gebhart/patrepeval huggingface dataset:
Total Syntheses of Epothilones A and B (1997)

Convergent, stereocontrolled total syntheses of the microtubule-stabilizing macrolides epothilones A (2) and B (3) have been achieved. Four distinct ring-forming strategies were pursued (see Scheme 1). Of these four, three were reduced to practice. In one approach, the action of a base on a substance possessing an acetate ester and a nonenolizable aldehyde brought about a remarkably effective macroaldolization see (89 → 90 + 91; 99 → 100 + 101), simultaneously creating the C2−C3 bond and the hydroxyl-bearing stereocenter at C-3. Alternatively, the 16-membered macrolide of the epothilones could be fashioned through a C12−C13 ring-closing olefin metathesis (e.g. see 111 → 90 + 117; 122 → 105 + 123) and through macrolactonization of the appropriate hydroxy acid (e.g. see 88 → 93). The application of a stereospecific B-alkyl Suzuki coupling strategy permitted the establishment of a cis C12−C13 olefin, thus setting the stage for an eventual site- and diastereoselective epoxidation reaction (see 96 → 2; 106 → 3). The development of a novel cyclopropane solvolysis strategy for incorporating the geminal methyl groups of the epothilones (see 39 → 40 → 41), and the use of Lewis acid catalyzed diene−aldehyde cyclocondensation (LACDAC) (see 35 + 36 → 37) and asymmetric allylation (see 10 → 76) methodology are also noteworthy.
Inactivation of Anthracyclines by Serum Heme Proteins (2007)

We have previously shown that the anticancer agent doxorubicin undergoes oxidation and inactivation when exposed to myeloperoxidase-containing human leukemia HL-60 cells, or to isolated myeloperoxidase, in the presence of hydrogen peroxide and nitrite. In the current study we report that commercial fetal bovine serum (FBS) alone oxidizes doxorubicin in the presence of hydrogen peroxide and that nitrite accelerates this oxidation. The efficacy of inactivation was dependent on the concentration of serum present; no reaction was observed when hydrogen peroxide or serum was omitted. Peroxidase activity assays, based on oxidation of 3,3',5,5'-tetramethylbenzidine, confirmed the presence of a peroxidase in the sera from several suppliers. The peroxidative activity was contained in the >10000 MW fraction. We also found that hemoglobin, a heme protein likely to be present in commercial FBS, is capable of oxidizing doxorubicin in the presence of hydrogen peroxide and that nitrite further stimulates the reaction. In contrast to intact doxorubicin, the serum + hydrogen peroxide + nitrite treated drug appeared to be nontoxic for PC3 human prostate cancer cells. Together, this study shows that (pseudo)peroxidases present in sera catalyze oxidation of doxorubicin by hydrogen peroxide and that this diminishes the tumoricidal activity of the anthracycline, at least in in vitro settings. Finally, this study also points out that addition of H2O2 to media containing FBS will stimulate peroxidase-type of reactions, which may affect cytotoxic properties of studied compounds.
Human vs. robotic tactile sensing: Detecting lumps in soft tissue (2010)

Humans can localize lumps in soft tissue using the distributed tactile feedback and processing afforded by the fingers and brain. This task becomes extremely difficult when the fingers are not in direct contact with the tissue, such as in laparoscopic or robot-assisted procedures. Tactile sensors have been proposed to characterize and detect lumps in robot-assisted palpation. In this work, we compare the performance of a capacitive tactile sensor with that of the human finger. We evaluate the response of the sensor as it pertains to robot-assisted palpation and compare the sensor performance to that of human subjects performing an equivalent task on the same set of artificial tissue models. Furthermore, we investigate the effects of various tissue parameters (lump size, lump depth, and surrounding tissue stiffness) on the performance of both the human finger and the tactile sensor. Using signal detection theory for determining tactile sensor lump detection thresholds, the tactile sensor outperforms the human finger in a palpation task.
Structural Role of Extracellular Domain 1 of α-Platelet-derived Growth Factor (PDGF) Receptor for PDGF-AA and PDGF-BB Binding (1995)

The purpose of this study was to bacterially express, purify, and refold combinations of the extracellular immunoglobulin (Ig)-like domains (2-3, 1-3, and 1-5) of the human alpha-platelet-derived growth factor receptor (alpha PDGFR) to characterize molecular interactions with its ligand, platelet-derived growth factor (PDGF). The far UV circular dichroism spectroscopy of the alpha-PDGFR extracellular domains (ECDs) revealed a predominantly beta-sheet protein, with a structure consistent with folded Ig-like domains. The addition of PDGF-BB to these ECD types changed the conformation of all three types with a decrease in mean residue ellipticity in the following rank order: 1-5 = 1-3 > 2-3. In striking contrast, addition of PDGF-AA to these ECD types markedly changed the conformation of ECD 2-3, by an increased mean residue ellipticity but no changes were observed for ECDs 1-3 and 1-5. PDGF-AA bound to the immobilized ECD types 2-3, 1-3, and 1-5 at concentrations of 20, 11, and 7.5 nM, respectively. In contrast, PDGF-BB bound the ECD types 2-3, 1-3, and 1-5 at concentrations of 3, 3, and 2.2 nM, respectively. Scatchard analysis of binding studies using labeled ECDs indicated that PDGF-BB bound ECD 1-3 and ECD 2-3 with KD values of 74 and 72 nM, respectively. While, PDGF-AA bound ECD 1-3 and ECD 2-3 with KD values of 33 and 87 nM, respectively. Therefore, our results indicated that the loss of ECD 1 impaired the binding affinity of alpha PDGFR ECD 1-3 toward PDGF-AA without having a similar effect on PDGF-BB binding. Together all of our data suggest that ECD 1 is differentially required for proper orientation of PDGF-AA but not PDGF-BB binding determinant within ECDs 2 and 3.
Sequence-specific antitumor activity of a phosphorothioate oligodeoxyribonucleotide targeted to human C- raf kinase supports an antisense mechanism of action in vivo (1996)

To determine the mechanism of action responsible for the in vivo antitumor activity of a phosphorothioate antisense inhibitor targeted against human C-raf kinase (ISIS 5132, also known as CGP69846A), a series of mismatched phosphorothioate analogs of ISIS 5132 or CGP69846A were synthesized and characterized with respect to hybridization affinity, inhibitory effects on C-raf gene expression in vitro, and antitumor activity in vivo. Incorporation of a single mismatch into the sequence of ISIS 5132 or CGP69846A resulted in reduced hybridization affinity toward C-raf RNA sequences and reduced inhibitory activity against C-raf expression in vitro and tumor growth in vivo. Moreover, incorporation of additional mismatches resulted in further loss of in vitro and in vivo activity in a manner that correlated well with a hybridization-based (i.e., antisense) mechanism of action. These results provide important experimental evidence supporting an antisense mechanism of action underlying the in vivo antitumor activity displayed by ISIS 5132 or CGP69846A.
Systematic review of randomised controlled trials: probiotics for functional constipation. (2010)

Until more data are available, we believe the use of probiotics for the treatment of constipation condition should be considered investigational.
Interactions Between Gut Microbiota and Host Metabolism Predisposing to Obesity and Diabetes (2010)

Novel, culture-independent, molecular and metagenomic techniques have provided new insight into the complex interactions between the mammalian host and gut microbial species. It is increasingly evident that gut microbes may shape the host metabolic and immune network activity and ultimately influence the development of obesity and diabetes. We discuss the evidence connecting gut microflora to obesity and to type 1 and type 2 diabetes, and we present recent insights into potential mechanisms underlying this relationship: increased nutrient absorption from the diet, prolonged intestinal transit time, altered bile acid entero-hepatic cycle, increased cellular uptake of circulating triglycerides, enhanced de novo lipogenesis, reduced free fatty acid oxidation, altered tissue composition of biologically active polyunsaturated fatty acid, chronic low-grade inflammation triggered by the endotoxin toll-like receptor 4 axis, and altered intestinal barrier function.
Guidance for the Discontinuation or Switching of Antidepressant Therapies in Adults (2013)

Antidepressants (ADs) are commonly used for the treatment of various psychological and other medical disorders. Patient response and regimen duration with individual agents varies, necessitating discontinuation (DC) and/or switching between ADs. However, withdrawal symptoms may occur upon DC of the AD, and clinical symptom control may be compromised if the change to a new AD agent is not initiated appropriately. The purpose of this evaluation was to review the available literature and resources to compile documented methods for discontinuing or changing AD regimens in the clinical setting into a single guidance document. The results of this evaluation have yielded both detailed and general recommendations for practitioners to use and consider in discontinuing an AD and making changes between AD agents. The information provided herein is intended to provide useful guidance for clinicians and other health care professionals in their management of patients discontinuing or switching between selected AD agents.
WNT/β‐catenin signaling in liver health and disease (2007)

Wnt/beta-catenin signaling is emerging as a forerunner for its critical roles in many facets of human biology. Its roles in embryogenesis, organogenesis, and maintaining tissue and organ homeostasis demonstrate its munificent character. Its roles in pathological conditions such as cancer and other human disorders such as inflammatory disorders and fibrosis reveal its villainous disposition. In liver, it also maintains its dual personality and is clearly of essence in several physiological events such as development, regeneration, and growth. Its aberrant activation is also evident in many different tumors of the liver, and recent studies are beginning to identify its role in additional hepatic pathological conditions. It is contributing to liver physiology and pathology by regulating various basic cellular events, including differentiation, proliferation, survival, oxidative stress, morphogenesis, and others. This review discusses the contribution of the Wnt/beta-catenin signaling pathway in these events and simultaneously provides an essential overview of the major developments in the field of Wnt/beta-catenin and liver pathobiology. In addition, areas that are currently deficient or understudied are identified and discussed along with the avenues of translational and clinical relevance.
Targeted Complement Inhibitors Protect against Posttransplant Cardiac Ischemia and Reperfusion Injury and Reveal an Important Role for the Alternative Pathway of Complement Activation (2010)

Ischemia reperfusion injury (IRI) is an unavoidable event during solid organ transplantation and is a major contributor to early graft dysfunction and subsequent graft immunogenicity. In a therapeutic paradigm using targeted complement inhibitors, we investigated the role of complement, and specifically the alternative pathway of complement, in IRI to heart isografts. Mouse heterotopic isograft heart transplants were performed in C57BL/6 mice treated with a single injection of either CR2-Crry (inhibits all complement pathways) or CR2-fH (inhibits alternative complement pathway) immediately posttransplantation. Transplanted hearts were harvested at 12 and 48 h for analysis. Both inhibitors resulted in a significant reduction in myocardial IRI, as measured by histology and serum cardiac troponin I levels. Furthermore, compared with untreated controls, both inhibitors reduced graft complement deposition, neutrophil and macrophage infiltration, adhesion molecule expression (P-selectin, E-selectin, and I-CAM-1), and proinflammatory cytokine expression (TNF-α, IL-1β, KC, and MCP-1). The reduction in myocardial damage and cellular infiltration was not significantly different between CR2-Crry- and CR2-fH-treated mice, although adhesion molecule and cytokine levels were significantly lower in CR2-Crry-treated mice compared with CR2-fH-treated mice. In conclusion, the alternative complement pathway plays a major contributing role in myocardial IRI after heart transplantation, and local (targeted) complement inhibition has the potential to provide an effective and safe therapeutic strategy to reduce graft injury. Although total complement blockade may be somewhat more efficacious in terms of reducing inflammation, specific blockade of the alternative pathway is likely to be less immunosuppressive in an already immunocompromised recipient.
Rearrangement, racemization and decomposition of peptides in aqueous solution. (1992)

We reported earlier that peptides containing glycine as the third amino acid from the amino end undergo sequence rearrangement of the first two amino acid residues. In the course of this experimental verification of the suggested reaction mechanism, we found extensive racemization of the amino acid residue in position 1. Racemization is preferred over rearrangement in peptides containing amino acids different from glycine in position 3. We demonstrate that this reaction can be used for the selective labeling of peptides. Using model peptides, we suggest a mechanism that explains both the rearrangement and racemization of these peptides in aqueous solution. This mechanism is based on formation of a diketopiperazine-like (DKP-like) structure by attack of the N-terminal amino group on the amide carbonyl group of the second residue in the peptide chain. This tetrahedral intermediate, which contains a secondary amino group derived from the amide bond between the second and third amino acid residue, can (i) decompose with the formation of diketopiperazine and a shortened peptide sequence; (ii) form a bicyclic structure by transanular attack on the first amino acid carbonyl group in the DKP-like ring by the newly formed amino group, leading to the rearranged product; and (iii) form a bicyclic structure by transanular attack of the newly formed hydroxyl group on the carbonyl group in the DKP-like ring, leading to the race-mixed product.
AA amyloidosis: basic knowledge, unmet needs and future treatments (2012)

Systemic AA amyloidosis is a long-term complication of several chronic inflammatory disorders, including rheumatoid arthritis, ankylosing spondylitis, autoinflammatory syndromes, Crohn's disease, malignancies and conditions predisposing to recurrent infections. Organ damage results from the extracellular deposition of proteolytic fragments of the acute-phase reactant serum amyloid A (SAA) as amyloid fibrils. A sustained high concentration of SAA is the prerequisite for developing AA amyloidosis. However, only a minority of patients with long-standing inflammation actually presents with this complication, pointing to the existence of disease-modifying factors, the best characterised of which being SAA1 genotype. The kidneys, liver and spleen are the main target organs of AA amyloid deposits. In more than 90% of patients proteinuria, nephrotic syndrome and/or renal dysfunction dominate the clinical picture at onset. If not effectively treated, this disease invariably leads to end stage kidney disease and renal replacement therapy, that are still associated with a poor outcome. Although the incidence of AA in rheumatoid arthritis and other chronic arthritides has continuously decreased over the past ten years, thanks to the increasing availability of more effective anti-inflammatory and immunosuppressive therapies, AA remains a life-threatening disease with several areas of uncertainty and unmet needs, deserving continuous efforts at prevention and effective treatment. The deeper understanding of the molecular mechanisms of amyloid formation and regression is now driving the development of novel treatments targeting different steps in the amyloidogenic cascade. These therapies will hopefully improve the quality of life and outcome of these patients in a near future.
Trapping of Proteins under Physiological Conditions in a Nanopipette (2005)

Caught in a trap and on camera: A nanopipette is used for electrodeless dielectrophoresis and clear evidence is shown, by using wide-field fluorescence imaging (see image), for the reversible trapping of Alexa-488-labeled proteins (protein G and immunoglobulin G) and also of the fluorophore alone. The dielectrophoretic concentration is enhanced by at least a factor of 300 for these fluorophore-labeled proteins. Supporting Information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2005/z500196_s.html or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Assessment of GDNF in Primate Models of Parkinson's Disease: Comparison with Human Studies (2005)

Potential future treatments for Parkinson's disease (PD) include those that not only provide symptomatic relief to patients but are also neuroprotective and/or neurorestorative. Glial cell line-derived neurotrophic factor (GDNF) may be a valuable candidate in this regard. Positive results using monkeys have encouraged the use of GDNF in human trials. These trials have unfortunately shown mixed results, illustrating the influence that various parameters of administration can have on clinical outcome. The aim of this review is to compare the findings of these clinical studies with available primate data. While bolus intraventricular injections of GDNF in primates have shown some behavioural efficacy, there was no clinical benefit in the first human trial using this method, which was most likely a result of inefficient GDNF distribution in the striatal parenchyma. In primates, however, continuous (rather than bolus) delivery of GDNF into the ventricles results in significant distribution in the striatum. While chronic delivery of GDNF into the ventricles has not been assessed in humans, intraputamenal protein delivery in two Phase I trials have demonstrated that GDNF considerably reduces PD symptoms, suggesting that the putamen is the optimal location for delivery. Primate studies have shown that vector mediated delivery of GDNF may provide a suitable means for long-term intraputamenal delivery. However, the possibility of high levels of GDNF resulting in widespread distribution of GDNF to non-targeted areas is a cause of concern, and vectors with transgene regulation are needed. The development of these vectors may be the way forward for GDNF treatment.
Impurity doping inSiO2: Formation energies and defect levels from first-principles calculations (2010)

Substitutional doping properties of silicon dioxide are investigated systematically with ab initio calculations. The dopants include a range of elements from group-III, group-V, and group-VII. We find that ${\text{SiO}}_{2}$ has a relatively symmetric doping profile in terms of its ionization energies, i.e., relatively shallow acceptor levels and donor levels are both predicted, despite its wide experimental band gap of 9.65 eV. The best candidates for $p$-type and $n$-type doping are ${\text{Al}}_{\text{Si}}$ and ${\text{P}}_{\text{Si}}$ with calculated ionization energy of 0.86 eV and 0.74 eV, respectively, both being less than 10% of the total band gap. Larger doping asymmetry exists in terms of the impurity formation energy: under optimum (O-rich) growth conditions, the shallowest acceptor, ${\text{Al}}_{\text{Si}}$, and donor, ${\text{P}}_{\text{Si}}$, have formation energies of 1.75 eV and 3.05 eV, respectively. These results provide theoretical insights on how to make this previously considered absolute insulator work as a wide-gap semiconductor at elevated temperatures.
Genetic Disruption of Myostatin Reduces the Development of Proatherogenic Dyslipidemia and Atherogenic Lesions In Ldlr Null Mice (2009)

Inactivation of Mstn protects against the development of insulin resistance, proatherogenic dyslipidemia, and aortic atherogenesis in Ldlr(-/-) mice. Myostatin may be a useful target for drug development for prevention and treatment of obesity and its associated type 2 diabetes and atherosclerosis.
Risk Factors for Delayed Healing and Recurrence of Chronic Venous Leg Ulcers—An Analysis of 1324 Legs (2004)

Elderly patients with longstanding ulcers should be targeted for further research and may benefit from adjunctive treatments to improve clinical outcomes. Patients not treated with superficial venous surgery were at increased risk of leg ulcer recurrence.
Perception threshold and electrode position for spinal cord stimulation (1994)

The perception threshold for epidural spinal cord stimulation in chronic pain management was analyzed on 3,923 testing data obtained from 136 implanted patients. The initial areas of paresthesiae due to stimulation were recorded and reported as the stimulation map according to the location of electrodes. Measurement of dorsal thickness of the cerebrospinal fluid (CSF) layer was obtained from 26 subjects using magnetic resonance imaging (MRI). The results indicate that the perception threshold is a function of the spinal level of the implanted electrodes, of the mediolateral position in the spinal canal and the contact separation of electrode. Differences in perception threshold at various vertebral levels are mainly due to varying depths of the dorsal CSF layer. The medially placed electrodes caudal to the mid-cervical levels have a higher perception threshold than more laterally placed ones. The electrodes at high and mid-cervical levels, however, have a smaller perception threshold if placed medially. The information obtained from this investigation has important implications for the design of a new-generation stimulation system and clinical application to maximize the longevity of the power source.