanomolar FXIa inhibitory activity with >1000-fold FXa selectivity and >100-fold thrombin selectivity. The X-ray structure of one of these inhibitors, 36, demonstrates its unique binding interactions with FXIa. Compound 32 caused a doubling of the activated partial thromboplastin time in human plasma at 2.4 microM and was efficacious in a rat model of venous thrombosis. These data suggest that factor XIa plays a significant role in venous thrombosis and may be a suitable target for the development of antithrombotic therapy.
Industrializing Autologous Adoptive Immunotherapies: Manufacturing Advances and Challenges (2018)

Cell therapy has proven to be a burgeoning field of investigation, evidenced by hundreds of clinical trials being conducted worldwide across a variety of cell types and indications. Many cell therapies have been shown to be efficacious in humans, such as modified T-cells and natural killer (NK) cells. Adoptive immunotherapy has shown the most promise in recent years, with particular emphasis on autologous cell sources. Chimeric Antigen Receptor (CAR)-based T-cell therapy targeting CD19-expressing B-cell leukemias has shown remarkable efficacy and reproducibility in numerous clinical trials. Recent marketing approval of Novartis' Kymriah™ (tisagenlecleucel) and Gilead/Kite's Yescarta™ (axicabtagene ciloleucel) by the FDA further underscores both the promise and legwork to be done if manufacturing processes are to become widely accessible. Further work is needed to standardize, automate, close, and scale production to bring down costs and democratize these and other cell therapies. Given the multiple processing steps involved, commercial-scale manufacturing of these therapies necessitates tighter control over process parameters. This focused review highlights some of the most recent advances used in the manufacturing of therapeutic immune cells, with a focus on T-cells. We summarize key unit operations and pain points around current manufacturing solutions. We also review emerging technologies, approaches and reagents used in cell isolation, activation, transduction, expansion, in-process analytics, harvest, cryopreservation and thaw, and conclude with a forward-look at future directions in the manufacture of adoptive immunotherapies.
The Research on Safety Evaluation of High-pile Wharf Structure (2013)

Due to a combination of the sea erosion,the ship collision,the change of ground condition,the effect of alternative static and dynamic load and the material deterioration,the structure of high-pile wharf is easily damaged.Once the structure of high-pile wharf destroyed,it is bound to be a great threat to the safety of various facilities and personnel in the port.Given all of that,the multi-level comprehensive evaluation method based on the extension theory is proposed in this paper.Using this method to assess the safety of high-pile wharf structure,the reasonable advice on its maintenance and reinforcement can be given in time.What’s more,the method is simple and can give more objective result of the evaluation.
Experimental Transmission of Ehrlichia chaffeensis (Rickettsiales: Ehrlichieae) Among White-Tailed Deer by Amblyomma americanum (Acari: Ixodidae) (1995)

Ehrlichia chaffeensis Anderson, Dawson & Wilson, causative agent of human (predominantly monocytic) ehrlichiosis, was successfully transmitted experimentally by Amblyomma americanum (L.) to white-tailed deer, Odocoileus virginianus (Zimmerman). Deer were needle-exposed intravenously to E. chaffeensis in tissue-culture canine macrophage (DH82) cells, and 11 d later were exposed to laboratory-reared A. americanum larvae, nymphs, and adults for acquisition feeding. Three months after this feeding, naive deer and dogs were exposed to recently molted nymphs and adults. Attempted reisolation of the pathogen by way of tissue culture was successful from one needle-exposed deer but not from the tick-exposed deer or dogs. Based on serologic evidence and polymerase chain reaction data, both nymphal and adult ticks transmitted E. chaffeensis to naive deer but not to dogs.
Exploring the potential of heterogeneous von neumann/dataflow execution models (2015)

General purpose processors (GPPs), from small inorder designs to many-issue out-of-order, incur large power overheads which must be addressed for future technology generations. Major sources of overhead include structures which dynamically extract the data-dependence graph or maintain precise state. Considering irregular workloads, current specialization approaches either heavily curtail performance, or provide simply too little benefit. Interestingly, well known explicit-dataflow architectures eliminate these overheads by directly executing the data-dependence graph and eschewing instruction-precise recoverability. However, even after decades of research, dataflow architectures have yet to come into prominence as a solution. We attribute this to a lack of effective control speculation and the latency overhead of explicit communication, which is crippling for certain codes.
Cytotoxic lymphokines produced by cloned human cytotoxic T lymphocytes. I. Cytotoxins produced by antigen-specific and natural killer-like CTL are dissimilar to classical lymphotoxins. (1985)

Several cloned lines of IL 2-dependent human T cells derived from alloantigen, mitogen, or IL 2-stimulated peripheral blood lymphocytes were examined for their surface marker expression, cytolytic activity in a 51Cr-release assay, and capacity to release cytotoxic lymphokines. Thirty cell lines exhibiting either antigen-specific natural killer cell activity or lectin-dependent killer cell function, which expressed either the CD4 or CD8 surface differentiation markers, were capable of producing cytotoxin(s) in response to the lectins phytohemagglutinin and concanavalin A. Cytotoxin activity was detected on the murine L929 target cell in a 16-hr cytotoxicity assay. In contrast, several nonlytic T cell tumor lines failed to produce a soluble cytotoxin. Antibodies capable of neutralizing human alpha-lymphotoxin were completely ineffective in inhibiting the cytotoxin(s) produced by any of the cytotoxic T lymphocytes (CTL) cell lines. Comparative gel filtration and HPLC hydrophobic chromatography of alpha-lymphotoxin and CTL toxin produced by the CTL-830.B2 clone revealed significant differences in their elution profiles. The CTL-produced toxin and alpha-lymphotoxin exhibited similar kinetics of lysis of the L929 target cells, with 50% target cell lysis occurring at 10 hr. These data indicate human CTL produce a cytotoxin(s) antigenically distinct from alpha-lymphotoxin and imply that human cytolytic effector T cells are not the cellular source for the production of human alpha-lymphotoxin. The relationship of alpha-lymphotoxin and CTL toxin production was investigated in unseparated peripheral blood mononuclear cells stimulated with lectins or IL 2 for 1 and 5 days. Anti-alpha-lymphotoxin antibodies were capable of neutralizing only 30 to 50% of the cytotoxic activity in 24-hr supernatants. Cytotoxic activity in supernatants harvested after 120 hr stimulation with PHA or Con A was neutralized 70 to 100%, whereas the toxin(s) released from IL 2-stimulated lymphocytes was only neutralized 30%. These data suggest the observed heterogeneity of cytotoxic lymphokines produced by unseparated mononuclear cells depends in part on the subpopulations of effector cells responding to a given stimulus and the capacity of different subpopulations to produce distinct cytotoxins.
Enhancement of nonparabolicity effects in a quantum well (1987)

The effects of conduction-band nonparabolicity on the confinement energy and energy dispersion parallel to the layers for a GaAs quantum well are investigated with the use of an expression for the bulk conduction-band dispersion expanded to fourth order in k. The anisotropy of the conduction band is included. We derive some accurate analytical expressions for the perpendicular mass, which gives the confinement energy, and the parallel mass, which is relevant for motion along the quantum well. These masses explicitly depend on the confinement energy. We find that the nonparabolicity enhancement for the parallel mass is about three times stronger than for the perpendicular mass. We finally compare with some recent experimental results.
SDGToolkit: A Toolkit for Rapidly Prototyping Single Display Groupware (2002)

A functional vascular system is a prerequisite for bone repair as disturbed angiogenesis often causes non-union. Paracrine factors released from human bone marrow derived mesenchymal stromal cells (BMSCs) have angiogenic effects on endothelial cells. However, whether these paracrine factors participate in blood flow dynamics within bone capillaries remains poorly understood. Here, we used two different microfluidic designs to investigate critical steps during angiogenesis and found pronounced effects of endothelial cell proliferation as well as chemotactic and mechanotactic migration induced by BMSC conditioned medium (CM). The application of BMSC-CM in dynamic cultures demonstrates that bioactive factors in combination with fluidic flow-induced biomechanical signals significantly enhanced endothelial cell migration. Transcriptional analyses of endothelial cells demonstrate the induction of a unique gene expression profile related to tricarboxylic acid cycle and energy metabolism by the combination of BMSC-CM factors and shear stress, which opens an interesting avenue to explore during fracture healing. Our results stress the importance of in vivo - like microenvironments simultaneously including biochemical, biomechanical and oxygen levels when investigating key events during vessel repair. STATEMENT OF SIGNIFICANCE: Our results demonstrate the importance of recapitulating in vivo - like microenvironments when investigating key events during vessel repair. Endothelial cells exhibit enhanced angiogenesis characteristics when simultaneous exposing them to hMSC-CM, mechanical forces and biochemical signals simultaneously. The improved angiogenesis may not only result from the direct effect of growth factors, but also by reprogramming of endothelial cell metabolism. Moreover, with this model we demonstrated a synergistic impact of mechanical forces and biochemical factors on endothelial cell behavior and the expression of genes involved in the TCA cycle and energy metabolism, which opens an interesting new avenue to stimulate angiogenesis during fracture healing.
NMR structural studies of the Ste11 SAM domain in the dodecyl phosphocholine micelle (2008)

The sterile alpha-motif (SAM), a relatively small ( approximately 70 amino acids) interaction domain, is found in a variety of proteins involved in cell signaling, transcription regulation, and scaffolding. The Ste11 protein kinase from the mitogen activated protein kinase (MAPK) signaling cascades of the budding yeast is regulated by a SAM domain located at the N-terminus of full-length protein. In solution, the Ste11 SAM domain exists as a well-folded dimeric structure that is involved in interaction with the cognate SAM domain from an adaptor protein Ste50. In this work, we show that the Ste11 SAM domain has an intrinsic affinity towards the lipid membranes. The solution conformation of the Ste11 SAM determined in perdeuterated DPC micelle, using NMR spectroscopy, is defined by five helices of different lengths connected by a number of loops. In the micelle bound state, the non-polar and aromatic residues of the Ste11 SAM lack a native-like packing and are presumably engaged in interactions with the micelle. Using two different paramagnetic doxyl-lipids; we have mapped out localization of Ste11 SAM residues at the micelle surface. Most of the residues appear to localize at the interfacial region of the micelle. However, a number of non-polar residues from the central region of the domain are found to be located inside the core of the micelle including residues from the helix 4 and a loop between helix 2 and helix 3. Isothermal titration calorimetry studies demonstrate that a facile insertion of the Ste11 SAM into the DPC micelle is primarily driven by a large change in enthalpy, -50 kcal/mol with an apparent equilibrium association constant (Ka) of 7.86 x 10(6) M(-1). Interestingly, an interfacial mutant L60R of the Ste11 SAM lacking the dimeric structure does not show detectable interactions with the lipid micelle. The micelle-bound structure of the Ste11 SAM domain described in this work may have potential implications in the regulation of MAPK signaling whereby positioning of the Ste11 protein in close proximity to the membrane may facilitate efficient phosphorylation of the Ste11 kinase by the membrane attached upstream Ste20/pak kinase.
Retrovirus-Mediated Gene Transfer to Tumors: Utilizing the Replicative Power of Viruses to Achieve Highly Efficient Tumor Transduction In Vivo (2004)

Vectors derived from retroviruses have been widely studied as tools for gene transfer into mammalian tissue in vivo. One application for which retroviral vectors have received particular attention is gene transfer into tumor cells for treatment of cancer. Simple retroviruses, such as murine leukemia virus (MLV), and the vectors derived from them, require cell division for infection and thus possess a degree of inherent specificity for the rapidly dividing cells of neoplastic tissue. This unique property and the ease with which retroviral vectors are manipulated and produced have provided much of the impetus for their use in experimental and clinical cancer gene-therapy studies.
The Quality of Care for Depressive and Anxiety Disorders in the United States (2001)

It is possible to evaluate mental health care quality on a national basis. Most adults with a probable depressive or anxiety disorder do not receive appropriate care for their disorder. While this holds across diverse groups, appropriate care is less common in certain demographic subgroups.
Pattern recognition techniques in handoff and service area determination (2002)

Pattern recognition algorithms are used to process the field strength intensities in order to select the base station which will serve the call. The algorithms are: the Isodata clustering algorithm and fuzzy classifiers based on membership functions. The performance and application of these algorithms, in a microcellular environment, are evaluated and discussed.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Cytotoxicity of Artemisinin-Related Endoperoxides to Ehrlich Ascites Tumor Cells (1993)

A series of artemisinin-related endoperoxides was tested for cytotoxicity to Ehrlich ascites tumor (EAT) cells using the microculture tetrazolium (MTT) assay. Artemisinin [1] had an IC50 value of 29.8 microM. Derivatives of dihydroartemisinin [2], being developed as antimalarial drugs (artemether [3], arteether [4], sodium artesunate [5], artelinic acid [6], and sodium artelinate [7]), exhibited a somewhat more potent cytotoxicity. Their IC50 values ranged from 12.2 to 19.9 microM. The presence of an exocyclic methylene fused to the lactone ring, as for artemisitene [9], led to higher cytotoxicity than 1. From the two epimeric 11-hydroxyartemisinin derivatives, the R form 12 showed a considerably higher cytotoxicity than the S form 13. Opening of the lactone ring of 1 dramatically reduced the cytotoxicity. The ether dimer 8 of 2 was the most potent cytotoxic agent, its IC50 being 1.4 microM. The variations in cytotoxicity between the structurally related compounds mostly correlated well with the theoretical capacity of radical formation and stabilization. In some cases lipophilicity or the presence of an electrophilic moiety seemed to have a determinant influence on cytotoxicity. The artemisinin-related endoperoxides showed cytotoxicity to EAT cells at higher concentrations than those needed for in vitro antimalarial activity, as reported in the literature.
Establishment and transformation diminish the ability of fibroblasts to contract a native collagen gel. (1980)

Cultures of established and transformed fibroblasts were less able to contract a hydrated collagen gel than normal precrisis cells. Postcrisis fibroblasts from different rodent strains and species underwent a further reduction in contraction ability and either spontaneous or simian virus 40 (SV40) transformation. Human precrisis fibroblasts contracted much more efficiently than two SV40-transformed human lines. Fibroblasts from a patient with Glanzmann's thrombasthenia were intermediate between all other human fibroblasts assayed and the SV40-transformed human lines. The absolute efficiency of contraction was dependent on temperature and serum concentration, but no conditions were found that resulted in equal efficiencies for the three types of cells. Precrisis cells were extremely sensitive to the passage procedures when assayed for collagen contraction.
The Potential of Circulating Tumor Cells as a Liquid Biopsy to Guide Therapy in Prostate Cancer (2012)

Miyamoto and colleagues present data that prostate-specific antigen/prostate-specific membrane antigen (PSA/PSMA)-based measurements of androgen receptor (AR) signaling in circulating tumor cells (CTC) enable real-time quantitative monitoring of intratumoral AR signaling. This finding indicates that measuring AR signaling within CTCs may help to guide therapy in metastatic prostate cancer and highlights the use of CTCs as liquid biopsy.