gebhart/patrepeval huggingface dataset:
Diagnosis and Treatment of Pituitary Tumors (1999)

We are fortunate to have multiple safe and effective therapeutic options available for the treatment of pituitary tumors. These options include medical therapy, transsphenoidal surgery and radiotherapy. The treatment of choice depends on the type of pituitary tumor. The majority, of PRL-secreting tumors can be effectively treated with dopamine agonists. Transsphenoidal surgery is also an effective option for patients who are resistant to or intolerant of these drugs. Transsphenoidal surgery remains the treatment of choice for the majority of patients with GH, ACTH, and TSH-secreting tumors and for large nonsecreting tumors. Medical therapy with somatostatin analogs and/or dopamine agonists should be undertaken in patients with persistent elevations of GH and IGF-I levels; radiotherapy should be considered for patients with significant residual tumor in whom medical therapy is unsuccessful. Radiotherapy is also indicated for ACTH-secreting tumors not cured by surgery; medical therapy with ketoconazole and other adrenal enzyme inhibitors can be used as adjunctive therapy to lower cortisol levels. Postoperative radiotherapy for nonsecreting tumors is also an option if there is considerable residual tumor or evidence of tumor growth on follow-up MRI. Evaluation and treatment of hypopituitarism is an important part of the management of all patients with pituitary tumors. Patients also should be monitored for the development of new deficits, particularly after radiotherapy. The development of new medical therapies, such as GH antagonists, as well as refinements of surgical, radiotherapy, and imaging techniques should continue to improve our management of pituitary tumors.
Algorithm and computer program Pro—Anal for analysis of relationship between structure and activity in a family of proteins or peptides (1993)

In this paper we introduce a computer algorithm and program Pro__Anal for analysis of the structure-activity relationship in a family of evolutionarily related (and/or artificially mutated) proteins/peptides. The program uses aligned amino acid sequences with data of their activity (pK, Km, ED50 or any other) and searches for correlations between data on activity and various physico-chemical characteristics of different regions in primary structures. In automatic mode, the program generates and verifies hypotheses on the disposition of a sequential modulating region in a protein, and key characteristics of the region. In manual mode, users can generate and analyze their own hypotheses. The program is implemented on IBM PC or compatible computers. It is designed to be easily handled by the occasional computer user and yet it is powerful enough for experienced professionals. Pro__Anal operation is demonstrated on the example of finding modulating centers in a family of disintegrins-proteins from snake venoms which inhibit fibrinogen interaction with platelet receptors. In another example it is shown that the immunogenicity of peptides is connected with their positive charge.
Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation. (1992)

Interaction of T and B lymphocytes, platelets, granulocytes, macrophages and mast cells with the subendothelial extracellular matrix (ECM) is associated with degradation of heparan sulfate (HS) by a specific endoglycosidase (heparanase) activity. The enzyme is released from intracellular compartments (i.e., lysosomes, specific granules) in response to various activation signals (i.e., thrombin, calcium ionophore, immune complexes, antigens, mitogens), suggesting its regulated involvement in inflammation and cellular immunity. In contrast, various tumor cells appear to express and secrete heparanase in a constitutive manner, in correlation with their metastatic potential. Heparanase enzymes produced by different cell types may exhibit different molecular properties and substrate cleavage specificities. The platelet enzyme appears also in a latent form. It can be activated by tumor cells and thereby facilitate their extravasation in the process of metastasis. Degradation of ECM-HS by all cell types was facilitated by a proteolytic activity residing in the ECM and/or expressed by the invading cells. This proteolytic activity produced a more accessible substrate for the heparanase enzymes. Heparanase-inhibiting, nonanticoagulant species of heparin markedly reduced the incidence of lung metastasis in experimental animals. These species of heparin also significantly impaired the traffic of T lymphocytes and suppressed cellular immune reactivity and experimental autoimmune diseases. Heparanase activity expressed by intact cells (i.e., platelets, mast cells, neutrophils, lymphoma cells) was found to release active HS-bound basic fibroblast growth factor from ECM and basement membranes. Heparanase may thus elicit an indirect neovascular response in processes such as wound repair, inflammation and tumor development. The significant anticancerous effect of heparanase-inhibiting molecules may therefore be attributed to their potential inhibition of both tumor invasion and angiogenesis. Both normal leukocytic cells and metastatic tumor cells can enter the bloodstream, travel to distant sites and extravasate to the parenchyma at these sites. We suggest that heparanase is utilized for this purpose by both types of cells. Other functions (i.e., enzyme activities, adhesive interactions, chemotactic and proliferative responses) of metastatic tumor cells seem to mimic the equivalent functions of leukocytes as they migrate across blood vessels to gain access to sites of inflammation.
A context dependent role for Wnt signaling in tumorigenesis and stem cells (2008)

The Wnt signal transduction pathway coordinates myriad activities, from development and differentiation to proliferation and tumorigenesis. What is perhaps most remarkable is that Wnt signaling is able to accomplish this diverse set of activities in a cell-specific and differentiation stage-dependent manner. In this review, we will highlight the diverse effect of Wnt signaling on three types of tissue stem cells and their corresponding malignancies.
METHODS OF GENE DELIVERY (1998)

Human gene therapy continues to be an exciting concept for the treatment of disease. This field of research remains in its early stages, but already a number of studies have provided "proof-of-principle." Although there is no unequivocal evidence of efficacy, there have been demonstrated physiologic changes that are relevant to the disease process. One of the major challenges still confronting the field is the design of more efficient vectors. The gene delivery systems being used today will undoubtedly be seen as crude when compared with future developments. It is unlikely that there will ever be a universal vector, but rather there will be multiple vectors specifically designed for certain organ sites and certain disease. It is reasonable to assume that, in the future, there will be synthetic vectors that co-opt the needed properties from both cells and viruses. It will be necessary to do much more fundamental research in cell biology, virology, immunology, and pathophysiology before vectors can be significantly improved. Many of the tools for this research are in place, and the driving force will be provided by the imaginativeness of the committed investigators.
Functional dissection of VP16, the trans-activator of herpes simplex virus immediate early gene expression. (1988)

Mature virions of herpes simplex virus type 1 contain an activating factor that primes transcription from the five virally encoded immediate early (IE) genes. This activator is specified by a 65-kD polypeptide termed VP16. The action of VP16 is mediated through cis-regulatory elements located in regions adjacent to each IE gene. Although VP16 is normally introduced into cells by infecting virions, its trans-activating function can also be observed by cotransfecting cells with a plasmid that encodes VP16 along with a reporter gene driven by IE cis-regulatory sequences. We have used such an assay to examine the function of mutant forms of VP16. Our results provide tentative identification of two domains of VP16 that are crucial to its role in the induction of IE gene expression. One domain is located within the carboxy-terminal 78 amino acids of VP16 and is characterized by its acidity. Another domain, located in a more amino-terminal region of the protein, appears to tailor the specificity of VP16 for IE genes. According to the results presented in this and the accompanying paper, we predict that VP16 achieves IE gene specificity via protein: protein, rather than protein: DNA, interaction.
Ring Closure to β-Turn Mimics via Copper-Catalyzed Azide/Alkyne Cycloadditions (2005)

[Structure: see text]. Copper-catalyzed azide alkyne cycloadditions of the linear substrates 1 were used to form the cyclic derivatives 2. Computational, NMR, and CD analyses of these compounds indicate that their most favorable conformational states include type I and type II beta-turn conformations. Selectivity for the dimeric products 6 in these cyclization reactions is discussed.
Differential roles of microtubule assembly and sliding in proplatelet formation by megakaryocytes (2005)

Megakaryocytes are terminally differentiated cells that, in their final hours, convert their cytoplasm into long, branched proplatelets, which remodel into blood platelets. Proplatelets elongate at an average rate of 0.85 microm/min in a microtubule-dependent process. Addition of rhodamine-tubulin to permeabilized proplatelets, immunofluorescence microscopy of the microtubule plus-end marker end-binding protein 3 (EB3), and fluorescence time-lapse microscopy of EB3-green fluorescent protein (GFP)-expressing megakaryocytes reveal that microtubules, organized as bipolar arrays, continuously polymerize throughout the proplatelet. In immature megakaryocytes lacking proplatelets, microtubule plus-ends initiate and grow by centrosomal nucleation at rates of 8.9 to 12.3 microm/min. In contrast, plus-end growth rates of microtubules within proplatelets are highly variable (1.5-23.5 microm/min) and are both slower and faster than those seen in immature cells. Despite the continuous assembly of microtubules, proplatelets continue to elongate when net microtubule assembly is arrested. One alternative mechanism for force generation is microtubule sliding. Triton X-100-permeabilized proplatelets containing dynein and its regulatory complex, dynactin, but not kinesin, elongate with the addition of adenosine triphosphate (ATP) at a rate of 0.65 microm/min. Retroviral expression in megakaryocytes of dynamitin (p50), which disrupts dynactin-dynein function, inhibits proplatelet elongation. We conclude that while continuous polymerization of microtubules is necessary to support the enlarging proplatelet mass, the sliding of overlapping microtubules is a vital component of proplatelet elongation.
MODES OF PROPAGATING LIGHT WAVES IN THIN DEPOSITED SEMICONDUCTOR FILMS (1969)

We report theory and experiment on modes of propagating light waves in deposited semiconductor films. The modes are excited by a novel prism-film coupler which is also used for the measurement of their phase velocities. Up to 50% of the incident laser energy has been fed into a single mode of propagation. The positions and linewidths of the modes, the wave intensity inside the film, and a dramatic view of the mode spectrum displayed by the scattered light are discussed in detail.
Combined Effects of Routine Blood Pressure Lowering and Intensive Glucose Control on Macrovascular and Microvascular Outcomes in Patients With Type 2 Diabetes (2009)

The effects of routine blood pressure lowering and intensive glucose control were independent of one another. When combined, they produced additional reductions in clinically relevant outcomes.
A Comparative Analysis of the Plant Cellulose Synthase (CesA) Gene Family (2000)

CesA genes are believed to encode the catalytic subunit of cellulose synthase. Identification of nine distinct CesA cDNAs from maize (Zea mays) has allowed us to initiate comparative studies with homologs from Arabidopsis and other plant species. Mapping studies show that closely related CesA genes are not clustered but are found at different chromosomal locations in both Arabidopsis and maize. Furthermore, sequence comparisons among the CesA-deduced proteins show that these cluster in groups wherein orthologs are often more similar than paralogs, indicating that different subclasses evolved prior to the divergence of the monocot and dicot lineages. Studies using reverse transcriptase polymerase chain reaction with gene-specific primers for six of the nine maize genes indicate that all genes are expressed to at least some level in all of the organs examined. However, when expression patterns for a few selected genes from maize and Arabidopsis were analyzed in more detail, they were found to be expressed in unique cell types engaged in either primary or secondary wall synthesis. These studies also indicate that amino acid sequence comparisons, at least in some cases, may have value for prediction of such patterns of gene expression. Such analyses begin to provide insights useful for future genetic engineering of cellulose deposition, in that identification of close orthologs across species may prove useful for prediction of patterns of gene expression and may also aid in prediction of mutant combinations that may be necessary to generate severe phenotypes.
Studies on the Protective Effect of Diphenylhydantoin Against Alloxan Diabetes in Mice (1973)

The protective effects of D–glu–cose and diphenylhydantoin (DPH) against alloxan–induced diabetes have been compared. Diphenylhydantoin, at intraperitoneal doses of either 10 or 45 mg/kg and D–glucose at an intravenous dose of 1.0 g/kg were found to afford complete protection against alloxan. An intravenous dose of 0.2 g/kg of D–glucose afforded only partial protection. Since the lower dose of D–glucose produced a greater increase in blood glucose than did the lower dose of DPH, it was concluded that the protective effect of DPH against alloxan can not be explained solely on the basis of the DPH–induced hyperglycemia. The 3–methyl analog of DPH was found to be ineffective in blocking the diabetogenic effect of alloxan. This finding suggests that the interaction between DPH and alloxan may be a reflection of a competition between the two agents for a common binding site on the pancreatic beta cell.
Disease Development in Ethylene-InsensitiveArabidopsis thalianaInfected with Virulent and AvirulentPseudomonasandXanthomonasPathogens (1992)

The plant hormone ethylene has been hypothesized to play roles both in disease resistance and in disease susceptibility. These processes were examined by using isogenic virulent and avirulent bacterial pathogens and mutants of Arabidopsis thaliana that were altered in ethylene physiology. Ethylene-insensitive ein1 and ein2 mutants of Arabidopsis were resistant to Pseudomonas syringae pv. tomato made avirulent by the addition of the cloned avirulence genes avrRpt2, avrRpm1, or avrB; this suggests that ethylene is not required for active resistance against avirulent bacteria. In a second set of experiments, susceptibility was monitored with virulent P. s. pv. tomato, P. s. pv. maculicola, or Xanthomonas campestris pv. campestris strains. Wild-type Arabidopsis and ein1 mutants were susceptible to these strains, but ein2 mutants developed only minimal disease symptoms. Despite these reduced symptoms, virulent P. s. pv. tomato grew extensively within ein2 leaves. The Pseudomonas phytotoxin coronatine induces ethylene biosynthesis and diseaselike symptoms on many plant species, but the reduced symptomology of ein2 mutants could not be attributed to insensitivity to coronatine. The enhanced disease tolerance of ein2 plants suggests that ethylene may mediate pathogen-induced damage, but the absence of tolerance in ein1 mutants has yet to be explained.
Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1 (2008)

Checkpoints are present in all phases of the cell cycle and are regarded as the gatekeepers maintaining the integrity of the genome. Many conventional agents used to treat cancer impart damage to the genome and activate cell cycle checkpoints. Many tumors are defective in the tumor suppressor p53 and therefore lack a functional G(1) checkpoint. In these tumors, however, the S-G(2) checkpoints remain intact and, in response to DNA damage, arrest cell cycle progression allowing time for DNA repair. Checkpoint kinase 1 (Chk1) is a key element in the DNA damage response pathway and plays a crucial role in the S-G(2)-phase checkpoints. Inhibiting Chk1 represents a therapeutic strategy for creating a "synthetic lethal" response by overriding the last checkpoint defense of tumor cells against the lethal damage induced by DNA-directed chemotherapeutic agents. Chk1 inhibition is consistent with emerging targeted therapies aiming to exploit molecular differences between normal and cancer cells. Adding a Chk1 inhibitor to DNA-damaging cytotoxic therapy selectively targets tumors with intrinsic checkpoint defects while minimizing toxicity in checkpoint-competent normal cells. PF-00477736 was identified as a potent, selective ATP-competitive small-molecule inhibitor that inhibits Chk1 with a K(i) of 0.49 nM. PF-00477736 abrogates cell cycle arrest induced by DNA damage and enhances cytotoxicity of clinically important chemotherapeutic agents, including gemcitabine and carboplatin. In xenografts, PF-00477736 enhanced the antitumor activity of gemcitabine in a dose-dependent manner. PF-00477736 combinations were well tolerated with no exacerbation of side effects commonly associated with cytotoxic agents.
Dehydrogenases/Reductases for the Synthesis of Chiral Pharmaceutical Intermediates (2010)

The increasing trend of chiral drugs in the pharmaceutical industry has promoted greatly on the development of numerous biocatalytic routes in combination with chemical methods. Because the resulting chiral alcohols are particularly valuable intermediates and precursors for the synthesis of chiral drugs, dehydrogenases and reductases have been extensively used in the synthesis of chiral compounds from ketone substrates with high regio- and stereo-selectivities. In this review, biocatalytic processes carried out by dehydrogenases and reductases are described for the synthesis of chiral intermediates for a wide variety of pharmaceuticals, including antidepressants, anti-anxieties, anti-asthmatics, anti-hypertensives, cholesterol-lowering agents, NK1 antagonists, ACE inhibitors and β- Lactamase inhibitors. Keywords: Biocatalysis, Dehydrogenases, Reductases, Chiral intermediates, Stereoselectivity, Cofactor regeneration
Distinct phenotypic states and spatial distribution of CD8+ T cell clonotypes in human brain metastases (2022)

Metastatic disease in the brain is difficult to control and predicts poor prognosis. Here, we analyze human brain metastases and demonstrate their robust infiltration by CD8(+) T cell subsets with distinct antigen specificities, phenotypic states, and spatial localization within the tumor microenvironment. Brain metastases are densely infiltrated by T cells; the majority of infiltrating CD8(+) T cells express PD-1. Single-cell RNA sequencing shows significant clonal overlap between proliferating and exhausted CD8(+) T cells, but these subsets have minimal clonal overlap with circulating and other tumor-infiltrating CD8(+) T cells, including bystander CD8(+) T cells specific for microbial antigens. Using spatial transcriptomics and spatial T cell receptor (TCR) sequencing, we show these clonally unrelated, phenotypically distinct CD8(+) T cell populations occupy discrete niches within the brain metastasis tumor microenvironment. Together, our work identifies signaling pathways within CD8(+) T cells and in their surrounding environment that may be targeted for immunotherapy of brain metastases.
Molecular Fluorescence, Phosphorescence, and Chemiluminescence Spectrometry (2004)

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTMolecular Fluorescence, Phosphorescence, and Chemiluminescence SpectrometryAleeta M. Powe, Kristin A. Fletcher, Nadia N. St. Luce, Mark Lowry, Sharon Neal, Matthew E. McCarroll, Philip B. Oldham, Linda B. McGown, and Isiah M. WarnerView Author Information Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, Department of Chemistry, University of Delaware, Newark, Delaware 19716, Department of Chemistry, Southern Illinois University, Carbondale, Illinois 62901, Department of Chemistry, Mississippi State University, Mississippi State, Mississippi 39762, and Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, New York 12180 Cite this: Anal. Chem. 2004, 76, 16, 4614–4634Publication Date (Web):June 19, 2004Publication History Published online19 June 2004Published inissue 1 August 2004https://pubs.acs.org/doi/10.1021/ac040095dhttps://doi.org/10.1021/ac040095dreview-articleACS PublicationsCopyright © 2004 American Chemical SocietyRequest reuse permissionsArticle Views3379Altmetric-Citations59LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Fluorescence,Fluorescence detection,Fluorescence spectroscopy,Genetics,Probes Get e-Alerts
Alkyl–Alkyl Suzuki Cross‐Coupling of Unactivated Secondary Alkyl Chlorides (2010)

No such thing as a problem substrate! In a reaction designed specifically for the title substrates CC coupling with alkyl boranes occurred in good yield at room temperature with commercially available catalyst components (see scheme). This versatile method is also suitable for Suzuki reactions of secondary and primary alkyl bromides and iodides, as well as primary alkyl chlorides.