tbuckley/cabot-search huggingface dataset:
Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation
Authors: Laetitia A. Mauti, Marie-Aude Le Bitoux, Karine Baumer, Jean-Christophe Stehle, Dela Golshayan, Paolo Provero, Ivan Stamenkovic
Journal: Journal of Clinical Investigation (2011)

Metastasis depends on the ability of tumor cells to establish a relationship with the newly seeded tissue that is conducive to their survival and proliferation. However, the factors that render tissues permissive for metastatic tumor growth have yet to be fully elucidated. Breast tumors arising during pregnancy display early metastatic proclivity, raising the possibility that pregnancy may constitute a physiological condition of permissiveness for tumor dissemination. Here we have shown that during murine gestation, metastasis is enhanced regardless of tumor type, and that decreased NK cell activity is responsible for the observed increase in experimental metastasis. Gene expression changes in pregnant mouse lung and liver were shown to be similar to those detected in premetastatic sites and indicative of myeloid cell infiltration. Indeed, myeloid-derived suppressor cells (MDSCs) accumulated in pregnant mice and exerted an inhibitory effect on NK cell activity, providing a candidate mechanism for the enhanced metastatic tumor growth observed in gestant mice. Although the functions of MDSCs are not yet understood in the context of pregnancy, our observations suggest that they may represent a shared mechanism of immune suppression occurring during gestation and tumor growth.
Beginning Psychiatry Training Syndrome
Authors: LEWIS MERKLIN, RALPH B. LITTLE
Journal: American Journal of Psychiatry (1967)

The psychological response of the resident to his first year of psychiatric training may be characterized by temporary neurotic symptoms, psychosomatic disturbances, and symptomatic behavior. The recognition of this "beginning psychiatric training syndrome" as a transient and often valuable adaptational response may lessen its intensity and encourage both the resident and his instructors to deal with it more constructively.
Itaconic Acid: The Surprising Role of an Industrial Compound as a Mammalian Antimicrobial Metabolite
Authors: Thekla Cordes, Alessandro Michelucci, Karsten Hiller
Journal: Annual Review of Nutrition (2015)

Itaconic acid is well known as a precursor for polymer synthesis and has been involved in industrial processes for decades. In a recent surprising discovery, itaconic acid was found to play a role as an immune-supportive metabolite in mammalian immune cells, where it is synthesized as an antimicrobial compound from the citric acid cycle intermediate cis-aconitic acid. Although the immune-responsive gene 1 protein (IRG1) has been associated to immune response without a mechanistic function, the critical link to itaconic acid production through an enzymatic function of this protein was only recently revealed. In this review, we highlight the history of itaconic acid as an industrial and antimicrobial compound, starting with its biotechnological synthesis and ending with its antimicrobial function in mammalian immune cells.
The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: a possible role for cyclooxygenase 2
Authors: H A Patsos
Journal: Gut (2005)

<b>Background and aims:</b> Cyclooxygenase 2 (COX-2) is upregulated in most colorectal cancers and is responsible for metabolism of the endogenous cannabinoid, anandamide, into prostaglandin-ethanolamides (PG-EAs). The aims of this study were to determine whether anandamide and PG-EAs induce cell death in colorectal carcinoma (CRC) cells, and whether high levels of COX-2 in CRC cells could be utilised for their specific targeting for cell death by anandamide. <b>Methods:</b> We determined the effect of anandamide on human CRC cell growth by measuring cell growth and cell death, whether this was dependent on COX-2 protein expression or enzyme activity, and the potential involvement of PG-EAs in induction of cell death. <b>Results:</b> Anandamide inhibited the growth of CRC cell lines HT29 and HCA7/C29 (moderate and high COX-2 expressors, respectively) but had little effect on the very low COX-2 expressing CRC cell line, SW480. Induction of cell death in HT29 and HCA7/C29 cell lines was partially rescued by the COX-2 selective inhibitor NS398. Cell death induced by anandamide was neither apoptosis nor necrosis. Furthermore, inhibition of fatty acid amide hydrolase potentiated the non-apoptotic cell death, indicating that anandamide induced cell death was mediated via metabolism of anandamide by COX-2, rather than its degradation into arachidonic acid and ethanolamine. Interestingly, both PGE<sub>2</sub>-EA and PGD<sub>2</sub>-EA induced classical apoptosis. <b>Conclusions:</b> These findings suggest anandamide may be a useful chemopreventive/therapeutic agent for colorectal cancer as it targets cells that are high expressors of COX-2, and may also be used in the eradication of tumour cells that have become resistant to apoptosis.
EVALUATION OF A CLINICAL CASE-DEFINITION OF ACQUIRED IMMUNODEFICIENCY SYNDROME IN AFRICA
Authors: Robert Colebunders, Henry Francis, Lebughe Izaley, Kanyinda Kabasele, Nzila Nzilambi, Guido Van Der Groen, Gaby Vercauteren, JonathanM. Mann, Kapita Bila, Ndangi Kakonde, Limbaka Ifoto, ThomasC. Quinn, JamesW. Curran, Peter Piot
Journal: The Lancet (1987)
Bronchial reactions to the inhalation of high-dose tobramycin in cystic fibrosis
Authors: W.H. Nikolaizik, K. Trociewicz, F. Ratjen
Journal: European Respiratory Journal (2002)

It has been established that inhaled tobramycin has a positive effect on respiratory function in Pseudomonas-aeruginosa positive patients with cystic fibrosis (CF). In a previous study the authors reported that low-dose tobramycin preparations containing the preservative phenol caused significant bronchial obstruction. Recently, high-dose tobramycin preparations with and without preservatives/phenol have become available. To assess the airway response to these preparations flow/volume curves in 12 patients with CF (four males, eight females, mean age±sd=19.0±7.4 yrs) were measured. The tobramycin preparations: Nebicina® 2.0 mL (150 mg, containing the preservative phenol), Distobram® 3.0 mL (150 mg, containing preservatives), Tobi® 5.0 mL (300 mg), Tobi® 2.5 mL (150 mg), and Tobi® 5.0 mL, were used after bronchodilator application. Immediately and/or 5 min after the tobramycin inhalations there was a significant fall in lung function with the different preparations. There was no significant difference between preparations with and without preservatives/phenol. The bronchial obstruction was comparable to that observed after the inhalation of low-dose tobramycin and after saline. After 10 min of inhalation, the lung function returned to baseline values. Most patients preferred the Tobi® 2.5 mL and disliked the Nebicina® preparation due to the unpleasant taste. Preceding treatment with bronchodilators prevented the decline in lung function. Assessment of bronchial response at the first nebulisation of high-dose tobramycin and, in case of significant obstruction, β‐agonists in combination with the antibiotic inhalation are recommended.
Diesel exhaust exposure enhances the ozone-induced airway inflammation in healthy humans
Authors: J. Bosson, S. Barath, J. Pourazar, A. F. Behndig, T. Sandstrom, A. Blomberg, E. Adelroth
Journal: European Respiratory Journal (2008)

Exposure to particulate matter and ozone cause adverse airway reactions. Individual pollutant effects are often addressed separately, despite coexisting in ambient air. The present investigation was performed to study the effects of sequential exposures to diesel exhaust (DE) and ozone on airway inflammation in human subjects. Healthy subjects underwent bronchoscopy with bronchoalveolar lavage (BAL) and bronchial wash (BW) sampling on two occasions. Once following a DE exposure (with 300 μg·m<sup>−3</sup> particles with a 50% cut-off aerodynamic diameter of 10 μm) with subsequent exposure to O<sub>3</sub> (0.2 ppm) 5 h later. The other bronchoscopy was performed after a filtered air exposure followed by an ozone exposure, using an identical protocol. Bronchoscopy was performed 24 h after the start of the initial exposure. Significant increases in neutrophil and macrophage numbers were found in BW after DE followed by ozone exposure <i>versus</i> air followed by ozone exposure. DE pre-exposure also raised eosinophil protein X levels in BAL compared with air. The present study indicates additive effects of diesel exhaust on the ozone-induced airway inflammation. Together with similar results from a recent study with sequential diesel exhaust and ozone exposures, the present data stress a need to consider the interaction and cumulative effects of different air pollutants.
Malnutrition and Atherosclerosis in Dialysis Patients
Authors: Srinivasan Beddhu, Lisa M. Pappas, Nirupama Ramkumar, Matthew H. Samore
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Longitudinal associations of malnutrition with atherosclerotic events in uremia are unclear. In 50,732 incident Medicare dialysis patients who had normal (18.5 to 24.9 kg/m2), low (<18.5 kg/m2), or high (≥ 25 kg/m2) body mass index (BMI) and initiated dialysis in the United States from January 1995 to December 1999 with reported measured creatinine clearances and acute coronary syndrome (ACS; International Classification of Diseases, Ninth Revision codes 410.x and 411.x) were examined in parametric survival models. Normal BMI was the referent group. Twenty-four-hour urinary creatinine (UCr) was used as a measure of muscle mass. There were 7213 (14.2%) hospitalized ACS events, 1528 (22%) of which were fatal (death within 30 d). One-year post-ACS mortality was 48%. Low BMI (hazard ratio [HR], 0.89; P = 0.02] was associated with lower hazard, and UCr was not predictive (NS) of hospitalized ACS in multivariable model. Low BMI (NS) was not associated with a composite end point of hospitalized ACS/suspected out-of-hospital ACS death, whereas lowest UCr quartile was associated with higher hazard (HR, 1.14; P < 0.001). Low BMI (HR, 1.24; P < 0.001) and decrease in UCr (highest quartile reference, second quartile HR, 1.11 [P < 0.001]; third quartile HR, 1.24 [P < 0.001]; and fourth quartile HR, 1.43 [P < 0.001]) were associated with increased hazard of death. Hospitalized ACS events in dialysis patients carry very high immediate and long-term mortality. Positive longitudinal associations of malnutrition with documented hospitalized ACS events could not be demonstrated. Further longitudinal studies are warranted to provide definitive evidence of malnutrition as a uremic risk factor for atherosclerosis.
Quantitative gene expression in Budd-Chiari syndrome: a molecular approach to the pathogenesis of the disease
Authors: V Paradis
Journal: Gut (2005)

Budd-Chiari syndrome (BCS) is associated with parenchymal changes leading to major architecture remodelling. In order to gain further insight into the pathogenesis of BCS, we investigated expression of a set of genes involved in the course of chronic liver diseases.Quantitative expression of 35 selected genes involved in extracellular matrix regulation, growth factors, and angiogenesis was investigated in 13 cases of BCS and compared with 10 normal livers and 13 cirrhosis cases by real time reverse transcription-polymerase chain reaction. Differential gene expression was considered significant for genes showing at least a twofold variation, with p < 0.05.Expression of 14 genes was significantly increased in BCS versus normal liver, with the highest increase in superior cervical ganglion 10 (SCG10) gene. BCS cases were classified according to their evolution and morphological pattern as either acute or chronic in six and seven cases, respectively. Unsupervised hierarchical clustering of acute and chronic BCS cases on the basis of similarity in gene expression pattern led to distinction between the two groups. Expression of three genes was significantly different in acute versus chronic BCS (increase in matrix metalloproteinase 7 and SCG10, decrease in thrombospondin-1 for chronic BCS). Seventeen and 10 genes, mainly involved in extracellular matrix and vascular remodelling, were significantly deregulated in acute BCS versus normal liver and cirrhosis, respectively.These results show that BCS cases display a specific gene expression profile that is different from that of normal liver and cirrhosis; the molecular configuration of BCS can be readily distinguished by its evolution and morphological pattern.
Phase II Study of Nelarabine (compound 506U78) in Children and Young Adults With Refractory T-Cell Malignancies: A Report From the Children’s Oncology Group
Authors: Stacey L. Berg, Susan M. Blaney, Meenakshi Devidas, Tom A. Lampkin, Anthony Murgo, Mark Bernstein, Amy Billett, Joanne Kurtzberg, Greg Reaman, Paul Gaynon, James Whitlock, Mark Krailo, Michael B. Harris
Journal: Journal of Clinical Oncology (2005)

Purpose Nelarabine (compound 506U78), a water soluble prodrug of 9-b-d-arabinofuranosylguanine, is converted to ara-GTP in T lymphoblasts. We sought to define the response rate of nelarabine in children and young adults with refractory or recurrent T-cell disease. Patients and Methods We performed a phase II study with patients stratified as follows: stratum 1: ≥ 25% bone marrow blasts in first relapse; stratum 2: ≥ 25% bone marrow blasts in ≥ second relapse; stratum 3: positive CSF; stratum 4: extramedullary (non-CNS) relapse. The initial nelarabine dose was 1.2 g/m 2 daily for 5 consecutive days every 3 weeks. There were two dose de-escalations due to neurotoxicity on this or other studies. The final dose was 650 mg/m 2 /d for strata 1 and two patients and 400 mg/m 2 /d for strata 3 and four patients. Results We enrolled 121 patients (106 assessable for response) at the final dose levels. Complete plus partial response rates at the final dose levels were: 55% in stratum 1; 27% in stratum 2; 33% in stratum 3; and 14% in stratum 4. There were 31 episodes of ≥ grade 3 neurologic adverse events in 27 patients (18% of patients). Conclusion Nelarabine is active as a single agent in recurrent T-cell leukemia, with a response rate more than 50% in first bone marrow relapse. The most significant adverse events associated with nelarabine administration are neurologic. Further studies are planned to determine whether the addition of nelarabine to front-line therapy for T-cell leukemia in children will improve survival.
Ecthyma gangrenosum in an AIDS patient with normal neutrophil count
Authors: Ellen J. Kim, Mona Foad, Robin Travers
Journal: Journal of the American Academy of Dermatology (1999)

Ecthyma gangrenosum is the cutaneous manifestation of Pseudomonas aeruginosa septicemia, typically affecting immunosuppressed patients, particularly those with neutropenia. Association with HIV disease has been rarely reported. We describe an unusual presentation of solitary ecthyma gangrenosum on the face of a non-neutropenic patient with AIDS. (J Am Acad Dermatol 1999;41:840-1.)
Regulation of plasma levels of low-density lipoprotein cholesterol: interpretation of data on low-density lipoprotein turnover in man.
Authors: J B Meddings, J M Dietschy
Journal: Circulation (1986)

At the present time the most useful technique with which to examine the kinetics of low-density lipoprotein (LDL) cholesterol in vivo is the labeled LDL turnover study. However, a major limitation of this method is that, despite its ability to accurately measure both the plasma LDL concentration and LDL production rate, it cannot directly quantify LDL receptor activity. The present study defines the equations that describe the relationship between LDL cholesterol production rate, LDL receptor number, and plasma LDL cholesterol concentration. These equations provide a method that allows calculation of total LDL receptor activity based on the results of an LDL turnover study. With the use of this technique and data from previously published series, the effects of the genetic absence of receptors, aging, and the treatment of hypercholesterolemia with mevinolin on LDL cholesterol kinetics were analyzed.
Unraveling the “Known Unknowns”: Lessons and Reflections from the New Directions in Leukemia Research 2012 Conference
Authors: Deborah L. White, Anna L. Brown, Richard J. D'Andrea, Alison M. Rice
Journal: Cancer Research (2012)

Patients diagnosed with leukemia approach their treatment with the hope of cure despite the effect on their quality of life. Some patients will be cured, others will die from treatment, and some will die of their disease. A common theme at the New Directions in Leukemia Research (NDLR 2012) meeting was that cure will come if the drivers of the disease are better understood. Key messages included the power of combination platforms to understand the genetic and epigenetic modifications in leukemia to enable development of rational therapies, which can be tested via new clinical trial designs ensuring rapid clinical implementation.
Pharmacologic Characterization of a Potent Inhibitor of Class I Phosphatidylinositide 3-Kinases
Authors: Florence I. Raynaud, Suzanne Eccles, Paul A. Clarke, Angela Hayes, Bernard Nutley, Sonia Alix, Alan Henley, Francesca Di-Stefano, Zahida Ahmad, Sandrine Guillard, Lynn M. Bjerke, Lloyd Kelland, Melanie Valenti, Lisa Patterson, Sharon Gowan, Alexis de Haven Brandon, Masahiko Hayakawa, Hiroyuki Kaizawa, Tomonubu Koizumi, Takahide Ohishi, Sonal Patel, Nahid Saghir, Peter Parker, Mike Waterfield, Paul Workman
Journal: Cancer Research (2007)

Abstract Extensive evidence implicates activation of the lipid phosphatidylinositide 3-kinase (PI3K) pathway in the genesis and progression of various human cancers. PI3K inhibitors thus have considerable potential as molecular cancer therapeutics. Here, we detail the pharmacologic properties of a prototype of a new series of inhibitors of class I PI3K. PI103 is a potent inhibitor with low IC50 values against recombinant PI3K isoforms p110α (2 nmol/L), p110β (3 nmol/L), p110δ (3 nmol/L), and p110γ (15 nmol/L). PI103 also inhibited TORC1 by 83.9% at 0.5 μmol/L and exhibited an IC50 of 14 nmol/L against DNA-PK. A high degree of selectivity for the PI3K family was shown by the lack of activity of PI103 in a panel of 70 protein kinases. PI103 potently inhibited proliferation and invasion of a wide variety of human cancer cells in vitro and showed biomarker modulation consistent with inhibition of PI3K signaling. PI103 was extensively metabolized, but distributed rapidly to tissues and tumors. This resulted in tumor growth delay in eight different human cancer xenograft models with various PI3K pathway abnormalities. Decreased phosphorylation of AKT was observed in U87MG gliomas, consistent with drug levels achieved. We also showed inhibition of invasion in orthotopic breast and ovarian cancer xenograft models and obtained evidence that PI103 has antiangiogenic potential. Despite its rapid in vivo metabolism, PI103 is a valuable tool compound for exploring the biological function of class I PI3K and importantly represents a lead for further optimization of this novel class of targeted molecular cancer therapeutic. [Cancer Res 2007;67(12):5840–50]
Family-Based Association between Alzheimer's Disease and Variants in<i>UBQLN1</i>
Authors: Lars Bertram, Mikko Hiltunen, Michele Parkinson, Martin Ingelsson, Christoph Lange, Karunya Ramasamy, Kristina Mullin, Rashmi Menon, Andrew J. Sampson, Monica Y. Hsiao, Kathryn J. Elliott, Gonül Velicelebi, Thomas Moscarillo, Bradley T. Hyman, Steven L. Wagner, K. David Becker, Deborah Blacker, Rudolph E. Tanzi
Journal: New England Journal of Medicine (2005)

Recent analyses suggest that the known Alzheimer's disease genes account for less than half the genetic variance in this disease. The gene encoding ubiquilin 1 (UBQLN1) is one of several candidate genes for Alzheimer's disease located near a well-established linkage peak on chromosome 9q22.We evaluated 19 single-nucleotide polymorphisms in three genes within the chromosome 9q linkage region in 437 multiplex families with Alzheimer's disease from the National Institute of Mental Health (NIMH) sample (1439 subjects). We then tested the single-nucleotide polymorphisms showing a positive result in an independently identified set of 217 sibships discordant for Alzheimer's disease (Consortium on Alzheimer's Genetics [CAG] sample; 489 subjects) and assessed the functional effect of an implicated single-nucleotide polymorphism in brain tissue from 25 patients with Alzheimer's disease and 17 controls.In the NIMH sample, we observed a significant association between Alzheimer's disease and various single-nucleotide polymorphisms in UBQLN1. We confirmed these associations in the CAG sample. The risk-conferring haplotype in both samples was defined by a single intronic single-nucleotide polymorphism located downstream of exon 8. The risk allele was associated with a dose-dependent increase in an alternatively spliced UBQLN1 (lacking exon 8) transcript in RNA extracted from brain samples of patients with Alzheimer's disease.Our findings suggest that genetic variants in UBQLN1 on chromosome 9q22 substantially increase the risk of Alzheimer's disease, possibly by influencing alternative splicing of this gene in the brain.
Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat.
Authors: K A Nath, G Balla, G M Vercellotti, J Balla, H S Jacob, M D Levitt, M E Rosenberg
Journal: Journal of Clinical Investigation (1992)

Heme proteins such as myoglobin or hemoglobin, when released into the extracellular space, can instigate tissue toxicity. Myoglobin is directly implicated in the pathogenesis of renal failure in rhabdomyolysis. In the glycerol model of this syndrome, we demonstrate that the kidney responds to such inordinate amounts of heme proteins by inducing the heme-degradative enzyme, heme oxygenase, as well as increasing the synthesis of ferritin, the major cellular repository for iron. Prior recruitment of this response with a single preinfusion of hemoglobin prevents kidney failure and drastically reduces mortality (from 100% to 14%). Conversely, ablating this response with a competitive inhibitor of heme oxygenase exacerbates kidney dysfunction. We provide the first in vivo evidence that induction of heme oxygenase coupled to ferritin synthesis is a rapid, protective antioxidant response. Our findings suggest a therapeutic strategy for populations at a high risk for rhabdomyolysis.