gebhart/patrepeval huggingface dataset:
Androgen-Stimulated UDP-Glucose Dehydrogenase Expression Limits Prostate Androgen Availability without Impacting Hyaluronan Levels (2009)

UDP-glucose dehydrogenase (UGDH) oxidizes UDP-glucose to UDP-glucuronate, an essential precursor for production of hyaluronan (HA), proteoglycans, and xenobiotic glucuronides. High levels of HA turnover in prostate cancer are correlated with aggressive progression. UGDH expression is high in the normal prostate, although HA accumulation is virtually undetectable. Thus, its normal role in the prostate may be to provide precursors for glucuronosyltransferase enzymes, which inactivate and solubilize androgens by glucuronidation. In this report, we quantified androgen dependence of UGDH, glucuronosyltransferase, and HA synthase expression. Androgen-dependent and androgen-independent human prostate cancer cell lines were used to test the effects of UGDH manipulation on tumor cell growth, HA production, and androgen glucuronidation. Dihydrotestosterone (DHT) increased UGDH expression approximately 2.5-fold in androgen-dependent cells. However, up-regulation of UGDH did not affect HA synthase expression or enhance HA production. Mass spectrometric analysis showed that DHT was converted to a glucuronide, DHT-G, at a 6-fold higher level in androgen-dependent cells relative to androgen-independent cells. The increased solubilization and elimination of DHT corresponded to slower cellular growth kinetics, which could be reversed in androgen-dependent cells by treatment with a UDP-glucuronate scavenger. Collectively, these results suggest that dysregulated expression of UGDH could promote the development of androgen-independent tumor cell growth by increasing available levels of intracellular androgen.
Structure—Activity Relationships of the Avermectins and Milbemycins (1997)

In 1976 scientists at Merck & Co. Inc. discovered a complex of eight closely related natural products, subsequently named avermectins, in a culture of Streptomyces avermitilis MA-4680 (NRRL8165) originating from an isolate by the Kitasato Institute from a soil sample collected at Kawana, Ito City, Shizuoka Prefecture, Japan. They are among the most potent anthelmintic, insecticidal and acaricidal compounds known. The avermectins are structurally related to another group of natural products, the milbemycins, the first examples of which were described by Japanese workers. Avermectin B1, under the non-proprietary name abamectin, is widely used as an agricultural miticide and its 22,23-dihydro derivative, ivermectin is used world wide as a broad spectrum parasiticide in animals and in man. More recently, a new avermectin, doramectin, has been prepared by directed biosynthesis and developed for similar use in animals. Three milbemycins are used for animal health, milbemycin D, milbemycin oxime and moxidectin. This presentation describes some of the structure-activity relationships between the avermectins and milbemycins and an intensive synthetic program on 4"-deoxy-4"-epiamino avermectins culminating in two novel compounds in development, emamectin benzoate as an agricultural insecticide and eprinomectin as a broad spectrum endectocide for use in animals. Mode of action studies have revealed a glutamate-gated chloride channel from C. elegans proposed to be the target site for both avermectins and milbemycins.
Hermetic packaging of resonators with vertical feedthroughs using a glass-in-silicon reflow process (2011)

A low-cost, hermetic wafer-level packaging solution with negligible parasitics suitable for MEMS resonators is presented. A glass cap with embedded 50µm diameter vertical single-crystal silicon feedthroughs is anodically bonded in vacuum to an SOI wafer prefabricated with mechanical resonators. This hermetic packaging process provides virtually zero-parasitic-capacitance vertical interconnects. A silicon-gold eutectic is used to ensure electrical contacts between the feedthroughs and the device wafer. An embedded wet-etched cavity in the glass cap allows mechanical motion of the resonator as well as the inclusion of a thin-film getter to further enhance and maintain vacuum. Temperature sweeps and quality factor measurements demonstrate the successful packaging of resonators using this technique.
Characterization of Novel Virulent Broad-Host-Range Phages of Xylella fastidiosa and Xanthomonas (2013)

The xylem-limited bacterium Xylella fastidiosa is the causal agent of several plant diseases, most notably Pierce's disease of grape and citrus variegated chlorosis. We report the isolation and characterization of the first virulent phages for X. fastidiosa, siphophages Sano and Salvo and podophages Prado and Paz, with a host range that includes Xanthomonas spp. Phages propagated on homologous hosts had observed adsorption rate constants of ~4 × 10(-12) ml cell(-1) min(-1) for X. fastidiosa strain Temecula 1 and ~5 × 10(-10) to 7 × 10(-10) ml cell(-1) min(-1) for Xanthomonas strain EC-12. Sano and Salvo exhibit >80% nucleotide identity to each other in aligned regions and are syntenic to phage BcepNazgul. We propose that phage BcepNazgul is the founding member of a novel phage type, to which Sano and Salvo belong. The lysis genes of the Nazgul-like phage type include a gene that encodes an outer membrane lipoprotein endolysin and also spanin gene families that provide insight into the evolution of the lysis pathway for phages of Gram-negative hosts. Prado and Paz, although exhibiting no significant DNA homology to each other, are new members of the phiKMV-like phage type, based on the position of the single-subunit RNA polymerase gene. The four phages are type IV pilus dependent for infection of both X. fastidiosa and Xanthomonas. The phages may be useful as agents for an effective and environmentally responsible strategy for the control of diseases caused by X. fastidiosa.
Apoptosis in Myocardial Ischemia‐Reperfusion (1999)

The signal transduction pathways by which ischemia-reperfusion leads to apoptosis may involve the JNK pathway, ceramide generation, and inhibition of protective PKC pathways. The biochemical events associated with apoptosis include mitochondrial inactivation, cytochrome c dislocation, caspase activation, and cytoplasmic acidification. Through the concerted efforts of multiple classes of enzymes, apoptosis is accomplished, resulting in the death of a cell in which potentially transforming oncogenes have been degraded and inflammatory contents are contained within the plasma membrane until the fragments can be ingested by phagocytes. This non-inflammatory mode of cell death permits tissue remodeling with minimal scar formation, and so is preferable to necrotic cell death. The distinction between apoptosis and necrosis, which implies different mechanisms of cell death, is blurred in the case of a pathologic insult such as ischemia-reperfusion. It is suggested that it is more useful to view cell death in the context of whether or not it can be prevented.
Neuroscience: Exploring the Brain (1996)

Accompanying compact disc titled "Student CD-ROM to accompany Neuroscience : exploring the brain" includes animations, videos, exercises, glossary, and answers to review questions in Adobe Acrobat PDF and other file formats.
Viricidal effect of Lactobacillus acidophilus on human immunodeficiency virus type 1: possible role in heterosexual transmission. (1991)

Peroxidase, H2O2, and a halide form a powerful antimicrobial system in phagocytes and tissue fluids, and certain microorganisms can serve as the source of H2O2 for this system. H2O2-generating Lactobacillus acidophilus (LB+) is present in the vagina of most normal women and peroxidase has been detected in vaginal fluid. LB+ at high concentration is viricidal to HIV-1, and, at levels where LB+ is ineffective alone, the addition of peroxidase (myeloperoxidase, eosinophil peroxidase) and a halide (chloride, iodide, bromide, thiocyanate) restore viricidal activity. LB+ can be replaced by H2O2, but not by non-H2O2-producing LB, and viricidal activity is inhibited by azide and catalase. The survival of HIV in the female genital tract and thus the likelihood of transmission may be influenced by the activity of the LB(+)-peroxidase-halide system in the vagina.
5-Hydroxyconiferyl Aldehyde Modulates Enzymatic Methylation for Syringyl Monolignol Formation, a New View of Monolignol Biosynthesis in Angiosperms (2000)

S-Adenosyl-L-methionine-dependent caffeate O-methyltransferase (COMT, EC 2.1.1.6) has traditionally been thought to catalyze the methylation of caffeate and 5- hydroxyferulate for the biosynthesis of syringyl monolignol, a lignin constituent of angiosperm wood that enables efficient lignin degradation for cellulose production. However, recent recognition that coniferyl aldehyde prevents 5-hydroxyferulate biosynthesis in lignifying tissue, and that the hydroxylated form of coniferyl aldehyde, 5-hydroxyconiferyl aldehyde, is an alternative COMT substrate, demands a re-evaluation of the role of COMT during monolignol biosynthesis. Based on recombinant aspen (Populus tremuloides) COMT enzyme kinetics coupled with mass spectrometry analysis, this study establishes for the first time that COMT is in fact a 5-hydroxyconiferyl aldehyde O-methyltransferase (AldOMT), and that 5-hydroxyconiferyl aldehyde is both the preferred AldOMT substrate and an inhibitor of caffeate and 5-hydroxyferulate methylation, as measured by K(m) and K(i) values. 5-Hydroxyconiferyl aldehyde also inhibited the caffeate and 5-hydroxyferulate methylation activities of xylem proteins from various angiosperm tree species. The evidence that syringyl monolignol biosynthesis is independent of caffeate and 5-hydroxyferulate methylation supports our previous discovery that coniferyl aldehyde prevents ferulate 5-hydroxylation and at the same time ensures a coniferyl aldehyde 5-hydroxylase (CAld5H)-mediated biosynthesis of 5-hydroxyconiferyl aldehyde. Together, our results provide conclusive evidence for the presence of a CAld5H/AldOMT-catalyzed coniferyl aldehyde 5-hydroxylation/methylation pathway that directs syringyl monolignol biosynthesis in angiosperms.
Plasma Brain Natriuretic Peptide as a Prognostic Indicator in Patients With Primary Pulmonary Hypertension (2000)

A high level of plasma BNP, and in particular, a further increase in plasma BNP during follow-up, may have a strong, independent association with increased mortality rates in patients with PPH.
Laboratory evidence for the hormonal dependency of meningiomas (1994)

Evidence for the hormonal dependency of meningiomas and of the value of various forms of endocrine therapy are described. Clinical features of the tumour are described. Laboratory evidence for the presence and activity of functional steroid receptors is described, and their characteristics are analysed. The effect of receptor antagonists on the growth of the tumour cells is indicated.
The role of glutamate in epilepsy and other CNS disorders. (1994)

Glutamate is the principal excitatory neurotransmitter in the brain and, as such, it inevitably plays a role in the initiation and spread of seizure activity. It also plays a critical role in epileptogenesis. The process of "kindling" limbic seizures in rodents by repeated electrical stimulation is dependent on activation of N-methyl-D-aspartate (NMDA) receptors. The function of these receptors is enhanced in the hippocampus of kindled rats and in the cerebral cortex of patients with focal epilepsy. Microdialysis studies show an increase in the extracellular concentration of glutamate and aspartate before or during seizure onset, suggesting that either enhanced amino acid release or impaired uptake contributes to seizure initiation. Glutamate antagonists selective for NMDA or non-NMDA receptors are potent anticonvulsants when given systemically in a wide variety of animal models of epilepsy. They are of limited efficacy against kindled seizures in rats and (on the basis of preliminary evidence) in patients with drug-refractory complex partial seizures. Cognitive side effects appear to be a significant problem with competitive, as well as noncompetitive, NMDA antagonists. Glutamate receptor antagonists provide significant protection against brain damage following global or focal cerebral ischemia or acute traumatic injury in rodent models. Anticonvulsant compounds of the lamotrigine type, which act on sodium channels and reduce ischemia-induced glutamate release, are cerebroprotective in rodent ischemia models and are free from the cognitive side effects of NMDA-receptor antagonists.
A Selective, Orally Bioavailable 1,2,4-Triazolo[1,5-a]pyridine-Based Inhibitor of Janus Kinase 2 for Use in Anticancer Therapy: Discovery of CEP-33779 (2012)

Members of the JAK family of nonreceptor tyrosine kinases play a critical role in the growth and progression of many cancers and in inflammatory diseases. JAK2 has emerged as a leading therapeutic target for oncology, providing a rationale for the development of a selective JAK2 inhibitor. A program to optimize selective JAK2 inhibitors to combat cancer while reducing the risk of immune suppression associated with JAK3 inhibition was undertaken. The structure-activity relationships and biological evaluation of a novel series of compounds based on a 1,2,4-triazolo[1,5-a]pyridine scaffold are reported. Para substitution on the aryl at the C8 position of the core was optimum for JAK2 potency (17). Substitution at the C2 nitrogen position was required for cell potency (21). Interestingly, meta substitution of C2-NH-aryl moiety provided exceptional selectivity for JAK2 over JAK3 (23). These efforts led to the discovery of CEP-33779 (29), a novel, selective, and orally bioavailable inhibitor of JAK2.
Tcl1 functions as a transcriptional regulator and is directly involved in the pathogenesis of CLL (2008)

B cell chronic lymphocytic leukemia (B-CLL) is the most common human leukemia. Deregulation of the T cell leukemia/lymphoma 1 (TCL1) oncogene in mouse B cells causes a CD5-positive leukemia similar to aggressive human B-CLLs. To examine the mechanisms by which Tcl1 protein exerts oncogenic activity in B cells, we investigated the effect of Tcl1 expression on NF-kappaB and activator protein 1 (AP-1) activity. We found that Tcl1 physically interacts with c-Jun, JunB, and c-Fos and inhibits AP-1 transcriptional activity. Additionally, Tcl1 activates NF-kappaB by physically interacting with p300/CREB binding protein. We then sequenced the TCL1 gene in 600 B-CLL samples and found 2 heterozygous mutations: T38I and R52H. Importantly, both mutants showed gain of function as AP-1 inhibitors. The results indicate that Tcl1 overexpression causes B-CLL by directly enhancing NF-kappaB activity and inhibiting AP-1.
Characterization of theHelicobacter pyloriCysteine-Rich Protein A as a T-Helper Cell Type 1 Polarizing Agent (2005)

Predominant T-helper 1 (Th1) responses with increased gamma interferon (IFN-gamma) levels have been proposed to play an important role in Helicobacter pylori-induced gastritis and peptic ulceration. However, bacterial factors contributing to the initiation of Th1 polarization of H. pylori-specific immune responses have not been characterized in detail thus far. We report here on the identification of Helicobacter cysteine-rich protein A (HcpA) as a novel proinflammatory and Th1-promoting protein. The capacity of HcpA to induce immune activation was studied in splenocyte cultures of naive H. pylori-negative mice. HcpA stimulated the release of high concentrations of the proinflammatory and Th1-promoting cytokines interleukin-6 (IL-6) and IFN-gamma, in addition to significant levels of IL-12, tumor necrosis factor alpha, and IL-10. The observed cytokine profile was comparable to that induced by lipopolysaccharide but differed in the kinetics and maximum levels of cytokine production. In addition, HcpA-induced cytokine release resembled that observed upon incubation with H. pylori except for IL-10, which was only moderately released upon HcpA stimulation. Both HcpA- and H. pylori-mediated IFN-gamma production was drastically reduced by a neutralizing antibody against IL-12 but not by an anti-IL-2 antibody. Thus, HcpA seems to represent a novel bacterial virulence factor triggering the release of a concerted set of cytokines to instruct the adaptive immune system for the initiation of proinflammatory and Th1-biased immunity.
The molecular evolution of bacterial alkaline phosphatase: correlating variation among enteric bacteria to experimental manipulations of the protein. (1990)

The phylogenetic distribution of the gene coding for bacterial alkaline phosphatase (phoA) was examined in nine species of enteric bacteria closely related to Escherichia coli. The nucleotide and protein sequences from the E. fergusonii and Serratia marcescens genes are presented. The spatial distribution of replaced amino acid residues in the aligned sequences is shown to be highly nonrandom and can be correlated with specific regions within the tertiary structure of the protein. There is an avoidance of replacements within the beta sheet of the protein, and there is an excess of replacements elsewhere, particularly in solvent-exposed residues. In addition, all positions across alpha helices do not accept replacements with equal frequency; there is a bias toward acceptance of replacements in the carboxyl ends of helices. To examine this further, mutations within the E. coli phoA gene were created using site-directed mutagenesis. The patterns seen from the sequence comparisons were verified in the laboratory-created mutants. The average activity of mutations within or near the beta sheet was approximately one-third of that within or near alpha helices, and multiple mutations within the carboxyl ends of alpha helices always possessed greater activity than did multiple mutations within the corresponding amino ends. The results indicate that identifiable regions within the protein are under different selective pressures and are therefore evolving at different rates.
Enzyme‐catalysed peptide amidation (1987)

A series of hydrazones and semicarbazones of glyoxylic acid were shown to have a potent inhibitory effect on the enzyme-catalysed conversion of D-Tyr-Val-Gly to D-Tyr-Val-NH2. Among the derivatives tested, the inhibitory activity was increased by the presence of hydrophobic substituents and decreased by polar substituents. The inhibition produced by glyoxylic acid phenylhydrazone was shown to be competitive. No inhibition was obtained with pyruvic acid phenylhydrazone, which possesses a methyl group in place of the alpha-H of glyoxylic acid phenylhydrazone. The inhibitory potencies of these non-peptide substances are in accord with the specificity exhibited by the amidating enzyme in its reaction with peptide substrates. The inhibition produced by the glyoxylic acid derivatives was shown to be due to their ability to act as substrates for the peptide-amidating enzyme. The product formed from [14C]glyoxylic acid phenylhydrazone was identified as oxalic acid phenylhydrazide by co-chromatography in three chromatographic systems. The results demonstrate that the enzyme-catalysed oxidation of glyoxylic acid phenylhydrazone takes place by a mechanism involving hydroxylation. It is implicit that peptide amidation catalysed by the same enzyme proceeds by a similar mechanism.
Rapid and Sustained Relief of Migraine Attacks With Intranasal Lidocaine: Preliminary Findings (1995)

In a noncontrolled study, 23 migraine headache patients were treated with intranasal instillation of 0.4 mL of a 4% lidocaine solution during attacks of varying intensities. Evaluated were pretreatment and posttreatment changes in pain intensity, nausea, and side effects. Posttreatment intensity ratings significantly improved over pretreatment ratings, as determined by a Sandler A analysis (0.077; P < .0005). Migraine attacks were aborted in 12 of 23 patients, of which 8 were completely relieved within 5 minutes. In no case did an aborted attack return to more than a dull level within 24 hours, as determined by follow-up telephone calls. A successful response of migraine attacks to lidocaine treatment was more apt to occur in patients having migraine solely, when compared to migraine patients who also had daily dull headaches; the difference was not significant. Unilateral attacks, however, were significantly more treatment-responsive when compared to bilateral attacks (X2 = 3.85; P = .05). Nausea, associated with migraine attacks in 6 of 12 responders, was similarly aborted by lidocaine in 5 of 6 patients. Other side effects included mild nasal and eye burning of short duration (seconds), and oropharyngeal numbness of approximately 20 minutes' duration. Despite the abrupt and absolute relief of migraine attacks afforded by lidocaine in most of our study patients, its level of efficacy awaits results of double-blind, placebo-controlled studies. Our findings raise new questions regarding the differential pathogenesis of migraine and cluster headache attacks.(ABSTRACT TRUNCATED AT 250 WORDS)
Antibody-targeted therapy for myeloid leukemia. (1999)

The availability of antibodies reactive with antigens expressed only by hematopoietic cells has provided clinical investigators with new tools for use in developing therapies for acute myeloid leukemia (AML). Studies performed to date have investigated the use of such antibodies in an unmodified state, combined with potent chemicals to form immunotoxins or combined with various radionuclides. Encouraging results have been obtained in all three settings. The CD33 antigen is expressed by most early myeloid cells and by more than 90% of cases of AML but is not present on the hematopoietic stem cell. Initial in vivo studies with an unmodified murine anti-CD33 antibody in patients with AML demonstrated that the antibody quickly bound to leukemia cells and that the antigen-antibody complex rapidly internalized following cell binding. However, when administered to patients with overt leukemia, unmodified antibody resulted in only brief decreases in peripheral blast counts, not in sustained response. A number of CD33-based immunotoxins have also been studied, including a calicheamicin conjugate, CMA-676. In a phase I dose-escalation study of patients with refractory AML, CMA-676 was well tolerated with the only consistent toxicities being the development of fevers and chills several hours after administration and the subsequent development of temporary pancytopenia. A phase III study has been performed involving patients with AML in first relapse. An interim analysis of the first 23 patients found that in 10, treatment with CMA-676 resulted in elimination of blasts from peripheral blood and marrow. This was achieved with far less toxicity than seen with standard chemotherapy. Radiolabeled antibodies have been explored as a stand-alone treatment or in the context of bone marrow transplantation. In an effort to avoid toxicities to normal stem cells residing alongside leukemic cells in the marrow, studies have been performed to explore the use of 231Bi conjugated to an anti-CD33 monoclonal antibody. The short path length of this alpha-emitter could theoretically allow killing of the targeted leukemic cell without damage to normal neighbors. Of 12 patients with recurrent AML who received this drug, eight had reductions in marrow and peripheral blast counts. Complete remissions (CRs) have not been observed to date. Another set of studies focused on the use of radiolabeled antibodies to deliver radiation specifically to sites of leukemia as part of a transplant preparative regimen. In a phase I clinical trial, 131I-labeled anti-CD45 antibody delivered at least threefold more radiotherapy to spleen and marrow than any other organ. In a phase II trial, among 25 AML patients in first remission, 22 are alive and in remission for periods up to 6 years.