gebhart/patrepeval huggingface dataset:
Oral toleragens in rheumatoid arthritis. (2000)

Rheumatoid arthritis (RA) is a common inflammatory and destructive arthropathy. Its precise pathogenesis remains unknown but there is evidence to suggest it is an autoimmune disease. Recently, a number of candidate autoantigens have been identified in RA. Modulating the immune response to the autoantigens by oral tolerance may lead to safer and more effective treatment. Oral tolerance is a state of systemic immune suppression to an antigen induced by oral feeding of the same antigen. In animal models, oral feeding with pathogenic antigens prevents and reduces the severity of autoimmune diseases. Even in diseases where the pathogenic autoantigens are unknown, bystander suppression can be induced using antigens present in the anatomical vicinity. Hence, oral tolerance has been advocated as a treatment strategy for autoimmune diseases including RA. Clinical trials of chicken and bovine type II collagen, a major constituent of articular cartilage, produced conflicting results in RA. This review examines the scientific basis of oral tolerance, discusses the apparent discrepancy in clinical trial results and looks at the future prospect.
A proapoptotic peptide for the treatment of solid tumors. (2001)

We have designed a novel peptide, DP1, which is able to mediate significant induction of apoptosis in solid tumors by local injection. This peptide, comprised of a protein transduction domain (PTD), PTD-5, fused to an antimicrobial peptide, (KLAKLAK)2, was able to trigger rapid apoptosis in a variety of cell lines in vitro, including MCA205 murine fibrosarcomas and human head and neck tumors. Furthermore, direct injection of DP1 into day 7 established MCA205 tumors in C57BL/6 mice resulted in the induction of tumor apoptosis and subsequent reduction in tumor volume. These results suggest that DP1 may be used clinically to treat accessible solid tumors or as an adjuvant therapy in conjunction with radiotherapy, standard chemotherapy, immunotherapy, or surgical debulking.
Biochemical analysis on the parallel pathways of methionine biosynthesis in Corynebacterium glutamicum. (2007)

Two alternative pathways for methionine biosynthesis are known in Corynebacterium glutamicum: one involving transsulfuration (mediated by metB and metC) and the other involving direct sulthydrylation (mediated by metY). In this study, MetB (cystathionine gamma-synthase) and MetY (O-acetylhomoserine sulfhydrylase) from C. glutamicum were purified to homogeneity and the biochemical parameters were compared to assess the functional and evolutionary importance of each pathway. The molecular masses of the native MetB and MetY proteins were measured to be approximately 170 and 280 kDa, respectively, showing that MetB was a homotetramer of 40-kDa subunits and MetY was a homohexamer of 45-kDa subunits. The Km values for the O-acetylhomoserine catalysis effected by MetB and MetY were 3.9 and 6.4 mM, and the maximum catalysis rates were 7.4 (kcat = 21 s(-1)) and 6.0 (kcat=28 s(-1)) micromol mg(-1) min(-1), respectively. This suggests that both MetB and MetY can be comparably active in vivo. Nevertheless, the Km value for sulfide ions by MetY was 8.6 mM, which was too high, considering the physiological condition. Moreover, MetB was active at a broad range of temperatures (30 and 65 degrees C) and pH (6.5 and 10.0), as compared with MetY, which was active in a range from 30 to 45 degrees C and at pH values from 7.0 to 8.5. In addition, MetY was inhibited by methionine, but MetB was not. These biochemical data may provide insight on the role of the parallel pathways of methionine biosynthesis in C. glutamicum with regard to cell physiology and evolution.
Surface plasmon polariton mediated energy transfer in organic photovoltaic devices (2007)

The performance of a phthalocyanine-based photovoltaic is boosted in the absorption gap between the phthalocyanine Q and Soret bands. Light absorption is decoupled from exciton diffusion using a light absorbing “antenna” layer external to the conventional charge generating layers. Radiation absorbed by the antenna is transferred into the charge generating layers via surface plasmon polaritons in an interfacial thin silver contact. The peak efficiency of energy transfer is measured to be at least (51±10)%.
Combining Fluorescence Detection and Mass Spectrometric Analysis for Comprehensive and Quantitative Analysis of Redox-Sensitive Cysteines in Native Membrane Proteins (2006)

Monobromobimane (MBB) is a lipophilic reagent that selectively modifies free cysteine residues in proteins. Because of its lipophilic character, MBB is capable of labeling cysteine residues in membrane proteins under native conditions. Reaction of MBB with the sulfhydryl groups of free cysteines leads to formation of highly fluorescent derivatives. Here we describe a procedure for the detection and relative quantitation of MBB-labeled cysteines using fluorescence and mass spectrometric analyses, which allow determination of free cysteine content and unambiguous identification of MBB-modified cysteine residues. We have applied this approach to the analysis of the free and redox-sensitive cysteine residues of a large membrane protein, the sarcoplasmic reticulum Ca2+ release channel with a molecular mass of 2.2 million Da. Labeling was performed under physiologic conditions where the channel complex is in its native environment and is functionally active. The purified MBB-labeled channel complex was enzymatically digested, and the resulting peptides were separated by reversed-phase high-performance chromatography. MBB-labeled peptides were detected by fluorescence and identified by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. Under MALDI conditions, partial photolytic fragmentation of the MBB-peptide bound occurred, thus allowing convenient screening for the MBB-modified peptides in the MS spectrum by detection of the specific mass increment of 190.07 Da for MBB-modified cysteine residues. Modification of the peptides was further confirmed by tandem mass spectrometric analysis, utilizing sequencing information and the presence of the specific immonium ion for the MBB-modified cysteine residues at m/z 266.6. Quantitative information was obtained by comparison of both fluorescence and MS signal intensities of MBB-modified peptides. Combination of fluorescence with MS detection and analysis of MBB-labeled peptides supported by a customized software program provides a convenient method for identifying and quantifying redox-sensitive cysteines in membrane proteins of native biological systems. Identification of one redox-sensitive cysteine (2327) in the native membrane-bound sarcoplasmic reticulum Ca2+ release channel is described.
Clarithromycin versus doxycycline in the treatment of rosacea (1997)

Forty patients with rosacea were entered into a study comparing clarithromycin with doxycycline in the systemic treatment of mild and severe rosacea. The patients, 25 women and 15 men, aged from 26 to 62 years, were subdivided into two homogeneous groups with regard to age, sex, and disease seventy. The first group of 23 patients, 14 women and 9 men, was treated with 250 mg of clarithromycin for 4 weeks twice daily, and then with 250 mg once daily for the following 4 weeks. The second group of 17 patients, 11 women and 6 men was treated with 100 mg of doxycycline for 4 weeks twice daily, and then with 100 mg once a day for the following 4 weeks. Both objective and subjective evaluations of the dermatosis were performed prior to therapy and after 4, 6, and 8 weeks of treatment.
Cu-filled carbon nanotubes by simultaneous plasma-assisted copper incorporation (2003)

Carbon nanotubes are filled with copper by means of chemical vapor deposition. Control of the density of copper in the plasma is crucial and is accomplished by adjusting the length of the copper electrodes that are exposed to the tungsten heating filament. Both simple and branched Cu-filled nanotubes were grown. Most of the branched nanotubes branch only once to form a regular trilateral starburst structure; others branch repeatedly in simple dendritic patterns. A model to account for the filling and growth characteristics is proposed based on observations made with a high-resolution transmission electron microscope and selected area electron diffraction.
Dose Escalation Methods in Phase I Cancer Clinical Trials (2009)

Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials. The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Here we review dose escalation methods for phase I trials, including the rule-based and model-based dose escalation methods that have been developed to evaluate new anticancer agents. Toxicity has traditionally been the primary endpoint for phase I trials involving cytotoxic agents. However, with the emergence of molecularly targeted anticancer agents, potential alternative endpoints to delineate optimal biological activity, such as plasma drug concentration and target inhibition in tumor or surrogate tissues, have been proposed along with new trial designs. We also describe specific methods for drug combinations as well as methods that use a time-to-event endpoint or both toxicity and efficacy as endpoints. Finally, we present the advantages and drawbacks of the various dose escalation methods and discuss specific applications of the methods in developmental oncotherapeutics.
Site-Specific Mass Tagging with Stable Isotopes in Proteins for Accurate and Efficient Protein Identification (2000)

Proteolytic peptide mass mapping as measured by mass spectrometry provides a major approach for the identification of proteins. A protein is usually identified by the best match between the measured and calculated m/z values of the proteolytic peptides. A unique identification is, however, heavily dependent upon the mass accuracy and sequence coverage of the fragment ions generated by peptide ionization. Without ultrahigh instrumental accuracy, it is possible to increase the specificity of the assignments of particular proteolytic peptides by the incorporation of selected amino acid residue(s) enriched with stable isotope(s) into the protein sequence. Here we report this novel method of generating residue-specific mass-tagged proteolytic peptides for accurate and efficient protein identification. Selected amino acids are labeled with 13C/15N/2H and incorporated into proteins in a sequence-specific manner during cell culturing. Each of these labeled amino acids carries a defined mass change encoded in its monoisotopic distribution pattern. Through their characteristic patterns, the peptides with mass tags can then be readily distinguished from other peptides in mass spectra. This method of identifying unique proteins can also be extended to protein complexes and will significantly increase data search specificity, efficiency, and accuracy for protein identifications.
Effect of asimadoline, a κ opioid agonist, on pain induced by colonic distension in patients with irritable bowel syndrome (2004)

Asimadoline decreases overall perception of pain over a wide range of pressure distension of the colon in irritable bowel syndrome patients, without altering its compliance. These data suggest that further studies should explore the potential benefit of asimadoline in treatment of pain in irritable bowel syndrome patients.
Significance Analysis of Prognostic Signatures (2013)

A major goal in translational cancer research is to identify biological signatures driving cancer progression and metastasis. A common technique applied in genomics research is to cluster patients using gene expression data from a candidate prognostic gene set, and if the resulting clusters show statistically significant outcome stratification, to associate the gene set with prognosis, suggesting its biological and clinical importance. Recent work has questioned the validity of this approach by showing in several breast cancer data sets that "random" gene sets tend to cluster patients into prognostically variable subgroups. This work suggests that new rigorous statistical methods are needed to identify biologically informative prognostic gene sets. To address this problem, we developed Significance Analysis of Prognostic Signatures (SAPS) which integrates standard prognostic tests with a new prognostic significance test based on stratifying patients into prognostic subtypes with random gene sets. SAPS ensures that a significant gene set is not only able to stratify patients into prognostically variable groups, but is also enriched for genes showing strong univariate associations with patient prognosis, and performs significantly better than random gene sets. We use SAPS to perform a large meta-analysis (the largest completed to date) of prognostic pathways in breast and ovarian cancer and their molecular subtypes. Our analyses show that only a small subset of the gene sets found statistically significant using standard measures achieve significance by SAPS. We identify new prognostic signatures in breast and ovarian cancer and their corresponding molecular subtypes, and we show that prognostic signatures in ER negative breast cancer are more similar to prognostic signatures in ovarian cancer than to prognostic signatures in ER positive breast cancer. SAPS is a powerful new method for deriving robust prognostic biological signatures from clinically annotated genomic datasets.
Mutagenesis of the human apolipoprotein B gene in a yeast artificial chromosome reveals the site of attachment for apolipoprotein(a). (1995)

Lipoprotein(a) [Lp(a)] is a lipoprotein formed by the disulfide linkage of apolipoprotein (apo) B100 of a low density lipoprotein particle to apolipoprotein(a). Prior studies have suggested that one of the C-terminal Cys residues of apo-B100 is involved in the disulfide linkage of apo-B100 to apo(a). To identify the apo-B100 Cys residue involved in the formation of Lp(a), we constructed a yeast artificial chromosome (YAC) spanning the human apo-B gene and used gene-targeting techniques to change Cys-4326 to Gly. The mutated YAC DNA was used to generate transgenic mice expressing the mutant human apo-B100 (Cys4326Gly). Unlike the wild-type human apo-B100, the mutant human apo-B100 completely lacked the ability to bind to apo(a) and form Lp(a). This study demonstrates that apo-B100 Cys-4326 is required for the assembly of Lp(a) and shows that gene targeting in YACs, followed by the generation of transgenic mice, is a useful approach for analyzing the structure of large proteins coded for by large genes.
Future paradigms for precision oncology (2016)

Research has exposed cancer to be a heterogeneous disease with a high degree of inter-tumoral and intra-tumoral variability. Individual tumors have unique profiles, and these molecular signatures make the use of traditional histology-based treatments problematic. The conventional diagnostic categories, while necessary for care, thwart the use of molecular information for treatment as molecular characteristics cross tissue types.This is compounded by the struggle to keep abreast the scientific advances made in all fields of science, and by the enormous challenge to organize, cross-reference, and apply molecular data for patient benefit. In order to supplement the site-specific, histology-driven diagnosis with genomic, proteomic and metabolomics information, a paradigm shift in diagnosis and treatment of patients is required.While most physicians are open and keen to use the emerging data for therapy, even those versed in molecular therapeutics are overwhelmed with the amount of available data. It is not surprising that even though The Human Genome Project was completed thirteen years ago, our patients have not benefited from the information. Physicians cannot, and should not be asked to process the gigabytes of genomic and proteomic information on their own in order to provide patients with safe therapies. The following consensus summary identifies the needed for practice changes, proposes potential solutions to the present crisis of informational overload, suggests ways of providing physicians with the tools necessary for interpreting patient specific molecular profiles, and facilitates the implementation of quantitative precision medicine. It also provides two case studies where this approach has been used.
Effects of acupuncture on the oxygenation of cerebral tissue (1998)

Monitoring of regional cerebral oxygen saturation (r. cereb. O2 satn.) was carried out continuously in 12 healthy subjects (mean age 35.2 +/- 4.4 years; range 26-41 years; 4 women, 8 men), prior to, during and following acupuncture. Measurements were obtained with the INVOS 3100 cerebral oximeter (Somanetics Corp., Troy, USA). In addition new robotic transcranial Doppler sonography (TCD) probes enabling three-dimensional imaging of the middle cerebral artery by the use of multi-scan techniques were used simultaneously. The results showed small increases in r. cereb. O2 satn. mean values (69.9% before, 70.3% during and 70.2% after acupuncture) and a significant (p < 0.01; ANOVA, Tukey test) increase in mean bloodflow velocity during acupuncture measured simultaneously at different depths within the right middle cerebral artery. There are reports in the literature about the effects of acupuncture on the oxygenation of cerebral tissue in a study with animals. An increase in the cerebral oxygen saturation could be registered with the help of microelectrodes in the cortex. This is parallel evidence to the present results with near infrared spectroscopy and transcranial Doppler sonography. Quantifiable changes in the physiological effects of acupuncture may contribute to improved acceptance of this unconventional complementary medical procedure.
Hypoxia modulates the purine salvage pathway and decreases red blood cell and supernatant levels of hypoxanthine during refrigerated storage (2017)

Hypoxanthine catabolism <i>in vivo</i> is potentially dangerous as it fuels production of urate and, most importantly, hydrogen peroxide. However, it is unclear whether accumulation of intracellular and supernatant hypoxanthine in stored red blood cell units is clinically relevant for transfused recipients. Leukoreduced red blood cells from glucose-6-phosphate dehydrogenase-normal or -deficient human volunteers were stored in AS-3 under normoxic, hyperoxic, or hypoxic conditions (with oxygen saturation ranging from <3% to >95%). Red blood cells from healthy human volunteers were also collected at sea level or after 1-7 days at high altitude (>5000 m). Finally, C57BL/6J mouse red blood cells were incubated <i>in vitro</i> with <sup>13</sup>C<sub>1</sub>-aspartate or <sup>13</sup>C<sub>5</sub>-adenosine under normoxic or hypoxic conditions, with or without deoxycoformycin, a purine deaminase inhibitor. Metabolomics analyses were performed on human and mouse red blood cells stored for up to 42 or 14 days, respectively, and correlated with 24 h post-transfusion red blood cell recovery. Hypoxanthine increased in stored red blood cell units as a function of oxygen levels. Stored red blood cells from human glucose-6-phosphate dehydrogenase-deficient donors had higher levels of deaminated purines. Hypoxia <i>in vitro</i> and <i>in vivo</i> decreased purine oxidation and enhanced purine salvage reactions in human and mouse red blood cells, which was partly explained by decreased adenosine monophosphate deaminase activity. In addition, hypoxanthine levels negatively correlated with post-transfusion red blood cell recovery in mice and - preliminarily albeit significantly - in humans. In conclusion, hypoxanthine is an <i>in vitro</i> metabolic marker of the red blood cell storage lesion that negatively correlates with post-transfusion recovery <i>in vivo</i> Storage-dependent hypoxanthine accumulation is ameliorated by hypoxia-induced decreases in purine deamination reaction rates.
Oligonucleotide-Poly(ethylene glycol) Conjugates: Synthesis, Properties, and Applications (1997)

The use of DNA and RNA oligonucleotides for therapeutic and diagnostic purposes has created great interest in methods of enhancing their stability and delivery. One promising strategy is covalent conjugation of oligonucleotides to polymers. This chapter discusses polyethylene glycol and related polymers suitable for conjugation, methods of conjugation, the properties of DNA-PEG and RNA-PEG conjugates and the possibilities for designing nucleic acid based drugs using these conjugates. In addition, an overview on the use of short oligoethylene glycol based linkers as synthetic loop replacements and for the development of molecular tools is presented.
Molecular and genetic aspects of obesity (1996)

Covers genetic models of obesity, the biology of animal models used in the research, the regulation of food intake, adipose tissue, the genetics of human obesity, molecular markers, and transgenic models. The 37 papers, from a symposium in Baton Rouge in February 1994, are informed by two recent dev
Fas and Fas Ligand Immunoexpression in Pancreatic Islets of NOD Mice during Spontaneous and Cyclophosphamide‐Accelerated Diabetes (2003)

During insulin-dependent diabetes mellitus, beta cell destruction may involve activation of the Fas-Fas ligand (Fas-FasL) system. Here, we employed dual-label immunohistochemistry to examine the intra-islet expression, distribution, and cellular sources of Fas and FasL in the NOD mouse. Pancreatic tissues were studied during spontaneous diabetes (days 21, 40, and 90) and following acceleration of diabetes with cyclophosphamide (days 0, 4, 7, 11, and 14 after cyclophosphamide administration). Our results show that FasL was expressed constitutively in most beta cells of NOD mice and in nondiabetes-prone mice, but not in glucagon or somatostatin cells or in islet inflammatory cells. It paralleled the loss of insulin immunolabeling with advancing disease. Immunolabeling for Fas was first observed in extra-islet macrophages and those close to the islet in NOD and nondiabetes-prone mice. During spontaneous and cyclophosphamide diabetes, it was observed in a higher proportion of islet infiltrating macrophages than in CD4 and CD8 cells. In the cyclophosphamide group, Fas expression in intra-islet CD4 and CD8 cells showed an increase close to the onset of diabetes. At days 11 and 14, several intra-islet macrophages with immunolabeling for Fas also coexpressed interleukin-1beta and inducible nitric oxide synthase. Fas was not detected in beta cells and other endocrine cells during spontaneous and cyclophosphamide diabetes. We show constitutive expression of FasL in beta cells in the NOD mouse and predominant expression of Fas in intra-islet macrophages and to a lesser extent in T cells prior to diabetes onset. The role of Fas-FasL in beta cell destruction in the NOD mouse requires further clarification.