gebhart/patrepeval huggingface dataset:
<title>Accuracy of point light target coordinate determination by dissectoral tracking system</title> (1995)

Dissectoral tracking systems are employed for coordinate determination and for tracking minor-dimensional light targets in optical coupling devices, laser location, and navigation systems. To analyze the accuracy of coordinate determination of minor dimensional point light target by dissectoral tracking system is suggested. The robustness and stability of the algorithm to deviation of the model parameters from nominal value and the accuracy of coordinate determination at different target contrasts, speed movement at the relationship signal/noise and dissectoral tracking system parameters, has been examined. The results are obtained by statistical simulation of the Kalman filter with a computer.
Current and Future Treatment Strategies for Patients with Advanced Hepatocellular Carcinoma: Role of mTOR Inhibition (2012)

Hepatocellular carcinoma (HCC) is a common cancer that has the third highest cancer-related mortality rate worldwide. Although potentially curable by transplantation if detected early, the majority of cases are diagnosed at an advanced stage of disease for which limited treatment options are available. The only proven systemic therapy for advanced HCC is sorafenib, a multi-kinase inhibitor that has demonstrated modest efficacy and reasonable tolerability in patients with advanced HCC. Five years after the approval of sorafenib, no other agent has been proven to be beneficial in the first- or second-line setting in advanced HCC. While molecular studies have highlighted various potential targets in HCC, the mammalian target of rapamycin (mTOR) has emerged as an exciting target for cancer therapy including HCC. Laboratory data have linked the phosphatidylinositol 3-kinase/AKT/mTOR axis to various oncogenic processes, including survival and angiogenesis. Historically, mTOR inhibitors have been used for their immunosuppressive properties, but more recently they have been approved as anticancer agents. Retrospective HCC studies suggest that the inclusion of mTOR inhibition as part of an immunosuppressant regimen after transplantation may reduce HCC recurrence compared with other immunosuppressive agents such as calcineurin inhibitors. More recently, single-arm, phase I/II studies have shown that mTOR inhibitors also have activity as monotherapy in cases of recurrent HCC or de novo advanced HCC. This article will review the rationale for targeting the mTOR pathway in HCC, and the currently available clinical data supporting its development for HCC.
The role of PIM1 in the ibrutinib-resistant ABC subtype of diffuse large B-cell lymphoma. (2016)

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous lymphoma and the most common subtype of non-Hodgkin lymphoma, accounting for roughly 30% of newly diagnosed cases in the United States. DLBCL can be separated into the activated B cell-like (ABC) and germinal center B cell-like (GCB) subtypes, with distinct gene expression profiles, oncogenic aberrations, and clinical outcomes. ABC-DLBCL is characterized by chronically active B-cell receptor (BCR) signaling that can be modulated by Bruton's tyrosine kinase (BTK) activity. Thus, BTK serves as an attractive therapeutic target in this type of B-cell malignancy. Ibrutinib, a first-in-class, orally available covalent BTK inhibitor, has demonstrated clinical activity in several B-cell leukemias and lymphomas. A phase 1/2 clinical trial of single-agent ibrutinib in relapsed and refractory DLBCL patients revealed an overall response rate of 37% in ABC-DLBCL patients. However, responses to kinase-directed therapies are often limited by emerging resistance mechanisms that bypass the therapeutic target. Here we report the discovery of point mutations within the kinase PIM1 that reduce sensitivity to ibrutinib in ABC-DLBCL. These mutations stabilize PIM1 and affect upstream regulators and downstream targets of NF-κB signaling. The introduction of mutant PIM1 into an ABC-DLBCL cell line, TMD8, increased colony formation and decreased sensitivity to ibrutinib. In addition, ibrutinib-resistant cell lines generated by prolonged ibrutinib exposure <i>in vitro</i> upregulated PIM1 expression, consistent with a role for PIM1 in antagonizing ibrutinib activity. The combination of a pan-PIM inhibitor with ibrutinib synergistically inhibited proliferation <i>in vitro</i> and tumor growth <i>in vivo</i>. Together, these data provide a rationale for combining BTK and PIM1 inhibition in the treatment of ABC-DLBCL.
Catalyzing the Translocation of Polypeptides through Attractive Interactions (2007)

Facilitated translocation of polypeptides through a protein pore is a ubiquitous and fundamental process in biology. Several translocation systems possess various well-defined binding sites within the pore lumen, but a clear mechanistic understanding of how the interaction of the polypeptides with the binding site alters the underlying kinetics is still missing. Here, we employed rational protein design and single-channel electrical recordings to obtain detailed kinetic signatures of polypeptide translocation through the staphylococcal alpha-hemolysin (alphaHL) transmembrane pore, a robust, tractable, and versatile beta-barrel protein. Acidic binding sites composed of rings of negatively charged aspartic acid residues, engineered at strategic positions within the beta barrel, produced dramatic changes in the functional properties of the alphaHL protein, facilitating the transport of cationic polypeptides from one side of the membrane to the other. When two electrostatic binding sites were introduced, at the entry and exit of the beta barrel, both the rate constants of association and dissociation increased substantially, diminishing the free energy barrier for translocation. By contrast, more hydrophobic polypeptides exhibited a considerable decrease in the rate constant of association to the pore lumen, having to overcome a greater energetic barrier because of the hydrophilic nature of the pore interior.
Dynamic target tracking with fringe-adjusted joint transform correlation and template matching (2004)

Target tracking in forward-looking infrared (FLIR) video sequences is a challenging problem because of various limitations such as low signal-to-noise ratio (SNR), image blurring, partial occlusion, and low texture information, which often leads to missing targets or tracking nontarget objects. To alleviate these problems, we developed a novel algorithm that involves local-deviation-based image preprocessing as well as fringe-adjusted joint-transform-correlation--(FJTC) and template-matching--(TM) based target detection and tracking. The local-deviation-based preprocessing technique is used to suppress smooth texture such as background and to enhance target edge information. However, for complex situations such as the target blending with background, partial occlusion of the target, or proximity of the target to other similar nontarget objects, FJTC may produce a false alarm. For such cases, the TM-based detection technique is used to compensate FJTC breaking points by use of cross-correlation coefficients. Finally, a robust tracking algorithm is developed by use of both FJTC and TM techniques, which is called FJTC-TM technique. The performance of the proposed FJTC-TM algorithm is tested with real-life FLIR image sequences.
NeuroD-null mice are deaf due to a severe loss of the inner ear sensory neurons during development (2001)

A key factor in the genetically programmed development of the nervous system is the death of massive numbers of neurons. Therefore, genetic mechanisms governing cell survival are of fundamental importance to developmental neuroscience. We report that inner ear sensory neurons are dependent on a basic helix-loop-helix transcription factor called NeuroD for survival during differentiation. Mice lacking NeuroD protein exhibit no auditory evoked potentials, reflecting a profound deafness. DiI fiber staining, immunostaining and cell death assays reveal that the deafness is due to the failure of inner ear sensory neuron survival during development. The affected inner ear sensory neurons fail to express neurotrophin receptors, TrkB and TrkC, suggesting that the ability of NeuroD to support neuronal survival may be directly mediated through regulation of responsiveness to the neurotrophins.
Mass spectrometric identification of proteins from silver-stained polyacrylamide gel: A method for the removal of silver ions to enhance sensitivity (1999)

Mass spectrometry is a powerful technique for the identification of proteins at nanogram quantities. However, some degree of sample preparation prior to mass spectrometry is required, and silver-stained protein gel samples are most problematic. Here we report our strategy to obtain peptide mass profiles from silver-stained protein gel samples from one- or two-dimensional gels by destaining prior to enzymatic digestion. This study demonstrates that by using the destaining method, the sensitivity and quality of mass spectra is increased for matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometric analysis, permitting more proteins to be identified by peptide mass database analysis.
SDZ PSC 833, A non‐immunosuppressive cyclosporine: Its potency in overcoming P‐glycoprotein‐mediated multidrug resistance of murine leukemia (1992)

Cyclosporin A (CsA, Sandimmune) is known to reverse P-glycoprotein (P-gp170)-mediated multidrug resistance as efficiently as other prototype compounds of resistance modifiers. The immunosuppressive activity and nephrotoxicity of CsA, however, may limit its clinical use. PSC-833, a new cyclosporine, exerts a similar resistance-modifying activity but lacks toxicity or immunosuppressive activity. We have tested its potency in vitro and in vivo on the L1210 leukemia cell line transfected with a full-length cDNA copy of the human mdr I gene, which showed a stable 30-fold resistance towards adriamycin as compared to the parental cell line. In vitro growth of the transfected cell was unchanged. In vivo growth was less aggressive; the survival time of inoculated mice was prolonged. In vitro, PSC-833 was at least as potent as CsA or verapamil in reversing multidrug resistance. In vivo, the drug-resistant L1210 leukemia was completely unresponsive to i.v. monotherapy with adriamycin at its maximum tolerated dose (MTD). PSC-833 enhanced the activity and toxicity of adriamycin. The MTD of adriamycin was about 3 times lower than when given alone. On this basis, the MTD of i.v. adriamycin in combination with oral PSC-833 successfully overcame refractoriness to treatment. Survival times of the mice were considerably prolonged and even some cures of leukemic mice occurred.
The human gene for xanthine dehydrogenase (XDH) is localized on chromosome band 2p22 (1995)

Mutations in the xanthine dehydrogenase gene (XDH), which codes for the last enzyme of the purine catabolic pathway in man, cause the autosomal recessive disease xanthinuria. We obtained cDNA clones from a human breast cDNA library and confirmed one of the two different sequences proposed for human XDH. Using a somatic cell hybrid mapping panel and specific primers for human XDH, we assigned the gene to chromosome 2. By fluorescence in situ hybridization, the gene was localized to bands 2p22.3-->p22.2. The FLpter probe location was 0.135 (SD = 0.016), as determined by digital image analysis.
Functional Chimeras of Human Immunodeficiency Virus Type 1 gp120 and Influenza A Virus (H3) Hemagglutinin (2005)

In an attempt to produce a protein that will allow determination of the native human immunodeficiency virus type 1 (HIV-1) gp120 (Env) structure in its trimeric state, we fused the globular head of gp120 to the stalk region of influenza virus A (X31) hemagglutinin (HA). The chimeric protein (EnvHA) has been expressed by using a recombinant vaccinia virus system, and its functional characteristics were determined. EnvHA is expressed as a 120- to 150-kDa protein that can oligomerize to form dimers and trimers. It retains the low-pH (5.2 to 5.4) requirement of X31-HA to trigger membrane fusion but, unlike X31-HA, it is not absolutely dependent on exogenously added trypsin for protein processing to release the HA2 fusion peptide. In terms of receptor binding the chimeric protein retains specificity for human CD4 but, in relation to the membrane fusion event, it appears to lose the Env coreceptor specificity of the parental HIV-1 strains: NL43 for CXCR4 and JRFL for CCR5. These properties suggest that stable, functional EnvHAs are being produced and that they may be exploited in terms of structural studies. Further, the potential of introducing the envHA genes into influenza viruses, by use of reverse genetics, and their use as a therapeutic vaccine for HIV are discussed.
Gastric Hypothermia (1966)

RODGERS, J. BEALL M.D.**; OLDER, THOMAS M. M.D.***; STABLER, E. VERNON M.D.† Author Information
Synthetic analogues of polynucleotides. Part VIII. Analogues of oligonucleotides containing carboxymethylthymidine (1972)

Analogues of oligonucleotides in which the nucleoside units are linked by acetate ester linkages (·O·CH2·CO2·) instead of the phosphodiester linkages of the natural compounds, have been synthesised. The compounds obtained were thymidinylacetyl-(3′→5′)-thymidinylacetyl-(3′→5′)-thymidinylacetyl-(3′→5′)-uridine, thymidinylacetyl-(3′→5′)-thymidinylacetyl-(3′→5′)-thymidinylacetyl-(3′→5′)-thymidinylacetyl-(3′→5′)-uridine, and thymidinylacetyl-(3′→5′)-thymidinylacetyl-(3′→5′)-thymidinylacetyl-(3′→5′)-thymidinylacetyl-(3′→5′)cytidine. The last was also obtained labelled with tritium in the cytidine residue. An oligomer of similar structure to these compounds having a molecular weight between 4 × 103 and 4.7 × 104 was obtained by copolymerising 3′-O-carboxymethylthymidine with 0.1 mol. equiv. of 2′,3′-O-isopropylideneuridine and removing the blocking group. This oligomer and the other two uridine-containing oligomers gave a small but significant hypochromic effect when mixed with polyadenylic acid in solution.
Ustekinumab: Lessons Learned from Targeting Interleukin‐12/23p40 in Immune‐Mediated Diseases (2009)

Interleukin (IL)-12 and IL-23 are related cytokines that have been implicated in the pathogenesis of several immune-mediated disorders. IL-12 and IL-23 are heterodimers made up of a common p40 subunit complexed to unique p35 (IL-12) or p19 (IL-23) subunits. Ustekinumab is a human monoclonal antibody that specifically binds the p40 subunit of IL-12/23. Ustekinumab prevents IL-12 and IL-23 from binding their cell surface receptor complexes, thereby blocking the T helper (Th) 1 (IL-12) and Th17 (IL-23) inflammatory pathways. Here, we discuss the preclinical and human translational data supporting a role for IL-12/23 in the pathogenesis of immune-mediated disorders, and how that rationale was challenged in the clinic during the course of the ustekinumab development program in several indications including psoriasis, psoriatic arthritis, Crohn's disease, and multiple sclerosis. We review the key efficacy and safety data in each of these immune-mediated diseases and compare and contrast the safety lessons learned from IL-12/23 genetically-deficient mice and humans in context of the overall clinical trial experience with ustekinumab.
Initial tumor targeting, biodistribution, and pharmacokinetic evaluation of the monoclonal antibody PAM4 in patients with pancreatic cancer. (1995)

This pharmacokinetic study was performed to assess the potential usefulness of the murine monoclonal antibody (MoAb) PAM4-IgG1 as an immunotargeting agent for pancreatic cancer imaging or therapy. This MoAb reacts specifically with mucin purified from human pancreatic cancer. 131I-labeled PAM4-IgG1 was injected i.v. into five patients with suspected pancreatic cancer. Whole-body scans and spot views of the abdominal area were recorded with a computerized gamma camera, and specific regions of interest were drawn over the liver and spleen to define the kinetics of activity in these organs. Blood samples taken from 0.1-144 h after injection served to define the kinetics of plasma distribution and removal of activity from the body. Surgery confirmed pancreatic cancer in four of the five patients, whereas chronic pancreatitis was present in the fifth patient; in all four pancreatic cancer patients, immunostaining with the MoAb PAM4 demonstrated the presence of the specific antigen, with a cytoplasmic and endoluminal/secretory pattern of distribution. Nonspecific radioactivity accumulation in the liver, spleen, and bone marrow was low, linked essentially to the blood pool effect of circulating activity in these organs. The overall quality of scintigraphic maps recorded over the abdomen was quite satisfactory due to the low liver and spleen activity, with good scintigraphic demonstration of the pancreatic cancers (either primary or metastatic); the patient subsequently found to have pancreatitis failed to show PAM4 targeting. Except in one patient with widespread peritoneal metastases (in whom these tumor implants were detected scintigraphically already 24-48 hours after tracer injection), scintigraphic evidence of the tumor lesions was usually late, starting at about 72-96 h after tracer injection. The results obtained in this preliminary study indicate the potential usefulness of MoAb PAM4 for immunoscintigraphy in patients with either primary and/or recurrent pancreatic cancer while also suggesting that the use of the faster-clearing Fab fragments of this MoAb probably would result in improved immunoscintigraphic properties.
Transition State Structure of 5‘-Methylthioadenosine/S-Adenosylhomocysteine Nucleosidase from Escherichia coli and Its Similarity to Transition State Analogues (2005)

Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) catalyzes reactions linked to polyamine metabolism, quorum sensing pathways, methylation reactions, and adenine salvage. It is a candidate target for antimicrobial drug design. Kinetic isotope effects (KIEs) were measured on the MTAN-catalyzed hydrolysis of 5'-methylthioadenosine (MTA) to determine the transition state structure. KIEs measured at pH 7.5 were near unity due to the large forward commitment to catalysis. Intrinsic KIEs were expressed by increasing the pH to 8.5. Intrinsic KIEs from MTAs labeled at 1'-(3)H, 1'-(14)C, 2'-(3)H, 4'-(3)H, 5'-(3)H, 9-(15)N, and Me-(3)H(3) were 1.160 +/- 0.004, 1.004 +/- 0.003, 1.044 +/- 0.004, 1.015 +/- 0.002, 1.010 +/- 0.002, 1.018 +/- 0.006, and 1.051 +/- 0.002, respectively. The large 1'-(3)H and small 1'-(14)C KIEs indicate that the Escherichia coli MTAN reaction undergoes a dissociative (D(N)A(N)) (S(N)1) mechanism with little involvement of the leaving group or participation of the attacking nucleophile at the transition state, causing the transition state to have significant ribooxacarbenium ion character. A transition state constrained to match the intrinsic KIEs was located with density functional theory [B3LYP/6-31G(d,p)]. The leaving group (N9) is predicted to be 3.0 A from the anomeric carbon. The small beta-secondary 2'-(3)H KIE of 1.044 corresponds to a modest 3'-endo conformation for ribose and a H1'-C1'-C2'-H2' dihedral angle of 53 degrees at the transition state. Natural bond orbital analysis of the substrate and the transition state suggests that the 4'-(3)H KIE is due to hyperconjugation between the lone pair (n(p)) of O3' and the antibonding (sigma) orbital of the C4'-H4' group, and the methyl-(3)H(3) KIE is due to hyperconjugation between the n(p) of sulfur and the sigma of methyl C-H bonds. Transition state analogues that resemble this transition state structure are powerful inhibitors, and their molecular electrostatic potential maps closely resemble that of the transition state.
Microencapsulated cells as hormone delivery systems. (1987)

Transplantation of pancreatic islets of Langerhans has been shown to prevent the development of many of the complications associated with diabetes. Transplanted islets, however, are readily rejected by the immune system. The use of artificial membranes to isolate the transplanted islets from the immune system of the host prolongs islet allografts in experimental animals. We have developed a method for encapsulating islets in semipermeable membranes composed of alginate and polylysine. The same technique can be applied to other endocrine cell types. The capsules are 700 to 800 micron in diameter with a hydrogel membrane approximately 4 micron thick. Intraperitoneal allografts of 5 x 10(3) encapsulated islets reversed diabetes in rats for up to 21 months and intact capsules with viable beta cells could be recovered from the recipients. Microencapsulation of endocrine cells for transplantation could potentially be used in the clinical treatment of hormone deficiency diseases.
Growth Hormone Receptor Expression in the Rat Gastrointestinal Tract* (1990)

We have used immunohistochemistry to define the cellular distribution of GH receptors in the gastrointestinal tract (GIT) and its derivatives. Immunohistochemistry was performed in the adult rat GIT with a panel of characterized monoclonal antibodies to the GH receptor. The most intense and heterogeneous immunoreactivity was observed in epithelial cell subpopulations of GIT mucosa. Mesenchymal elements of the GIT were homogenously and moderately immunoreactive. Intense immunoreactivity was observed in the ductal epithelium of the sublingual gland, scattered basal epidermal cells of the esophageal mucosa, zymogen cells of the gastric glands, scattered surface epithelial cells of the stomach, and scattered peripheral pancreatic acinar groups. Scattered enteroendocrine cells and parietal cells, crypt and villous columnar cells of the small intestine, surface columnar cells of the cecum/colon, crypt base columnar cells of the colon, and contiguous peripheral cords of pancreatic islet cells displayed strong immunoreactivity. No immunoreactivity was detectable in the mucous and serous acini of the sublingual and submandibular gland, respectively, mucous-secreting cells of the base of the cardiac and pyloric glands, surface epithelial cells of the fundus, paneth cells, goblet cells of cecum/colon, or mucous cells at the base of the cecal crypt. Other elements of the GIT were moderately or weakly immunoreactive. In support of our localization we can detect high affinity binding (Ka = 3 x 10(9] of [125I]human GH with ovine GH as displacing ligand to crude homogenates of adult rat stomach and intestine. We conclude that discrete epithelial cell subpopulations of the GIT and its derivatives are directly responsive to GH action. GH may, therefore, act independently of or synergistically with hepatic insulin-like growth factor-I in executing its physiological and/or growth-promoting role in the GIT.
Engineering and scientific processing on the IBM 3090 (1986)

The IBM 3090 processor implementation of the System/370 Vector Architecture represents a major new system design for engineering and scientific processing, featuring both scalar and vector capability in a uniprocessor and in a dyadic and four-way parallel processing environment. The history of large-scale scientific processing is reviewed, leading to a statement of current requirements. The design objectives for scalar, parallel, and vector capabilities are identified, followed by a summary of the resulting 3090 features. Selected highlights of the vector hardware are given, followed by a summary of the supporting software. The paper concludes with a discussion of performance, beginning with the identification of suitable applications. An example is given of one application utilizing each of the three capabilities: scalar, parallel, and vector. Several of the most important performance parameters are identified.
CDK9 inhibition strategy defines distinct sets of target genes (2014)

The nature of the strategy used to inhibit CDK9 profoundly affects the patterns of gene expression resulting from CDK9 inhibition. These results suggest multiple variables that affect outcome, including kinetics of inhibition, potency, off-target effects, and selectivity issues. This is particularly important when considering CDK9 as a potential target for therapeutic intervention.