gebhart/patrepeval huggingface dataset:
N-ACETYLCYSTEINE AND/OR URSODEOXYCHOLIC ACID ASSOCIATED WITH METFORMIN IN NON-ALCOHOLIC STEATOHEPATITIS: AN OPEN-LABEL MULTICENTER RANDOMIZED CONTROLLED TRIAL (2019)

ABSTRACT BACKGROUND: Nowadays, pharmacological treatment of non-alcoholic fatty liver disease (NAFLD) is still limited and it is based on the treatment of conditions associated comorbities. Oxidative stress and insulin resistance are the mechanisms that seem to be mostly involved in its pathogenesis. OBJECTIVE: To evaluate the efficacy of N-acetylcysteine (NAC) in combination with metformin (MTF) and/or ursodeoxycholic acid (UDCA) for treatment of non-alcoholic steatohepatitis (NASH). METHODS: Open-label multicenter randomized trial was conducted for 48 weeks. It included patients with biopsy-proven NASH. The patients were randomized into three groups: NAC (1.2 g) + UDCA (15 mg/kg) + MTF (850-1500 mg/day) (n=26); UDCA (20 mg/kg) + MTF (850-1500 mg/day) (n=13); NAC (1.2g) + MTF (850-1500 mg/day) (n=14) for 48 weeks. Clinical, laboratory and the second liver biopsies were performed after 48 weeks. RESULTS: A total of 53 patients were evaluated; 17 (32.1%) were males; median age ±54 (IQR=15, 21-71) years. In the baseline, no difference was seen between groups according clinical and histological parameters. The groups differed only in cholesterol, LDL and triglycerides. No significant differences in biochemical and histologic parameters were found between these the three groups after 48 weeks of treatment. In the intragroup analysis (intention-to-treat) comparing histological and biochemical features, there were significant improvements in the steatosis degree (P=0.014), ballooning (0.027) and, consequently, in the NAFLD Activity Score (NAS) (P=0.005), and in the ALT levels at the end of the treatment only in the NAC + MTF group. No significant evidence of modification in the liver fibrosis could be observed in any of the groups. CONCLUSION: This multicenter study suggests that the association of NAC + MTF could reduce the liver disease activity in patients with NASH. These data stimulate further controlled studies with this therapy for these patients.
Jak3 Kinase Domain Crystal Structures and Implications for Jak-Specific Drug Design. (2005)

Abstract Janus (Jak) family non-receptor tyrosine kinases are critical for appropriate signaling of many growth factors and cytokines. The four vertebrate Jak kinase family members demonstrate differential receptor cytoplasmic tail binding associations and transduce discrete signals on extracellular binding of ligand to the transmembrane cytokine or growth factor receptor. On ligand binding, a rapid tyrosine phosphorylation mediated signaling cascade is initiated, culminating in translocation of cytosolic latent transcription factors, signal transducer and activator of transcription (Stat) proteins, to the nucleus and targeted activation of transcription. Dysregulation of this Jak-mediated signaling pathway is documented in a number of hematological diseases: Improper upregulation of Jak activity is seen in certain hematological malignancies [1] and inability to appropriately transduce signals from the common gamma chain, γc, through Jak3 is responsible for approximately 60% of human severe combined immunodeficiency cases [2]. In addition, Jak2 point mutation V617F is frequently documented in myeloproliferative disorders including polycythemia vera; this activating mutation may disrupt an autoinhibited conformation [3]. Therapies targeting restraint of Jak family tyrosine kinase activity may be useful for treating inappropriate activation of Jak signaling cascades or for suppressing the immune response. Advances towards structure-directed drug design of Jak-specific inhibitors were made recently with solution of the Jak3 kinase domain X-ray crystal structure [4], representing the first three-dimensional structural data for any portion of the Jak family of tyrosine kinases. Here three further crystal structures of the kinase domain of Jak3 are presented: an improved resolution co-crystal structure with staurosporine analog AFN-941 and two crystal forms of Jak3 kinase domain in complex with the kinase inhibitor small molecule compound QAD-409. Comparisons between these three solved Jak3 kinase domain crystal structures illustrate conformational flexibility between the kinase domain lobes and in the area of the catalytic cleft. Further structure analysis is also presented documenting in silico modeling of the binding of small molecule CP-690,550 [5] to the different Jak3 kinase domain crystal forms. Potential binding conformations of this inhibitor to the Jak3 kinase domain are suggested with one highly scored binding conformation predicted for all crystal forms. The crystal structures and modeling studies presented further define the extent of the Jak kinase catalytic cleft, demonstrate conformational plasticity in the active conformation Jak3 kinase domain and will aid the design of higher specificity Jak inhibitors.
Remoting Peripherals using Memory-Mapped Networks (1998)

Memory-mapped networks such as Scalable Coherent Interconnect (SCI) [5] and Memory Channel [4] offer a new method for constructing network peripherals by remoting a host&amp;apos;s IO bus. This paper details our experiences from building such an endpoint, and examines how greater support may be provided. 1 Introduction At ORL we have experimented with an exploded workstation configuration, where low-cost multimedia peripherals known as network end-points are attached directly to an ATM network. End-points include video [3], audio, compact liquid-crystal display [1] and storage devices [2]. Whilst our experience of directly networked peripherals has been encouraging, there were some shortcomings: ffl The backend of a networked peripheral must be heavily re-engineered to interface with the network. This development effort means that networked peripherals are usually behind the state of the art. ffl The use of networked peripherals requires driver reimplementation, even if the peripheral is sup...
Pseudouridine in RNA: What, Where, How, and Why (2000)

Pseudouridine (5-ribosyluracil) is a ubiquitous yet enigmatic constituent of structural RNAs (transfer, ribosomal, small nuclear, and small nucleolar). Although pseudouridine (psi) was the first modified nucleoside to be discovered in RNA, and is the most abundant, its biosynthesis and biological roles have remained poorly understood since its identification as a "fifth nucleoside" in RNA. Recently, a combination of biochemical, biophysical, and genetic approaches has helped to illuminate the structural consequences of psi in polyribonucleotides, the biochemical mechanism of U-->psi isomerization in RNA, and the role of modification enzymes (psi synthases) and box H/ACA snoRNAs, a class of eukaryotic small nucleolar RNAs, in the site-specific biosynthesis of psi. Through its unique ability to coordinate a structural water molecule via its free N1-H, psi exerts a subtle but significant "rigidifying" influence on the nearby sugar-phosphate backbone and also enhances base stacking. These effects may underlie the biological role of most (but perhaps not all) of the psi residues in RNA. Certain genetic mutants lacking specific psi residues in tRNA or rRNA exhibit difficulties in translation, display slow growth rates, and fail to compete effectively with wild-type strains in mixed culture. In particular, normal growth is severely compromised in an Escherichia coli mutant deficient in a pseudouridine synthase responsible for the formation of three closely spaced psi residues in the mRNA decoding region of the 23S rRNA. Such studies demonstrate that pseudouridylation of RNA confers an important selective advantage in a natural biological context.
FLT3L and Plerixafor Combination Increases Hematopoietic Stem Cell Mobilization and Leads to Improved Transplantation Outcome (2013)

Hematopoietic stem cell (HSC) transplantation has curative potential for patients with hematological malignancies. Clinically, HSCs derived from mobilized peripheral blood are used more frequently than bone marrow. However, current standard mobilizing agents yield grafts that may not contain sufficient HSCs. Here, using murine models, we discovered that FLT3L synergized with plerixafor to mobilize phenotypically defined HSCs and their combination (FP) was superior to granulocyte colony-stimulating factor (G-CSF) alone or in combination with plerixafor (GP). Additionally, FP mobilized more regulatory T cells, natural killer cells, and plasmacytoid dendritic cells compared with G-CSF alone or GP. Both syngeneic and allogeneic grafts mobilized by FP led to long-term survival in transplanted mice. Collectively, FP represents a promising novel and potent mobilization regimen with potential clinical application in both the autologous and allogeneic transplantation settings.
PSEUDO-RESPONSE REGULATORS, PRR9, PRR7 and PRR5, Together Play Essential Roles Close to the Circadian Clock of Arabidopsis thaliana (2005)

In Arabidopsis thaliana, a number of clock-associated protein components have been identified. Among them, CCA1 (CIRCADIAN CLOCK-ASSOCIATED 1)/LHY (LATE ELONGATED HYPOCOTYL) and TOC1 (TIMING OF CAB EXPRESSION 1) are believed to be the essential components of the central oscillator. CCA1 and LHY are homologous and partially redundant Myb-related DNA-binding proteins, whereas TOC1 is a member of a small family of proteins, designated as PSEUDO-RESPONSE REGULATOR. It is also believed that these two different types of clock components form an autoregulatory positive/negative feedback loop at the levels of transcription/translation that generates intrinsic rhythms. Nonetheless, it was not yet certain whether or not other PRR family members (PRR9, PRR7, PRR5 and PRR3) are implicated in clock function per se. Employing a set of prr9, prr7 and prr5 mutant alleles, here we established all possible single, double and triple prr mutants. They were examined extensively by comparing them with each other with regard to their phenotypes of circadian rhythms, photoperiodicity-dependent control of flowering time and photomorphogenic responses to red light during de-etiolation. Notably, the prr9 prr7 prr5 triple lesions in plants resulted in severe phenotypes: (i) arrhythmia in the continuous light conditions, and an anomalous phasing of diurnal oscillation of certain circadian-controlled genes even in the entrained light/dark cycle conditions; (ii) late flowering that was no longer sensitive to the photoperiodicity; and (iii) hyposensitivity (or blind) to red light in the photomorphogenic responses. The phenotypes of the single and double mutants were also characterized extensively, showing that they exhibited circadian-associated phenotypes characteristic for each. These results are discussed from the viewpoint that PRR9/PRR7/PRR5 together act as period-controlling factors, and they play overlapping and distinctive roles close to (or within) the central oscillator in which the relative, PRR1/TOC1, plays an essential role.
Antibody responses to the blood group antigen D in SCID mice reconstituted with human blood mononuclear cells. (1992)

Mice with severe combined immunodeficiency (SCID) were reconstituted with peripheral blood mononuclear cells (PBMC) obtained from D-negative individuals who had been sensitized to D-positive erythrocytes. Anti-D was spontaneously secreted in mice reconstituted with PBMC obtained from donors within 14 days of re-immunization with D-positive erythrocytes, but was not detected in murine plasma when mice were reconstituted with PBMC obtained from the same donors many years after sensitization, even though anti-D was still present in the serum of these donors. In the murine plasma the anti-D titres were not related to the total human immunoglobulin concentrations. SCID mice reconstituted with PBMC from some donors immune to D-positive erythrocytes (but not immunized within 34 days of donating the sample) made a recall response to the D antigen, which in some cases was maintained for at least 84 days. Depletion of adherent cells from the reconstituting PBMC reduced the total concentration of human IgG obtained. These results show that SCID mice reconstituted with human PBMC (Hu PBMC-SCID) can make a recall response to the D antigen which cannot be attributed to non-specific polyclonal B-lymphocyte activation, and that efficient antigen processing and presentation of the integral erythrocyte membrane D polypeptide occurs in the Hu PBMC-SCID model.
Cancer biomarkers (2012)

Biomarkers have many potential applications in oncology, including risk assessment, screening, differential diagnosis, determination of prognosis, prediction of response to treatment, and monitoring of progression of disease. Because of the critical role that biomarkers play at all stages of disease, it is important that they undergo rigorous evaluation, including analytical validation, clinical validation, and assessment of clinical utility, prior to incorporation into routine clinical care. In this review we address key steps in the development of biomarkers, including ways to avoid introducing bias and guidelines to follow when reporting results of biomarker studies.
Mutational analysis of the HIS4 translational initiator region in Saccharomyces cerevisiae. (1988)

We have mutated various features of the 5' noncoding region of the HIS4 mRNA in light of established Saccharomyces cerevisiae and mammalian consensus translational initiator regions. Our analysis indicates that insertion mutations that introduce G + C-rich sequences in the leader, particularly those that result in stable stem-loop structures in the 5' noncoding region of the HIS4 message, severely affect translation initiation. Mutations that alter the length of the HIS4 leader from 115 to 39 nucleotides had no effect on expression, and sequence context changes both 5' and 3' to the HIS4 AUG start codon resulted in no more than a twofold decrease of expression. Changing the normal context at HIS4 5'-AAUAAUGG-3' to the optimal sequence context proposed for mammalian initiator regions 5'-CACCAUGG-3' did not result in stimulation of HIS4 expression. These studies, in conjunction with comparative and genetic studies in S. cerevisiae, support a general mechanism of initiation of protein synthesis as proposed by the ribosomal scanning model.
The Significance of Plasma Lysophospholipids in Patients with Renal Failure on Hemodialysis. (1998)

Abnormal phospholipid metabolism may play an important role in the progression of atherosclerosis in renal failure. We analyzed plasma phospholipid and lysophospholipid contents and fatty acid composition in the phospholipids of 18 patients with renal failure on hemodialysis (HD) and compared the levels with those of healthy controls. HD patients had a notably higher molar ratio of the plasma lysophosphatidylcholine (lysoPC)/phosphatidylcholine (PC) distributed from 0.072 to 0.207, and the control group showed a ratio lower than 0.150. Plasma phosphatidylethanolamine (PE) concentration significantly increased in HD patients compared with control subjects. A much higher level of plasma lysophosphatidic acid (lysoPA) (1.41 +/- 0.16 nmol/mL) was observed in HD patients compared with controls (0.54 +/- 0.08 nmol/mL). A strong correlation was found between plasma lysoPA and lysoPC concentrations (r = 0.609, p < 0.01) in HD patients. Serum inorganic phosphate (P) concentration was associated with the abnormal plasma lysoPC/PC, PE, and lysoPA levels in HD patients. Important decreases in eicosapentaenoic acid (EPA) of plasma PC and of dietary intake were observed in HD patients. Plasma thiobarbituric acid reactive substance (TBARS) concentration was negatively correlated with the amount of vitamin E intake in both subjects. These findings demonstrated the specific characteristics of the abnormal phospholipid metabolism in HD patients. The cause and consequences of elevated lysoPC/PC molar ratio and lysoPA in the plasma of HD patients remain to be established.
Synthesis and Properties of Biodegradable Polymers Used as Synthetic Matrices for Tissue Engineering (1997)

Organ or tissue failure remains a frequent, costly, and serious problem in health care despite advances in medical technology. The large number of patients suffering from tissue losses or organ failures is demonstrated by the approximately 8 million surgical procedures and 40 to 90 million hospital days required annually to treat these problems (Langer and Vacanti, 1993). Available treatments now include transplantation of organs from one individual to another, performing surgical reconstruction, use of mechanical devices (e.g., kidney dialyzer), and drug therapy. However, these treatments are not perfect solutions. Transplantation of organs is limited by the lack of organ donors, possible rejection, and other complications. For example, there are only 3000 donors available in contrast to 30,000 patients who die from liver failure each year (American Liver Foundation, 1988). Mechanical devices cannot perform all functions of an organ, e.g., kidney dialysis can only help remove some metabolic wastes from the body. Likewise, drugs can only replace limited biochemical functions of an organ or tissue, and physiologic control of drug levels comparable to the control systems of the body is difficult to achieve. For example, although diabetes can be partially treated by administration of insulin, it is still the leading cause of chronic renal failure and blindness (Chukwuma, 1995; Hoelscher et al, 1995; Sander and Wilson, 1993). This is partly due to difficulties in controlling the drug level in vivo (Levesque et al, 1992). Financially, the cost of surgical procedures is very high ($150,000 for a liver transplant). It is estimated that almost half of the United States $800 billion in annual health care costs are due to loss or malfunction of tissue or organs (Langer and Vacanti, 1993).
The Olfactory Responses of Flies in a New Type of Insect Olfactometer II: Responses of the Housefly to Ammonia, Carbon Dioxide and Ethyl Alcohol* (1939)

It is an interesting circumstance that although there is world wide interest in the housefly, Musca domestica L., and although a wealth of observation and experiment exists proving that response to volatile substances plays an important part in the fly's feeding and oviposition habits, almost no quantitative data on its chemotropic reactions have been published. Most of the experiments have consisted in counting the number of flies attracted to traps baited with various substances often in process of fermentation or putrefaction (Morrill 1914; Richardson 1916, 1917; Crumb & Lyon 1917, 1921; Laake et al. 1931).
Pedigree of multiple benign adnexal tumours of Brooke–Spiegler type (2003)

A pedigree of autosomal dominant expression of multiple benign adnexal tumours is presented. Seven cases spanning three generations are discussed. The clinical manifestations of these tumours are quite variable, including multiple papules concentrated on the face, scalp nodules and a large turban tumour. One member of the family had a linear papular eruption involving one half of his body. Histopathology of all lesions demonstrated benign adnexal characteristics, including well-characterized eccrine spiradenomas, trichoepitheliomas and an eccrine cylindroma. The cutaneous tumours occurring in these patients have continued to develop during their lifetimes. The authors propose that this pedigree has phenotypic characteristics consistent with Brooke-Spiegler syndrome.
Effects of moving mobiles on performance of channel reservation for ahead cells in street micro-cellular systems (2002)

We consider a novel channel reservation scheme for ahead cells (CRAC) in street micro-cellular systems. The scheme enables mobiles to reserve the same channel over several cells at once, in order to lessen channel changings when mobiles cross a cell boundary. Numerical results show that if the priority control which gives priority to hand-off calls over new calls is employed for the CRAC scheme, the average number of channel changings (CC) and the forced call termination rate (FCTR) of the CRAC scheme are reduced remarkably compared with the ones of the fixed channel assignment (FCA).
Control menus (2000)

We propose a new type of contextual pop-up menu called a control menu. These menus combine the selection of an operation and the control of this operation. They integrate up to two scroll bars or spin-boxes and thus allow users to keep their attention focused on the menu during the operation. Control menus can have sub-menus, and also retain the novice and expert modes of use found in marking menus. We describe control menus and how they are useful in different types of user interfaces. A program incorporating our control menus can be tested at http://www.infobiogen.fr/services/zomit/.
Use of French lyophilized plasma transfusion in severe trauma patients is associated with an early plasma transfusion and early transfusion ratio improvement (2018)

Therapeutic, level IV.
Alternative Sources of Pluripotent Stem Cells: Ethical and Scientific Issues Revisited (2010)

Stem cell researchers in the United States continue to face an uncertain future, because of the changing federal guidelines governing this research, the restrictive patent situation surrounding the generation of new human embryonic stem cell lines, and the ethical divide over the use of embryos for research. In this commentary, we describe how recent advances in the derivation of induced pluripotent stem cells and the isolation of germ-line-derived pluripotent stem cells resolve a number of these uncertainties. The availability of patient-matched, pluripotent stem cells that can be obtained by ethically acceptable means provides important advantages for stem cell researchers, by both avoiding protracted ethical debates and giving U.S. researchers full access to federal funding. Thus, ethically uncompromised stem cells, such as those derived by direct reprogramming or from germ-cell precursors, are likely to yield important advances in stem cell research and move the field rapidly toward clinical applications.
Ancient Pathways Programmed by Small RNAs (2002)

Double-stranded RNA can now be used in a wide variety of eukaryotes to suppress the expression of virtually any gene, allowing the rapid analysis of that gene's function, a technique known as RNA interference. But how cells use the information in double-stranded RNA to suppress gene expression and why they contain the machinery to do so remain the subjects of intense scrutiny. Current evidence suggests that RNA interference and other "RNA silencing" phenomena reflect an elaborate cellular apparatus that eliminates abundant but defective messenger RNAs and defends against molecular parasites such as transposons and viruses.
A Single Treatment of Yttrium-90-labeled CHX-A″–C6.5 Diabody Inhibits the Growth of Established Human Tumor Xenografts in Immunodeficient Mice (2004)

Antitumor diabody molecules are noncovalent single-chain Fv dimers that recapitulate the divalent binding properties of native IgG antibodies. Diabodies are capable of substantial accumulation in tumor xenografts expressing relevant antigens in immunodeficient mouse models. With a Mr of approximately 55,000, diabodies are rapidly cleared from the circulation, resulting in tumor-to-blood ratios that significantly exceed those achieved early after the administration of monoclonal antibodies. We have evaluated the therapeutic potential of the beta-emitting isotope yttrium-90 (t1/2, 64 hours) conjugated to the C6.5K-A diabody that specifically targets the HER2/neu human tumor-associated antigen. We have found that a single intravenous dose of 150 microCi (200 microg) 90Y-CHX-A"-C6.5K-A diabody substantially inhibits the growth rates of established MDA-361/DYT2 human breast tumor xenografts in athymic nude mice. In contrast, 300 microCi (300 microg) 90Y-CHX-A"-C6.5K-A diabody resulted in only a minor delay in the growth of SK-OV-3 human ovarian cancer xenografts. The maximum tolerated dose was also dependent on the tumor xenograft model used. These studies indicate that genetically engineered antitumor diabody molecules can be used as effective vehicles for radioimmunotherapy.