gebhart/patrepeval huggingface dataset:
CD73-Deficient Mice Are Resistant to Carcinogenesis (2012)

CD73 is a cell surface 5'-nucleotidase that converts AMP to adenosine, an immune suppressive molecule. CD73 may promote immune escape in cancer by contributing to the degradation of extracellular ATP released by dying cancer cells in hypoxic tumors or following chemotherapy. However, whether CD73 exerts a critical oncogenic function during tumorigenesis is unknown. In this study, we used genetically deficient mice to investigate its contribution to autochthonous tumor formation. CD73 deficiency suppressed the development of 3-methylcholanthrene (MCA)-induced fibrosarcomas through a mechanism relying upon IFN-γ, natural killer (NK) cells, and CD8(+) T cells. Similarly, CD73 deficiency also suppressed prostate tumorigenesis in TRAMP transgenic mice. Importantly, treatment with an anti-CD73 monoclonal antibody effectively suppressed growth of established MCA-induced tumors or TRAMP-C1 prostate tumors and inhibited the development of TRAMP-C1 lung metastases. The therapeutic activity of anti-CD73 monoclonal antibody against primary tumors was dependent on CD8(+) T cells, whereas its antimetastatic activity was dependent on host CD73 expression independent of T cells or NK cells. Taken together, our findings indicate that CD73 is a critical factor in tumorigenesis and that anti-CD73 antibodies may offer a novel generalized strategy to blunt immune escape and treat cancer.
Antiinflammatory 4,5-Diarylpyrroles. 2. Activity as a Function of Cyclooxygenase-2 Inhibition (1995)

The antiinflammatory activity of a series of 2-substituted- and 2,3-disubstituted-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1H- pyrroles was previously shown by quantitative structure-activity relationship (QSAR) studies to be correlated with the molar refractivity and inductive field effect of the 2-substituent and the lipophilicity of the 3-substituent. The present study demonstrates that much of the antiinflammatory activity of these pyrroles could be correlated with the inhibition of the inducible isoform of cyclooxygenase (COX2). Additional QSAR studies have been used to identify the molecular parameters necessary for maximizing COX2 inhibition while simultaneously minimizing the inhibition of constitutively expressed cyclooxygenase-1. Such an effort should facilitate the discovery and development of selective COX inhibitors that should lead to safer nonsteroidal antiinflammatory drugs.
Interleukin-6-type cytokines stimulate mesenchymal progenitor differentiation toward the osteoblastic lineage. (1999)

Cytokines that transduce their signals either through glycoprotein 130 (gp130) homodimers or gp 130/leukemia inhibitory factor (LIF) receptor beta heterodimers are potent inducers of osteoclast development in vitro as well as in vivo; and interleukin (IL)-6 has been recognized as an important pathogenic factor in diseases characterized by increased bone remodeling, such as the osteoporosis of sex steroid deficiency. Based on evidence that the same cytokines can also promote committed osteoblast differentiation and stimulate bone formation in vitro and in vivo and that mesenchymal cell differentiation toward the osteoblast lineage may be a prerequisite for osteoclastogenesis, we have investigated whether gp130 activation can affect the differentiation of uncommitted mesenchymal progenitors. Using as our model murine embryonic fibroblasts (EF), we found that IL-6 or IL-11 in combination with their soluble receptors (sIL-6R or sIL-11R) increased dose-dependently the number of alkaline phosphatase (AP)-positive cells in 3-6-day-long cultures. Moreover, EF cells maintained with IL-6/sIL-6R in the presence of ascorbic acid and beta-glycerophosphate expressed osteocalcin messenger RNA (mRNA) by 2 weeks and formed a matrix containing mineralized collagen fibers by 3 weeks. This prodifferentiation effect was specific for the osteoblastic lineage, as we found no evidence for increased differentiation of chondrocytes, adipocytes, or muscle cells. Unlike IL-6/sIL-6R, LIF, oncostatin M (OSM), and ciliary neurotrophic factor (CNTF) did not promote osteoblastic differentiation of EF cells. This pattern of specificity was accounted for by the finding that EF cells express gp130, but not the ligand-binding subunit of the IL-6 receptor (gp80) nor the LIF receptor beta. These observations add credence to the contention that increased production of gp130-utilizing cytokines and their receptors in pathological conditions like sex steroid deficiency is indeed responsible for not only the increased osteoclastogenesis, but also the increased osteoblastogenesis, and thereby for the increased rate of bone remodeling.
Prevention of Type I Diabetes in NOD Mice by Adjuvant Immunotherapy (1990)

The nonobese diabetic (NOD) mouse is an excellent model of insulin-dependent (type I) human diabetes mellitus. We report that a single injection of complete Freund's adjuvant (CFA) given at an early age (5 wk) prevented the appearance of diabetes and greatly increased the life span of NOD mice without additional therapy. No treated mouse developed hyperglycemia by the age of 12 mo (n = 13), whereas all untreated mice died of diabetes before 8 mo of age (n = 38). All CFA-treated mice were alive and healthy at 12 mo of age. Some CFA-treated NOD mice that were monitored for long-term survival are still alive with no sign of disease at 18 mo of age (n = 5). Administration of CFA resulted in decreased in vitro splenic lymphocyte proliferative responses to alloantigen and mitogen. Cell-mixing experiments indicated that antigen-nonspecific inhibitory cells were elicited in the spleen and increased in the bone marrow. These regulatory cells were Thy-1- and nonadherent to nylon wool, as has been described for natural suppressor (NS) cells. These data lend support to a relationship between the boosting of endogenous NS activity and the establishment of tolerance to self in the context of autoimmunity. Our results suggest that early nonspecific immunotherapy of genetically predisposed individuals could prevent the development of autoimmune diabetes.
Long-term course and outcome of functional capacity in rheumatoid arthritis: The effect of disease activity and radiologic damage over time (1999)

Functional capacity is strongly influenced by disease activity throughout the course of RA. Even in longstanding RA, disease activity proves to be the main determinant of the HAQ score for functional capacity.
Identification of a Novel 4-Aminomethylpiperidine Class of M3Muscarinic Receptor Antagonists and Structural Insight into Their M3Selectivity (2006)

Identification of a novel class of potent and highly selective M(3) muscarinic antagonists is described. First, the structure-activity relationship in the cationic amine core of our previously reported triphenylpropionamide class of M(3) selective antagonists was explored by a small diamine library constructed in solid phase. This led to the identification of M(3) antagonists with a novel piperidine pharmacophore and significantly improved subtype selectivity from a previously reported class. Successive modification on the terminal triphenylpropionamide part of the newly identified class gave 14a as a potent M(3) selective antagonist that had >100-fold selectivity versus the M(1), M(2), M(4), and M(5) receptors (M(3): K(i) = 0.30 nM, M(1)/M(3) = 570-fold, M(2)/M(3) = 1600-fold, M(4)/M(3) = 140-fold, M(5)/M(3) = 12000-fold). The possible rationale for its extraordinarily higher subtype selectivity than reported M(3) antagonists was hypothesized by sequence alignment of multiple muscarinic receptors and a computational docking of 14a into transmembrane domains of M(3) receptors.
Mutation creates an open reading frame within the 5' untranslated region of macaque erythrocyte carbonic anhydrase (CA) I mRNA that suppresses CA I expression and supports the scanning model for translation. (1992)

A variant allele at the CA I locus that produces a deficiency of erythrocyte-specific CA I occurs as a widespread polymorphism in pigtail macaques from southeast Asia. Sequence analyses revealed a C----G substitution 12 nucleotides downstream of the cap site in the variant erythrocyte CA I mRNA. This mutation forms a new AUG start site and an open reading frame coding for 26 amino acids that terminates 6 nucleotides before the normal AUG initiation codon for CA I. It appears that the presence of this upstream open reading frame greatly diminishes reinitiation of translation from the normal start site, resulting in trace levels of CA I in erythrocytes. Preferential use of the first AUG codon supports the scanning model for translation initiation in eukaryotes.
Cediranib: profile of a novel anti-angiogenic agent in patients with glioblastoma (2009)

Cediranib is an effective drug in patients with glioblastoma, acting through inhibition of angiogenesis and normalization of tumor vasculature. Reduction of vasogenic brain edema is a key component of its treatment effect in this patient population. The primary side effects of cediranib include fatigue, diarrhea and hypertension.
Antiphlogistische 2.3‐Dihydro‐1H‐pyrrolizine, 10. Mitt. 6.7‐Diarylsubstituierte 1‐ und 3‐Pyrrolizinone (1‐DAPON und 3‐DAPON) (1986)

Abstract Bei der SeO 2 ‐Oxidation von 6.7‐Diphenyl‐2.3‐dihydro‐1 H ‐pyrrolizin entstehen das 1‐Pyrrolizinon 2 und das zugehörige Selenid 3 . Die Struktur der 1‐Oxoverbindung 2 wird anhand von Folgereaktionen, spektralen Daten und durch Gegenüberstellung mit dem 3‐Pyrrolizinon 10 , das auf unabhängigem Wege synthetisiert wurde, gesichert.
Adaptive Huber-Based Filtering Using Projection Statistics: Application to Spacecraft Attitude Estimation (2008)

This paper discusses the development of an adaptive discrete-time robust flltering technique. The technique is based on a recursive form of Huber’s mixed minimum ‘1/‘2 norm approach to estimation, which is robust with respect to deviations from the assumed Gaussian error probability distributions inherent to the Kalman fllter. An adaptive scheme is proposed whereby the fllter can estimate the process noise and measurement noise covariance matrices along with the state estimate and state estimate error covariance matrix. The adaptation technique also adopts a robust approach to estimating these covariances that can resist the efiects of outliers. The adaptive/robust fllter is applied to the spacecraft attitude quaternion estimation problem, using a standard multiplicative approach for handling the quaternion norm constraint. Simulation cases involving both Gaussian and non-Gaussian error distributions are provided.
Genetic Analysis of the Role of Proteolysis in the Activation of Latent Myostatin (2008)

Myostatin is a secreted protein that normally acts to limit skeletal muscle growth. As a result, there is considerable interest in developing agents capable of blocking myostatin activity, as such agents could have widespread applications for the treatment of muscle degenerative and wasting conditions. Myostatin normally exists in an inactive state in which the mature C-terminal portion of the molecule is bound non-covalently to its N-terminal propeptide. We previously showed that this latent complex can be activated in vitro by cleavage of the propeptide with members of the bone morphogenetic protein-1/tolloid (BMP-1/TLD) family of metalloproteases. Here, I show that mice engineered to carry a germline point mutation rendering the propeptide protease-resistant exhibit increases in muscle mass approaching those seen in mice completely lacking myostatin. Mice homozygous for the point mutation have increased muscling even though their circulating levels of myostatin protein are dramatically increased, consistent with an inability of myostatin to be activated from its latent state. Furthermore, I show that a loss-of-function mutation in Tll2, which encodes one member of this protease family, has a small, but significant, effect on muscle mass, implying that its function is likely redundant with those of other family members. These findings provide genetic support for the hypothesis that proteolytic cleavage of the propeptide by BMP-1/TLD proteases plays a critical role in the activation of latent myostatin in vivo and suggest that targeting the activities of these proteases may be an effective therapeutic strategy for enhancing muscle growth in clinical settings of muscle loss and degeneration.
Fidaxomicin: A Novel Macrocyclic Antibiotic Approved for Treatment of Clostridium difficile Infection (2011)

Fidaxomicin, a nonabsorbed macrocyclic compound, is the first antimicrobial agent approved by the FDA for the treatment of Clostridium difficile infection (CDI) in adults over the last 25 years. It is bactericidal, and its mechanism of action relates to inhibition of a RNA polymerase at a site distinct from where rifamycins interact. Fidaxomicin, 200 milligrams by mouth twice daily, is not inferior to vancomycin, 125 milligrams by mouth 4 times daily, for treatment of CDI as determined by clinical response after 10 days of treatment and is superior to vancomycin for sustained response without recurrence 25 days after treatment completion. These results are a significant advance in the treatment of CDI and herald the development of narrow-spectrum anti-C. difficile agents that relatively spare the indigenous fecal microbiota. Continued vigilance for the development of resistance and unanticipated side affects will be important as the drug is introduced into clinical practice.
Efficacy and safety of perhexiline maleate in refractory angina. A double-blind placebo-controlled clinical trial of a novel antianginal agent. (1990)

Despite large gains in the medical and surgical treatment of angina pectoris in the past two decades, many patients are refractory to conventional medical therapy and are unsuitable for a first or, more commonly, repeat coronary revascularization procedure. We evaluated the efficacy of perhexiline maleate, a drug with an antianginal mechanism of action in humans that is as yet unknown, by using a randomized double-blind placebo-controlled crossover design in 17 patients with refractory angina who continued to receive maximal antianginal therapy, typically including nitrates, a beta-blocker, and a calcium channel antagonist. In view of perhexiline's potential for hepatic and neurological toxicity, plasma drug levels were monitored and maintained in the 150-600 ng/ml range. Sixty-three percent of patients were judged perhexiline responders by objective exercise testing criteria, as compared with 18% of patients on placebo (p less than 0.05). By blinded review of subjective measures of anginal frequency and severity, 65% of patients noted an improvement while on perhexiline, whereas no patient identified the placebo phase with improvement. Side effects observed in 29% of patients were minor and related to transient elevations of blood levels of more than 600 ng/ml; no patient suffered hemodynamic or cardiac conduction abnormalities attributable to perhexiline. With attention to the pharmacokinetics of perhexiline's elimination in individual patients, this novel antianginal agent seems to be safe and effective and deserves further evaluation in patients already receiving maximal antianginal therapy who are not candidates for revascularization procedures.
Respiratory drive and breathing pattern during exercise in man. (1984)

Changes in respiratory drive, as assessed by mouth occlusion pressure (P0.1), and in breathing pattern were studied in 19 healthy subjects who exercised on a cycle ergometer with work loads ranging from loadless pedalling up to the highest load that could be sustained for 4 min. In the P0.1 studies, experiments were carried out both at normal atmospheric pressure and during hyperbaric conditions in which the density (D) of the respired gas was increased. Analyses of observed changes in P0.1 and in the interrelations of minute ventilation (V), tidal volume (VT), inspiratory (TI), expiratory (TE) and total breath (Ttot) durations, and lung volumes yielded the following results and conclusions: Analyses of inspiratory and expiratory volume threshold curves in terms of the relations between end-inspiratory volume and TI on one hand, and end-expiratory volume and TE on the other, suggest that the termination of inspiration during cycle exercise is dependent on volume-related afferent feedback from the lungs and/or chest wall, not only in the high but also in the low volume range, and expiratory muscle activity occurs already at low exercise intensities, combined with active control of expiratory flow, end-expiratory volume and TE as exercise hyperpnea intensifies. TI/Ttot increased with V and work intensity through a number of mechanisms which accelerate the increase in mean expiratory flow compared with that in mean inspiratory flow (VT/TI), the change in timing presumably reducing the oxygen cost of respiration at any given exercise-induced ventilatory demand. With increments in work load, P0.1 increased at higher rates than V and VT/TI, both in the normo- and hyperbaric conditions. Respiratory impedance, P0.1/(VT/TI), increased with both D and VT/TI. The relationship of P0.1, D and VT/TI approximated the equation P0.1 = K X D0.5(VT/TI)b, where K varies among subjects due to differences in i.a. vital capacity, and b has a value close to 1.5. The observed changes in P0.1 suggest that the respiratory drive was reflexly enhanced in response to loading as airway resistance increased with D and/or VT/TI, whereby any depression of V or VT/TI attributable to the increased respiratory impedance was counteracted.
Blockade of chronic graft-versus-host disease by alloantigen-induced CD4+CD25+Foxp3+ regulatory T cells in nonlymphopenic hosts (2007)

CD4(+)CD25(+) regulatory T cells (Tregs) are well known to suppress immunopathology induced in lymphopenic animals following T cell reconstitution, including acute graft-versus-host disease (GVHD) post-bone marrow transplantation. The regulatory potential of this subset in nonlymphopenic hosts and in chronic, Th2-mediated GVHD is less clear. We have generated alloantigen-specific cells from CD4(+)CD25(+) populations stimulated with MHC-disparate dendritic cells and found them to express a stable Treg forkhead box p3(+) phenotype with enhanced suppressive activity mediated by cell contact. When transferred into nonlymphopenic F1 hosts, nonspecific Tregs proliferated as rapidly as CD4(+)CD25(-) cells but displayed distinct growth kinetics in vitro. Tregs, expanded in response to alloantigen in vitro, displayed greatly enhanced suppressive activity, which was partially antigen-specific. They were effective inhibitors of chronic GVHD, blocking donor cell engraftment, splenomegaly, autoantibody production, and glomerulonephritis. CD25(+) and CD25(-) cells were equally susceptible to inhibition by immunosuppressive drugs targeting TCR signaling and rapamycin, but Tregs were resistant to inhibition by dexamethasone. The data indicate that alloantigen-driven expansion, rather than homeostatic proliferation, is key to the effectiveness of CD4(+)CD25(+) Tregs in GVHD and suggest that cellular therapy with alloantigen-induced Tregs in combination with glucocorticoid treatment would be effective in prevention of chronic GVHD after immune reconstitution.
Does ultrasound-guided central line insertion reduce complications and time to placement in elective patients undergoing cardiac surgery (2004)

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether ultrasound probe central line placement reduced complications and time to placement in patients undergoing coronary artery bypass grafting surgery. Altogether, 193 papers were found from Medline using the reported search of which 6 papers presented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses and comments were tabulated. We conclude that in patients with a potentially difficult central line insertion, the ultrasound technique reduces complications and time to insertion. However, in those patients where no difficulty is predicted, there is no evidence that the ultrasound technique confers any advantage.
The role of accreditation in transforming health services management education. (2000)

The core function of the Accrediting Commission on Education for Health Services Administration (ACEHSA) is to improve quality in health services management education. All specialized accrediting agencies provide quality assurance by developing standards of quality, assessing programs and reporting to stakeholders, as part of their public accountability function (Council for Higher Education Accreditation). Standards of quality derive from the level of competency considered essential within the domain of practice of health services managers. Accreditation review by ACEHSA is oriented to quality improvement and quality assurance, which have different purposes and are difficult to accomplish in the same process. The purpose of this paper is to discuss ACEHSA's role in evaluating the quality of health services management education programs in North America. The first objective is to describe the process of defining quality and to identify the skills, knowledge and abilities derived from it. The second objective is to discuss the measurement of quality, including using standardized measures, and determining whether the purpose is quality improvement or quality assurance. The third objective is to examine how quality measures are reported, and how reporting impacts the quality assessment process. Finally, the future role of ACEHSA is discussed, with regard to benchmarking measures of quality and publicly reporting relative levels of academic program quality.
Genetic and Biochemical Analysis of Dimer and Oligomer Interactions of the λ S Holin (2000)

Bacteriophage lambda uses a holin-endolysin system for host cell lysis. R, the endolysin, has muralytic activity. S, the holin, is a small membrane protein that permeabilizes the inner membrane at a precisely scheduled time after infection and allows the endolysin access to its substrate, resulting in host cell lysis. lambda S has a single cysteine at position 51 that can be replaced by a serine without loss of the holin function. A collection of 27 single-cysteine products of alleles created from lambda S(C51S) were tested for holin function. Most of the single-cysteine variants retained the ability to support lysis. Mutations with the most defective phenotype clustered in the first two hydrophobic transmembrane domains. Several lines of evidence indicate that S forms an oligomeric structure in the inner membrane. Here we show that oligomerization does not depend on disulfide bridge formation, since the cysteineless S(C51S) (i) is functional as a holin and (ii) shows the same oligomerization pattern as the parental S protein. In contrast, the lysis-defective S(A52V) mutant dimerizes but does not form cross-linkable oligomers. Again, dimerization does not depend on the natural cysteine, since the cysteineless lysis-defective S(A52V/C51S) is found in dimers after treatment of the membrane with a cross-linking agent. Furthermore, under oxidative conditions, dimerization via the natural cysteine is very efficient for S(A52V). Both S(A52V) (dominant negative) and S(A48V) (antidominant) interact with the parental S protein, as judged by oxidative disulfide bridge formation. Thus, productive and unproductive heterodimer formation between the parental protein and the mutants S(A52V) and S(A48V), respectively, may account for the dominant and antidominant lysis phenotypes. Examination of oxidative dimer formation between S variants with single cysteines in the hydrophobic core of the second membrane-spanning domain revealed that positions 48 and 51 are on a dimer interface. These results are discussed in terms of a three-step model leading to S-dependent hole formation in the inner membrane.