tbuckley/cabot-search huggingface dataset:
Laterally spreading tumour in which interstitial deletion of -catenin exon 3 was detected
Authors: K Nosho
Journal: Gut (2005)

Laterally spreading tumours (LSTs) of the colon and rectum are defined as lesions greater than 10 mm in diameter with a low vertical axis that extend laterally along the luminal wall.1 As most LSTs remain as adenomas or early invasive cancers, LSTs have been thought to have relatively little malignant potential. LSTs are divided into two macroscopic subtypes: flat (F)-type, which is composed of superficially spreading lesions with flat and smooth surfaces, and granular (G)-type, which is composed of superficially spreading aggregates of nodules.2 Despite distinctive biological behaviours of LSTs, only a few genetic alterations have been reported, such as K-ras and p53 mutations3,4 and cyclooxygenase 2 overexpression.5

A 62 year old Japanese woman was referred to our hospital for treatment of a colonic tumour. Colonoscopy in our hospital showed an F-type LST with a central depression surrounded by a flat elevated area with a smooth surface in the …
Periodic neutropenia and monocytopenia
Authors: William H. Adams, Yong K. Liu
Journal: American Journal of Hematology (1982)

Abstract A patient with periodic neutropenia exhibited simultaneous monocytopenia, and epinephrine infusion revealed no monocytes in the marginating pool during neutropenia. Lymphocytes, eosinophils, and platelets also fluctuated periodically, but serial bone marrow studies and epinephrine infusion data indicate these fluctuations could have represented epiphenomena rather than a more global form of periodic hematopoiesis. Bone marrow descriptions of most cases of periodic neutropenia have indicated a “maturation arrest” at the promyelocyte or myelocyte stage prior to development of neutropenia; peripheral blood monocytes are usually normal or fluctuate out of phase with neutrophils. In the present case, “maturation arrest” occurred at the myeloblast stage, and neutrophils and monocytes cycled together. Morphologically normal eosinophilopoiesis with a mean eosinophil to erythroid ratio in the marrow of 0.27 ± 0.10 (SD) persisted despite a sustained disappearance of promyelocytes.
Antigen-reactive T cell clones. I. Transcomplementing hybrid I-A-region gene products function effectively in antigen presentation.
Authors: M Kimoto, C G Fathman
Journal: The Journal of Experimental Medicine (1980)

Studies in our laboratory and elsewhere have shown that it is possible to propagate antigen-specific murine T cells in vitro with resultant specific stepwise enrichment of antigen-induced proliferative cells. The proliferative responses of these T cells are antigen specific and dependent upon the presence of antigen-presenting cells (spleen cells) that share the I-A subregion with the proliferating T cell. Using techniques of soft-agar cloning, it has been further possible to isolate clones of antigen-reactive T lymphocytes from such long-term cultures. Data suggesting that these were clones of antigen-reactive T cells were obtained by studying the recognition of antigen in association with antigen-presenting cells with a panel of such clones of antigen-reactive T cells. Proof of clonality was obtained by subcloning. Clones derived from F1-immune mice can be divided into three separate categories: one clone recognizes antigen in association with antigen-presenting determinants of parent A and the F1; the second type recognizes antigen in association with antigen-presenting determinants of parent B and the F1; and the third type recognizes antigen only in association with antigen-presenting determinants of the F1 mouse. Genetic studies on the major histocompatibility complex requirements for antigen presentation to such F1-reactive T cell clones suggests that the hybrid antigen-presenting determinant in this system results from transcomplementation of products of the I-A region of haplotypes a and b. These studies support the concept developed in our laboratory that there exist unique F1 hybrid determinants on (A/J X C57BL/6) F1 cells and suggest that these determinants can be utilized physiologically by hybrid mice in immunocompetent cellular interactions.
Should Physicians Screen for Mild Thyroid Failure?
Authors: H. Gilbert Welch
Journal: JAMA (1996)

<h3>To the Editor.</h3> —In their analysis of thyroid screening, Mr Danese and colleagues<sup>1</sup>point out that most of the net benefit comes from minimizing the sequelae of mild thyroid failure and clinically overt hypothyroidism. Since these conditions are rarely fatal, the value of thyroid screening is thus largely attributable to quality-of-life improvements. In a Markov model (as used by the authors), the quality-of-life effect of an adverse clinical condition is a function of the quality-adjustment factor (utility) and the time patients spend in the state. Thirty percent of the net benefit of thyroid screening (for women) was the result of reducing the symptoms associated with the health state "mild thyroid failure"—patients with an elevated thyrotropin (TSH), but no sign of overt hypothyroidism. This state was given a utility of 0.90, similar to that assigned to patients with severe back pain, ulcer disease, or angina. The authors either have assigned
Mouse alloantibodies capable of blocking cytotoxic T-cell function. I. Relationship between the antigen reactive with blocking antibodies and the Lyt-2 locus.
Authors: N Shinohara, D H Sachs
Journal: The Journal of Experimental Medicine (1979)

In an attempt to produce allonatibodies to cytotoxic T-cell receptors, hyperimmune anti-lymphocyte antisera have been raised in mice of various strain combinations, and have been tested for their ability to block allogeneic cell-mediated lymphocytotoxicity (CML) in the absence of complement at the T killer cell level. Most of the sera failed to show any significant and reproducible inhibitory effects. However, among C3H anti-B10.BR antisera, some sera were found to be capable of significantly inhibiting CML. This effect was attributable to antibodies reacting with the killer population rather than the target cells, because the sera inhibited B10 anti-C3H CML but not C3H anti-b10 CML. Among mouse strains tested, A/J, BALB/c, B10, and B6 strains were sensitive to the inhibitory effect of the sera whereas AKR, CBA, C3H, and DBA/2 strains were insensitive. The sensitivity of killer cells to the inhibitory effect correlated well with the strain distribution of the Lyt-2.2 antigen. In the presence of complement, these same sera were toxic to 100% of spleen cells of AKR, BALB/c, B10, and DBA/2 strains, with comparable cytotoxic titers. Thus, the inhibitory activity of the sera could not be explained by nonspecific effects of high-titered antibodies. To study the relationship between the antigen(s) responsible for the blocking effect and Lyt-2-linked genes, killer cells from Lyt-2 congenic strains were tested and conventional anti-Lyt-2.2 antisera were raised in an appropriate congenic strain combination. Killer cells from B6, but not from B6.Ly2.1 animals, were significantly sensitive to the blocking effects of the inhibitory C3H anti-B10.BR sera. The conventional anti-Lyt.2.2 sera did produce CML blocking, although there was no apparent correlation between such blocking and the anti-Lyt-2.2 cytotoxic titer. These results thus indicate that the target molecules responsible for blocking of killer cells are encoded or regulated by genes that are closely linked to or identical with Lyt-2.
Role of Cardiac Stem Cells in Cardiac Pathophysiology: A Paradigm Shift in Human Myocardial Biology
Authors: Annarosa Leri, Jan Kajstura, Piero Anversa
Journal: Circulation Research (2011)

For nearly a century, the human heart has been viewed as a terminally differentiated postmitotic organ in which the number of cardiomyocytes is established at birth, and these cells persist throughout the lifespan of the organ and organism. However, the discovery that cardiac stem cells live in the heart and differentiate into the various cardiac cell lineages has changed profoundly our understanding of myocardial biology. Cardiac stem cells regulate myocyte turnover and condition myocardial recovery after injury. This novel information imposes a reconsideration of the mechanisms involved in myocardial aging and the progression of cardiac hypertrophy to heart failure. Similarly, the processes implicated in the adaptation of the infarcted heart have to be dissected in terms of the critical role that cardiac stem cells and myocyte regeneration play in the restoration of myocardial mass and ventricular function. Several categories of cardiac progenitors have been described but, thus far, the c-kit-positive cell is the only class of resident cells with the biological and functional properties of tissue specific adult stem cells.
Reward/Punishment Reversal Learning in Older Suicide Attempters
Authors: Alexandre Y. Dombrovski, Luke Clark, Greg J. Siegle, Meryl A. Butters, Naho Ichikawa, Barbara J. Sahakian, Katalin Szanto
Journal: American Journal of Psychiatry (2010)

Objective Suicide rates are high in old age, and the contribution of cognitive risk factors remains poorly understood. Suicide may be viewed as an outcome of an altered decision process. The authors hypothesized that impairment in reward/punishment-based learning, a component of affective decision making, is associated with attempted suicide in late-life depression. They expected that suicide attempters would discount past reward/punishment history, focusing excessively on the most recent rewards and punishments. The authors further hypothesized that this impairment could be dissociated from executive abilities, such as forward planning. Method The authors assessed reward/punishment-based learning using the probabilistic reversal learning task in 65 individuals age 60 and older: suicide attempters, suicide ideators, nonsuicidal depressed elderly, and nondepressed comparison subjects. The authors used a reinforcement learning computational model to decompose reward/punishment processing over time. The Stockings of Cambridge test served as a control measure of executive function. Results Suicide attempters but not suicide ideators showed impaired probabilistic reversal learning compared to both nonsuicidal depressed elderly and nondepressed comparison subjects, after controlling for effects of education, global cognitive function, and substance use. Model-based analyses revealed that suicide attempters discounted previous history to a higher degree relative to comparison subjects, basing their choice largely on reward/punishment received on the last trial. Groups did not differ in their performance on the Stockings of Cambridge test. Conclusions Older suicide attempters display impaired reward/punishment-based learning. The authors propose a hypothesis that older suicide attempters make overly present-focused decisions, ignoring past experiences. Modification of this "myopia for the past" may have therapeutic potential.
Randomized, Placebo-Controlled, Phase III Trial of Sunitinib Plus Prednisone Versus Prednisone Alone in Progressive, Metastatic, Castration-Resistant Prostate Cancer
Authors: M. Dror Michaelson, Stephane Oudard, Yen-Chuan Ou, Lisa Sengeløv, Fred Saad, Nadine Houede, Peter Ostler, Arnulf Stenzl, Gedske Daugaard, Robert Jones, Fredrik Laestadius, Anders Ullèn, Amit Bahl, Daniel Castellano, Juergen Gschwend, Tristan Maurina, Edna Chow Maneval, Shaw-Ling Wang, Maria Jose Lechuga, Jolanda Paolini, Isan Chen
Journal: Journal of Clinical Oncology (2013)

We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of metastatic castration-resistant prostate cancer (mCRPC).Men with progressive mCRPC after docetaxel-based chemotherapy were randomly assigned 2:1 to receive sunitinib 37.5 mg/d continuously or placebo. Patients also received oral prednisone 5 mg twice daily. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS). Two interim analyses were planned.Overall, 873 patients were randomly assigned to receive sunitinib (n = 584) or placebo (n = 289). The independent data monitoring committee stopped the study for futility after the second interim analysis. After a median overall follow-up of 8.7 months, median OS was 13.1 months and 11.8 months for sunitinib and placebo, respectively (hazard ratio [HR], 0.914; 95% CI, 0.762 to 1.097; stratified log-rank test, P = .168). PFS was significantly improved in the sunitinib arm (median 5.6 v 4.1 months; HR, 0.725; 95% CI, 0.591 to 0.890; stratified log-rank test, P < .001). Toxicity and rates of discontinuations because of adverse events (AEs; 27% v 7%) were greater with sunitinib than placebo. The most common treatment-related grade 3/4 AEs were fatigue (9% v 1%), asthenia (8% v 2%), and hand-foot syndrome (7% v 0%). Frequent treatment-emergent grade 3/4 hematologic abnormalities were lymphopenia (20% v 11%), anemia (9% v 8%), and neutropenia (6% v < 1%).The addition of sunitinib to prednisone did not improve OS compared with placebo in docetaxel-refractory mCRPC. The role of antiangiogenic therapy in mCRPC remains investigational.
Regulating Insulin-Receptor-Gene Expression by Differentiation and Hormones
Authors: P W Mamula, A R McDonald, A Brunetti, Y Okabayashi, K Y Wong, B A Maddux, C Logsdon, I D Goldfine
Journal: Diabetes Care (1990)

Insulin regulates cell function by first binding to the insulin receptor (IR) localized on the cell surface. With the cloning of IR cDNA and the IR-gene promoter, the regulation of the IR gene during differentiation and by various hormones can be studied. Muscle is a major target tissue for insulin action. BC3H1 cells, a mouse muscle cell line in culture, are a model cell type for studying insulin action. Differentiation in these cells results in a 5- to 10-fold increase in IR binding and a 5- to 10-fold increase in IR content. Studies of IR mRNA by Northern and slot-blot analyses reveal a 10-fold increase in IR mRNA after differentiation. These studies indicate that there is a selective increase in IR-gene expression during muscle differentiation. A similar increase in IR-gene expression is observed for the IR during pancreatic acinar cell differentiation. Glucocorticoids increase IR content in several target tissues. Studies in cultured IM-9 lymphocytes indicate that glucocorticoids induce a 5-fold increase in IR mRNA levels. Studies of IR mRNA half-life indicate that glucocorticoids do not alter IR mRNA stability. When the transcription of the IR is measured by elongation assays, glucocorticoids directly stimulate IR transcription 5- to 10-fold. The effect is detectable within 30 min of glucocorticoid treatment and is maximal within 2 h. Therefore, these studies demonstrate that the IR gene is under the direct regulation of glucocorticoids. Insulin downregulates the IR in various target tissues. Prior studies indicate that this downregulation was partly because of accelerated IR degradation. Studying AR42J pancreatic acinar cells, we also found that insulin accelerates IR degradation. Moreover, in these cells, insulin decreases IR biosynthesis by approximately 50%. Studies of IR mRNA indicate there is a concomitant decrease in IR mRNA levels after insulin treatment. Thus, insulin decreases IR-gene expression. The genomic structure of the IR promoter has been elucidated. Primer extension and nuclease S1 analysis indicate that IR mRNA has multiple start sites. The promoter fragment was ligated to a promoterless "reporter" plasmid containing the bacterial gene chloramphenicol acetyltransferase (CAT). When this plasmid is transfected into cultured cells, CAT activity is detected, indicating promoter activity. Various portions of a genomic fragment were ligated to a promoter to study glucocorticoid regulation of the IR promoter. These studies indicate that IR-gene expression is regulated by differentiation and hormonal agents.(ABSTRACT TRUNCATED AT 400 WORDS)
Importance of Timing of Preprandial Subcutaneous Insulin Administration in the Management of Diabetes Mellitus
Authors: George D Dimitriadis, John E Gerich
Journal: Diabetes Care (1983)

Since little is known regarding the appropriate time for preprandial insulin administration, we compared the effects of 30-min subcutaneous insulin infusions started 60 min, 30 min, and immediately before meal ingestion on postprandial plasma glucose and insulin profiles in eight subjects with insulin-dependent diabetes mellitus. Of these three regimens, administration of insulin 60 min before meal ingestion provided plasma glucose and insulin profiles closest to normal and permitted less insulin to be used. Our results suggest that adjustments in the timing as well as in the amount of insulin administered preprandially may be used in the management of diabetes and that prolonging the interval between administration of insulin and meal ingestion may reduce insulin requirements and thus decrease the hyperinsulinemia usually associated with insulin therapy.
Relevance of Na+–Ca2+ exchange in heart failure
Authors: W Schillinger
Journal: Cardiovascular Research (2003)

Recent topological studies suggested that the exchange blamed for provoking arrhythmogenic, delayed afterdepoprotein is comprised of nine transmembrane helices (TMs) larizations.We have dedicated section 5 to recent literature with connecting loop regions and a large cytoplasmic 1 and clinical studies that may elucidate the role of Nahydrophilic domain between TM 5 and 6 [13-15].Site-21 Ca exchange in arrhythmogenesis.directed mutagenesis studies have suggested that TMs 2 and 3 and TMs 7 and 8 together with their connecting loops participate in the formation of the ion translocation
<i>N</i>-[<i>N</i>-[(<i>S</i>)-1,3-Dicarboxypropyl]Carbamoyl]-4-[18F]Fluorobenzyl-<scp>l</scp>-Cysteine, [18F]DCFBC: A New Imaging Probe for Prostate Cancer
Authors: Ronnie C. Mease, Crystal L. Dusich, Catherine A. Foss, Hayden T. Ravert, Robert F. Dannals, Jurgen Seidel, Andrew Prideaux, James J. Fox, George Sgouros, Alan P. Kozikowski, Martin G. Pomper
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Previously, we showed successful imaging of xenografts that express the prostate-specific membrane antigen (PSMA) using small-animal positron emission tomography (PET) and the radiolabeled PSMA inhibitor N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-[11C]methyl-l-cysteine. Herein, we extend that work by preparing and testing a PSMA inhibitor of the same class labeled with fluorine-18. Experimental Design: N-[N-[(S)-1,3-Dicarboxypropyl]carbamoyl]-4-[18F]fluorobenzyl-l-cysteine ([18F]DCFBC) was prepared by reacting 4-[18F]fluorobenzyl bromide with the precursor (S)-2-[3-[(R)-1-carboxy-2-mercaptoethyl]ureido]-pentanedioic acid in ammonia-saturated methanol at 60°C for 10 min followed by purification using C-18 reverse-phase semipreparative high-performance liquid chromatography. Severe combined immunodeficient mice bearing a s.c. PSMA+ PC-3 PIP tumor behind one shoulder and a PSMA− PC-3 FLU tumor behind the other shoulder were injected via the tail vein with either 1.85 MBq (50 μCi) of [18F]DCFBC for ex vivo biodistribution or 7.4 MBq (200 μCi) for imaging. For biodistribution, mice were sacrificed at 5, 15, 30, 60, and 120 min. Tumor, blood, and major organs were harvested and weighed, and radioactivity was counted. Imaging was done on the GE eXplore Vista small-animal PET scanner by collecting 12 consecutive 10-min frames. Results: Radiochemical yield for [18F]DCFBC averaged 16 ± 6% (n = 8) from 4-[18F]fluorobenzyl bromide. Specific radioactivities ranged from 13 to 133 GBq/μmol (350-3,600 Ci/mmol) with an average of 52 GBq/μmol (1,392 Ci/mmol; n = 6). Biodistribution and imaging studies showed high uptake of [18F]DCFBC in the PIP tumors with little to no uptake in FLU tumors. High radiopharmaceutical uptake was also seen in kidneys and bladder; however, washout of radioactivity from these organs was faster than from the PIP tumors. The maximum PIP tumor uptake was 8.16 ± 2.55% injected dose per gram, achieved at 60 min after injection, which decreased to 4.69 ± 0.89 at 120 min. The PIP tumor to muscle ratio was 20 at 120 min after injection. Based on the mouse biodistribution, the dose-limiting organ is the kidneys (human estimated absorbed dose: 0.05 mGy/MBq; 0.2 rad/mCi). Conclusion: [18F]DCFBC localizes to PSMA+-expressing tumors in mice, permitting imaging by small-animal PET. This new radiopharmaceutical is an attractive candidate for further studies of PET imaging of prostate cancer.
Metabolic network driven analysis of genome-wide transcription data from Aspergillus nidulans.
Authors: Helga David, Gerald Hofmann, Ana Paula Oliveira, Hanne Jarmer, Jens Nielsen
Journal: Genome biology (2006)

Abstract Background Aspergillus nidulans (the asexual form of Emericella nidulans ) is a model organism for aspergilli, which are an important group of filamentous fungi that encompasses human and plant pathogens as well as industrial cell factories. Aspergilli have a highly diversified metabolism and, because of their medical, agricultural and biotechnological importance, it would be valuable to have an understanding of how their metabolism is regulated. We therefore conducted a genome-wide transcription analysis of A. nidulans grown on three different carbon sources (glucose, glycerol, and ethanol) with the objective of identifying global regulatory structures. Furthermore, we reconstructed the complete metabolic network of this organism, which resulted in linking 666 genes to metabolic functions, as well as assigning metabolic roles to 472 genes that were previously uncharacterized. Results Through combination of the reconstructed metabolic network and the transcription data, we identified subnetwork structures that pointed to coordinated regulation of genes that are involved in many different parts of the metabolism. Thus, for a shift from glucose to ethanol, we identified coordinated regulation of the complete pathway for oxidation of ethanol, as well as upregulation of gluconeogenesis and downregulation of glycolysis and the pentose phosphate pathway. Furthermore, on change in carbon source from glucose to ethanol, the cells shift from using the pentose phosphate pathway as the major source of NADPH (nicotinamide adenine dinucleotide phosphatase, reduced form) for biosynthesis to use of the malic enzyme. Conclusion Our analysis indicates that some of the genes are regulated by common transcription factors, making it possible to establish new putative links between known transcription factors and genes through clustering.