gebhart/patrepeval huggingface dataset:
(2-Methyl-5-(methylsulfonyl)benzoyl)guanidine Na+/H+ Antiporter Inhibitors (1997)

The inhibition of the Na+/H+ exchanger during cardiac ischemia and reperfusion has been shown to be beneficial for the preservation of the cellular integrity and functional performance. The aim of the present investigation was to come up with potent and selective benzoylguanidines as NHE inhibitors for their use as an adjunctive therapy in the treatment of acute myocardial infarction. During the course of our investigations it became clear that the substitution ortho to the acylguanidine was of crucial importance for the potency of the compounds. 4-Chloro- and 4-fluoro-2-methylbenzoic acids 6 and 7 were prepared using the directed ortho metalation technique with the carboxylic acid as the directing group. With the LDA/methyl iodide system the 2-methyl group could be extended to an ethyl group. 4-Alkyl groups were inserted by the palladium-catalyzed cross-coupling reaction into the 4-bromo-2-methylbenzoic acid methyl ester (20). Starting with benzoic acids 6-19, the methylsulfonyl group was introduced by a sequence of standard reactions (sulfochlorination, reduction, and methylation). 4-Aryl derivatives 68-75 were synthesized by the palladium-catalyzed Suzuki reaction. A large number of nucleophilic displacement reactions in the 4-position were carried out with S-, O-, and N-nucleophiles as well as with the cyano and trifluoromethyl group. Using the ester method, acid chlorides, or Mukaiyama's procedure, the 5-(methylsulfonyl)benzoic acid derivatives were finally converted to the (5-(methylsulfonyl)benzoyl)guanidines 165-267 with excessive guanidine. In some cases nucleophilic substitutions with pyridinols and piperidine derivatives were carried out at the end of the reaction sequence with the 4-halo-N-(diaminomethylene)-5-(methylsulfonyl)-benzamides. Variations in the 4-position were most reasonable, but the volume of the substituents was of crucial importance. Substitution in the 3- and particularly in the 6-position led to considerable worsening of the inhibitory effects of the Na+/H+ exchanger. The 2-methyl compounds, however, showed without exception higher in vitro activities than their respective demethyl counterparts as they are exemplified by the reference compounds 266 and 267, obviously caused by a conformational restriction of the acylguanidine chain. The development compound (2-methyl-5-(methylsulfonyl)-4-pyrrolobenzoyl)guanidine, methanesulfonate (246) is a NHE-1 subtype specific NHE inhibitor, being 27-fold more potent toward the NHE-1 than the NHE-2 isoform. 246 was found to act cardioprotectively not only when given before an experimentally induced ischemia, but also curatively after the onset of symptoms of acute myocardial infarction when given prior to the induction of reperfusion.
Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer (2014)

Infiltrating inflammatory cells are highly prevalent within the tumor microenvironment and mediate many processes associated with tumor progression; however, the contribution of specific populations remains unclear. For example, the nature and function of tumor-associated neutrophils (TANs) in the cancer microenvironment is largely unknown. The goal of this study was to provide a phenotypic and functional characterization of TANs in surgically resected lung cancer patients. We found that TANs constituted 5%-25% of cells isolated from the digested human lung tumors. Compared with blood neutrophils, TANs displayed an activated phenotype (CD62L(lo)CD54(hi)) with a distinct repertoire of chemokine receptors that included CCR5, CCR7, CXCR3, and CXCR4. TANs produced substantial quantities of the proinflammatory factors MCP-1, IL-8, MIP-1α, and IL-6, as well as the antiinflammatory IL-1R antagonist. Functionally, both TANs and neutrophils isolated from distant nonmalignant lung tissue were able to stimulate T cell proliferation and IFN-γ release. Cross-talk between TANs and activated T cells led to substantial upregulation of CD54, CD86, OX40L, and 4-1BBL costimulatory molecules on the neutrophil surface, which bolstered T cell proliferation in a positive-feedback loop. Together our results demonstrate that in the earliest stages of lung cancer, TANs are not immunosuppressive, but rather stimulate T cell responses.
An uncertainty analysis and sensitivity analysis of the ASSA2002 AIDS and Demographic model (2006)

1 Centre for Actuarial Research, University of Cape Town 2 School of Physics, University of KwaZulu-Natal Available: www.commerce.uct.ac.za/care Correspondence to: Leigh Johnson Centre for Actuarial Research 10 University Avenue University of Cape Town Private Bag Rondebosch 7701 South Africa Tel: +27 21 650 5761 Fax: +27 21 650 5475 E-mail: ljohnson@commerce.uct.ac.za
Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice. (1994)

We have examined the regulatory role of the individual components of the immunoglobulin antigen receptor in B-cell development by transgenic complementation of Rag-1 deficient (Rag-1-) mice. Complementation with a membrane mu heavy chain (mu HC) gene allows progression of developmentally arrested Rag-1- pro-B-cells to the small pre-B cell stage, whereas the introduction of independently integrated mu HC and kappa light chain (kappa LC) transgenes promotes the appearance of peripheral lymphocytes which, however, remain unresponsive to external stimuli. Complete reconstitution of the B-cell lineage and the emergence of functionally nature Rag-1- peripheral B cells is achieved by the introduction of cointegrated heavy and light chain transgenes encoding an anti-H-2k antibody. This experimental system demonstrates the competence of the mu HC and kappa LC to direct and regulate the sequential stages of B-cell differentiation, defines the time at which negative selection of self-reactive B cells occurs, and shows that elimination of these cells occurs equally well in the absence of Rag-1 as in its presence. These data also support the hypothesis that Rag-1 directly participates in the V(D)J recombination process.
Chirped-pulse amplification of ultrashort pulses with a multimode Tm:ZBLAN fiber upconversion amplifier (1995)

Microjoule pulse energies are achieved from a single-stage upconversion fiber amplifier for the first time, to our knowledge, in this demonstration of chirped-pulse amplification with a multimode Tm:ZBLAN fiber. A Ti:sapphire laser system provides the seed pulse for the fiber upconversion amplifier that produces picosecond pulse trains with energies as great as 16 μJ at a repetition rate of 4.4 kHz.
A review of atypical antipsychotic medications for posttraumatic stress disorder (2011)

Posttraumatic stress disorder (PTSD) can be a chronic and disabling illness with a limited response to antidepressant treatment, particularly in the case of combat-induced PTSD. The purpose of this study is to review randomized controlled and open-label trials of atypical antipsychotics for the treatment of PTSD. We conducted PUBMED and PILOTS database searches for clinical trials of atypical antipsychotic medications for PTSD in May 2010. Eighteen clinical trials (10 double-blind placebo-controlled, eight open-label) of atypical antipsychotics for PTSD were found and reviewed. Effect sizes of double-blind placebo-controlled trials were small, but were positive for risperidone and quetiapine. Intrusive and hypervigilance symptom subscales showed the most improvement. We concluded that atypical antipsychotic medications have a modest benefit for the treatment of PTSD. Larger randomized controlled trials are needed to clarify the potential utility of these medications in the treatment of PTSD and more rigorous examination of metabolic side effects is warranted.
Preclinical pharmacology of the natural product anticancer agent bryostatin 1, an activator of protein kinase C. (1996)

Bryostatin 1, a natural product anticancer agent isolated from a marine bryozoan, has been shown in tissue culture to activate protein kinase C. This agent has recently undergone Phase I testing in humans given either as a bolus i.v. injection or a continuous infusion. To understand how bryostatin 1 might be used best as an anticancer agent, a study of the pharmacokinetics, tissue distribution, metabolism, and elimination of bryostatin 1 in mice was undertaken, using [C26-3H]-labeled bryostatin 1. Following i.v. administration, the plasma disappearance curve for bryostatin 1 could be described by a two-compartment model, with half-lives of 1.05 and 22.97 h, respectively. In contrast, the plasma disappearance curve for bryostatin 1 administered i.p. was better described by a first order absorption one-compartment model, with an absorption half-life of 0.81 h and an elimination half-life of 28.76 h, respectively. The majority of radioactivity in plasma was associated with the intact drug for up to 24 h after dosing. In the first 12 h after i.v administration, urinary excretion represented the major pathway of elimination, with 23.0 +/- 1.9% (mean +/- SD) of the administered dose excreted. Within 72 h after i.v. administration, approximately equal amounts of radioactivity (40%) were excreted in feces compared to urine. Bryostatin 1 was widely distributed in many organs but concentrated in the lung, liver, gastrointestinal tract, and fatty tissue. The concentration in the gastrointestinal tract, along with the fecal excretion, suggests the possibility of enterohepatic circulation of this drug. In summary, this study demonstrates that bryostatin 1 is relatively stable in vivo, widely distributed but concentrated in some major tissues, and rapidly excreted first through urine and at later times through the feces. The data from this animal study should be useful in the design of future human trials with this anticancer drug.
Computerized tomographic and pathologic studies of the untreated, quiescent, and recurrent glioblastoma multiforme (1983)

Pathological findings in 20 cases of glioblastoma multiforme were correlated with clinical histories and computerized tomographic (CT) scans. This was done to define the neoplasm in three stages: before treatment, during remission, and during recurrence. The untreated lesions were markedly cellular neoplasms composed predominantly of small anaplastic cells. The radiographic central region of low density was necrosis, the enhancing rim was a cellular zone of viable neoplasm, and the perilesional low-density area was edema with infiltrating tumor. In these 20 cases, all of the identifiable neoplasms lay within the zone of peritumoral edema or contrast enhancement, although small anaplastic cells may have been present in more distant regions. The lesions in remission were remarkable for their minimal mass effect, discrete nature, extensive necrosis, and content of large bizarre glia. The large cells were confined to the original tumor bed and were consistent with neoplastic cells inactivated and immobilized by radio- and chemotherapy. These lesions were accurately localized by CT scanning. The recurrent lesions were heterogeneous, but most were formed of widely disseminated small anaplastic cells. The highly cellular regions of such lesions could be localized by CT scanning, but CT could not detect less cellular foci in the cerebrum, cerebellum, or brain stem. In one patient, the contrast-enhancing lesions of "recurrence," were foci of radionecrosis, underscoring the difficulty in distinguishing this entity from recurrent neoplasm.
Reductive alkylation with oxidized nucleotides. Use in affinity labeling or affinity chromatography. (1985)

A study has been made of the products of a reaction of oxidized ribonucleotides with a primary amine. As a model reaction, periodate-oxidized adenosine was combined with glycine in the presence of NaCNBH3. The purified major product of this reaction, adenine 9,2'-(4'-carboxymethyl-6'-hydroxymethylmorpholine), was characterized by 13C and 1H NMR spectroscopy, ultraviolet spectroscopy, and thin layer chromatography. When used to generate affinity columns, oxidized adenosine or oxidized ATP formed stable products with immobilized diaminohexane when treated with NaCNBH3. Failure to treat with NaCNBH3 yielded an unstable affinity matrix. These results are used in the interpretation of differing results when oxidized nucleotides have been used as affinity labels for different proteins.
Hypoactive Sexual Desire Disorder: Prevalence and Comorbidity in 906 Subjects (1991)

The frequency of hypoactive sexual desire disorder (HSDD) and the frequency of comorbidity of sexual disorders was recorded from a total population of 906 subjects studied in a multisite pharmaceutical study. Sixty-five percent had a primary diagnosis of HSDD, HSDD was far more common in females than male subjects. Males diagnosed with HSDD were significantly older than women diagnosed with HSDD. Approximately, 40% of the subjects with a primary diagnosis of HSDD had second diagnoses of arousal or orgasm disorders.
Regulatory CD8+T cells fine-tune the myelin basic protein-reactive T cell receptor Vβ repertoire during experimental autoimmune encephalomyelitis (2003)

A significant number of self-reactive T cell clones escape thymic negative selection and are released into the periphery, where some are potentially pathogenic. The clonal expansion of self-reactive T cells is known to be limited during initial antigen encounter by apoptotic or anergic mechanisms, regulatory CD4+ T cells, and cytokines. Here we report that superimposed on these mechanisms, during the evolution of autoimmunity in experimental autoimmune encephalomyelitis (EAE), CD8+ T cells are induced, which fine-tune the peripheral self-reactive T cell receptor (TCR) repertoire. We assayed the myelin basic protein-reactive TCR repertoire in naive, EAE-recovered mice as well as EAE-recovered mice depleted of CD8+ T cells by TCRV beta surface expression, complementarity-determining region 3 length distribution, and complementarity-determining region 3 sequencing analysis. In EAE-recovered mice, certain myelin basic protein-reactive CD4+V beta 8.2+ clones are significantly decreased and this decrease is not observed if CD8+ T cells were depleted from these mice. The clones that persist in CD8+ T cell-intact mice are highly diverse in contrast to the clones expanded in CD8+ T cell-depleted mice, which are dominated by the significant outgrowth of a few clones. Importantly, the T cell clones that expand in the absence of CD8+ T cell control are enriched in potentially pathogenic self-reactive T cell clones capable of inducing EAE in vivo.
Low-dose, Fractionated Radioimmunotherapy for B-cell Malignancies using 131 I-LYM-1 Antibody (1998)

Although advanced disease often interrupted therapy prematurely, the results from 131I-Lym-1 therapy are clearly promising and warrant additional trials.
A combined computational-experimental approach to define the structural origin of antibody recognition of sialyl-Tn, a tumor-associated carbohydrate antigen (2018)

Anti-carbohydrate monoclonal antibodies (mAbs) hold great promise as cancer therapeutics and diagnostics. However, their specificity can be mixed, and detailed characterization is problematic, because antibody-glycan complexes are challenging to crystallize. Here, we developed a generalizable approach employing high-throughput techniques for characterizing the structure and specificity of such mAbs, and applied it to the mAb TKH2 developed against the tumor-associated carbohydrate antigen sialyl-Tn (STn). The mAb specificity was defined by apparent K<sub>D</sub> values determined by quantitative glycan microarray screening. Key residues in the antibody combining site were identified by site-directed mutagenesis, and the glycan-antigen contact surface was defined using saturation transfer difference NMR (STD-NMR). These features were then employed as metrics for selecting the optimal 3D-model of the antibody-glycan complex, out of thousands plausible options generated by automated docking and molecular dynamics simulation. STn-specificity was further validated by computationally screening of the selected antibody 3D-model against the human sialyl-Tn-glycome. This computational-experimental approach would allow rational design of potent antibodies targeting carbohydrates.
A monoclonal antibody identifies a protective C-protein alpha-antigen epitope in group B streptococci (1991)

Group B streptococci (GBS) are the leading causes of neonatal sepsis and meningitis in the United States, with a high rate of fatality and serious morbidity despite appropriate therapy. The C-protein antigens of GBS appear to be important in immunity to experimental infection, yet these antigens remain incompletely characterized with respect to their number, structure, and function. None of these proteins has yet been purified to homogeneity. We have developed a novel method for extraction of surface proteins from the A909 (Ia/c) strain of GBS by using mutanolysin. Antibodies raised in rabbits against these partially purified proteins conferred passive protection to lethal GBS infection in mice challenged with a GBS strain expressing C proteins with a heterologous capsule type. In addition, mouse monoclonal antibodies were produced and identified by reactivity with the mutanolysin-extracted proteins. One of these monoclonal antibodies (4G8) identifies an epitope on the alpha-antigen of the GBS C proteins (identified by protease susceptibility and mouse protection). On sodium dodecyl sulfate-polyacrylamide gels, this epitope appears as a series of regularly spaced bands ranging in apparent molecular mass from 160,000 to 30,000 Da. The monoclonal antibody 4G8 induces opsonic killing of GBS and protects mice from lethal challenge with GBS. Thus, the 4G8 monoclonal antibody identifies a fully protective epitope on the C-protein alpha-antigen of GBS.
ESR1 mutations: Moving towards guiding treatment decision-making in metastatic breast cancer patients (2016)

Mutations in the gene coding for the estrogen receptor (ER), ESR1, have been associated with acquired endocrine resistance in patients with ER-positive metastatic breast cancer (MBC). Functional studies revealed that these ESR1 mutations lead to constitutive activity of the ER, meaning that the receptor is active in absence of its ligand estrogen, conferring resistance against several endocrine agents. While recent clinical studies reported that the occurrence of ESR1 mutations is rare in primary breast cancer tumors, these mutations are more frequently observed in metastatic tissue and circulating cell-free DNA of MBC patients pretreated with endocrine therapy. Given the assumed impact that the presence of ESR1 mutations has on outcome to endocrine therapy, assessing ESR1 mutations in MBC patients is likely to be of significant interest to further individualize treatment for MBC patients. Here, ESR1 mutation detection methods and the most relevant pre-clinical and clinical studies on ESR1 mutations regarding endocrine resistance are reviewed, with particular interest in the ultimate goal of guiding treatment decision-making based on ESR1 mutations.
Persistent photoconductivity in Hf–In–Zn–O thin film transistors (2010)

Passivated Hf–In–Zn–O (HIZO) thin film transistors suffer from a negative threshold voltage shift under visible light stress due to persistent photoconductivity (PPC). Ionization of oxygen vacancy sites is identified as the origin of the PPC following observations of its temperature- and wavelength-dependence. This is further corroborated by the photoluminescence spectrum of the HIZO. We also show that the gate voltage can control the decay of PPC in the dark, giving rise to a memory action.
Experimental study of decubitus ulcer formation in the rabbit ear lobe (2003)

An animal model of decubitus ulcer was created with the use of ear lobes of Japanese white rabbits. When the strength of the cyclic compressions and the duration of the cycles of compression and release are adjusted, the model successfully reproduced the four grades used to characterize decubitus ulcer. Compressions were recorded with video microscopy to continuously monitor the changes in tissue blood flow, in both the compressed and surrounding regions. This model is unique insofar as the blood-flow characteristics are clearly visible before, during, and after compression. Because long-term observation is possible in a living-body model, our study can easily be extended.
Amino acid sequence and variant forms of favin, a lectin from Vicia faba. (1982)

We have determined the complete amino acid sequence (182 residues) of the beta chain of favin, the glucose-binding lectin from fava beans (Vicia faba), and have established that the carbohydrate moiety is attached to Asn 168. Together with the sequence of the alpha chain previously reported (Hemperly, J. J., Hopp, T. P., Becker, J. W., and Cunningham, B. A. (1979) J. Biol. Chem. 254, 6803-6810), these data complete the analysis of the primary structure of the lectin. We have also examined minor polypeptides that appear in all preparations of favin. Two lower molecular weight species (Mr = 9,500-11,600) appear to be fragments of the beta chain resulting from cleavage following Asn 76, whereas six high molecular weight forms (Mr = 25,000 or greater) appear to include aggregates of the beta chain and possibly some alternative products of chain processing.
Thermal Conductivity of Sm<sub>2</sub>Zr<sub>2</sub>O<sub>7</sub>-Carbon Nanotube Composite (2010)

CNT (carbon nanotube) was purified by acid washing method and then dispersed in alcohol. Sm2Zr2O7-CNT composite powders containing different amounts of CNT were synthesized by corprecipitation method and hot-press sintering were selected to prepare the composites. The density and thermal conductivity of the samples were tested. The micro-morphology and phase structure of composites were characterized by field emission scanning electron microscope and X-ray diffraction, respectively. Based on these experiments and theoretical analyses, the influences of carbon nanotube on the micro-morphology, phase structure and thermal conductivity of Sm2Zr2O7-CNT composite were revealed. Results showed that the carbon nantube uniformly dispersed in Sm2Zr2O7 matrix and the thermal conductivity of composites varied with the different amounts of CNT. In this article, the variation of thermal conductivity can be explained by the comprehensive evaluation of Sm2Zr2O7, CNT, pore and the heterogeneous interfaces thermal resistance between matrix and additives.