tbuckley/cabot-search huggingface dataset:
Conditional Gata2 inactivation results in HSC loss and lymphatic mispatterning
Authors: Kim-Chew Lim, Tomonori Hosoya, William Brandt, Chia-Jui Ku, Sakie Hosoya-Ohmura, Sally A. Camper, Masayuki Yamamoto, James Douglas Engel
Journal: Journal of Clinical Investigation (2012)

The transcription factor GATA-2 plays vital roles in quite diverse developmental programs, including hematopoietic stem cell (HSC) survival and proliferation. We previously identified a vascular endothelial (VE) enhancer that regulates GATA-2 activity in pan-endothelial cells. To more thoroughly define the in vivo regulatory properties of this enhancer, we generated a tamoxifen-inducible Cre transgenic mouse line using the Gata2 VE enhancer (Gata2 VECre) and utilized it to temporally direct tissue-specific conditional loss of Gata2. Here, we report that Gata2 VECre-mediated loss of GATA-2 led to anemia, hemorrhage, and eventual death in edematous embryos. We further determined that the etiology of anemia in conditional Gata2 mutant embryos involved HSC loss in the fetal liver, as demonstrated by in vitro colony-forming and immunophenotypic as well as in vivo long-term competitive repopulation experiments. We further documented that the edema and hemorrhage in conditional Gata2 mutant embryos were due to defective lymphatic development. Thus, we unexpectedly discovered that in addition to its contribution to endothelial cell development, the VE enhancer also regulates GATA-2 expression in definitive fetal liver and adult BM HSCs, and that GATA-2 function is required for proper lymphatic vascular development during embryogenesis.
INTRACUTANEOUS REACTIONS IN PERTUSSIS
Authors: EDWIN A. RIESENFELD
Journal: JAMA (1923)

During the last four years, several epidemics of pertussis have occurred in a large institution for the care of children harboring about 400, ranging in age from 1 day to 6 years. The opportunity was thus afforded us to study the disease with special reference to ( a ) natural immunity, ( b ) acquired immunity, and ( c ) the diagnosis of the disease in its earliest stages, and before the onset of the characteristic spasmodic cough, whoop and vomiting.  Children exposed in previous epidemics and not acquiring the disease were considered as possessing a natural immunity. Other children giving a history of having had the disease before admission, or having had an attack of pertussis while in the institution, were grouped as those possessing an acquired immunity.  To possess a method whereby it would be possible to designate a child as having a natural or acquired immunity, and to be able to diagnose pertussis
Abstract 337: Carfilzomib synergistically enhances ABT-263-induced apoptosis due to NOXA induction in <i>KRAS</i> wild type and mutant colorectal cancer cell lines
Authors: Shengbing Huang, Koichi Okamoto, Frank A. Sinicrope
Journal: Cancer Research (2014)

Abstract BACKGROUND. Proteosome inhibition is associated with induction of the proapoptotic BH3 protein NOXA. Therefore, we hypothesize that the combination of the irreversible proteosome inhibitor, carfilzomib, will cooperatively enhance apoptosis induction by the BH3 mimetic drug, ABT-263. Given that nononcogenic addiction to proteosome activity has been reported in KRAS mutant cells, we utilized isogenic colorectal cancer (CRC) cell lines in which the endogenous wild-type (wt) or mutant alleles had been inactivated through targeted homologous recombination. Since proteasome blockade results in proteotoxic stress, we determined whether an autophagy inhibitor can enhance chemosensitivity. EXPERIMENTAL METHODS. Isogenic KRAS mutant (MUT) CRC cells (HCT116, DLD1; obtained from B. Vogelstein, JHU) were incubated with carfilzomib (25,50nM) alone or combined with ABT-263 (1 µM) and apoptosis was measured by caspase cleavage and annexin V+ labeling. Synergy was measured by calculation of the combination index. Effect of carfilzomib on Bcl-2 family proteins was determined by immunoblotting. Interaction of NOXA with MCL-1 was examined by immunoprecipitation. Knockdown of NOXA was achieved by lentiviral shRNA. Cells were incubated with drugs alone or combined with chloroquine, and autophagy (LC3I/II conversion) and apoptosis were analyzed. RESULTS. Carfilzomib was shown to potently and synergistically enhance ABT-263-induced apoptosis (2-fold) in both KRAS MUT and wild type (WT) cell lines, with the effect being modestly higher in wild type cells, as shown by annexin V+ staining and caspase cleavage. Carfilzomib induced NOXA expression in both KRAS MUT and WT cells, and reduced MCL-1 expression. Induced NOXA was shown to bind and sequester MCL-1 proteins. Knockdown of NOXA attenuated drug-induced apoptosis. Autophagy inhibition by chloroquine accumulated LC3II, but only modestly increased carfilzomib-induced cell death. CONCLUSION. Irreversible proteasome inhibition by carfilzomib synergistically enhanced ABT-263-induced cell death that is mediated by NOXA upregulation and its sequestration/neutralization of MCL-1. The finding of similar efficacy in KRAS MUT vs WT cells suggests that this combination may represent a novel therapeutic strategy in this tumor subset. Citation Format: Shengbing Huang, Koichi Okamoto, Frank A. Sinicrope. Carfilzomib synergistically enhances ABT-263-induced apoptosis due to NOXA induction in KRAS wild type and mutant colorectal cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 337. doi:10.1158/1538-7445.AM2014-337
Prospective Study Of Maternal Intake Of Vitamin D During Pregnancy And Risk Of Wheezing Illnesses In Children At Age 2 Years
Authors: C.A. Camargo, S.L. Rifas-Shiman, A.A. Litonjua, J.W. Rich-Edwards, S.T. Weiss, D.R. Gold, M.W. Gillman
Journal: Journal of Allergy and Clinical Immunology (2006)
Anti–4-1bb Monoclonal Antibodies Abrogate T Cell–Dependent Humoral Immune Responses in Vivo through the Induction of Helper T Cell Anergy
Authors: Robert S. Mittler, Tina S. Bailey, Kerry Klussman, Mark D. Trailsmith, Michael K. Hoffmann
Journal: The Journal of Experimental Medicine (1999)

The 4-1BB receptor (CDw137), a member of the tumor necrosis factor receptor superfamily, has been shown to costimulate the activation of T cells. Here we show that anti-mouse 4-1BB monoclonal antibodies (mAbs) inhibit thymus-dependent antibody production by B cells. Injection of anti-4-1BB mAbs into mice being immunized with cellular or soluble protein antigens induced long-term anergy of antigen-specific T cells. The immune response to the type II T cell-independent antigen trinintrophenol-conjugated Ficoll, however, was not suppressed. Inhibition of humoral immunity occurred only when anti-4-1BB mAb was given within 1 wk after immunization. Anti-4-1BB inhibition was observed in mice lacking functional CD8(+) T cells, indicating that CD8(+) T cells were not required for the induction of anergy. Analysis of the requirements for the anti-4-1BB-mediated inhibition of humoral immunity revealed that suppression could not be adoptively transferred with T cells from anti-4-1BB-treated mice. Transfer of BALB/c splenic T cells from sheep red blood cell (SRBC)-immunized and anti-4-1BB-treated mice together with normal BALB/c B cells into C.B-17 severe combined immunodeficient mice failed to generate an anti-SRBC response. However, B cells from the SRBC-immunized, anti-4-1BB-treated BALB/c mice, together with normal naive T cells, exhibited a normal humoral immune response against SRBC after transfer, demonstrating that SRBC-specific B cells were left unaffected by anti-4-1BB mAbs.
Did a Majority of the Board of Trustees Vote for the Removal of the Journal to Washington?
Authors: H. Martyn Scudder
Journal: JAMA (1891)

every surgeon favored supra-pubic cystotomy rather than the perineal operation for stone in the bladder.The only objection raised against supra-pubic cystotomy was the difficulty of drain¬ age.The objections against the perineal opera¬
Abstract LB-283: Prognostic significance of <i>BRMS1</i> promoter methylation in operable breast cancer.
Authors: Maria Chimonidou, Galatea Kallergi, Vasilis Georgoulias, Danny Welch, Evi Lianidou
Journal: Cancer Research (2013)

Abstract Introduction: Breast Cancer Metastasis Suppressor-1 (BRMS1) encodes a predominantly nuclear protein that differentially regulates expression of multiple genes, leading to suppression of metastasis without affecting orthotopic tumor growth. We examined the clinical relevance of BRMS1 promoter methylation in early breast cancer. Methods: We analyzed 118 formalin-fixed paraffin embedded samples: 5 pairs of breast tumors and adjacent non-cancerous tissues, 14 non-cancerous tissues, 10 benign fibroadenomas, and 84 primary breast tumors. Peripheral blood mononuclear cells were isolated from 39/84 of these patients and were fixed in cytospins. BRMS1 methylation status was investigated in all FFPE and cytospin stained circulating tumor cells using methylation specific PCR. BRMS1 expression was examined using double-immunofluorescence in isolated PBMC cytospins using anti-BRMS1 and pancytokeratin A45-B/B3 antibodies. Results: BRMS1 promoter methylation was observed in 0/19 noncancerous breast tissues, 0/10 benign fibroadenomas and 31/84(37.8%) breast tumors. During the follow-up period 27/84(32.1%) patients relapsed of which 19/84(22.6%) patients died as a consequence of disease progression. BRMS1 methylation was detected in 15/27(55.6%) patients that relapsed and in 10/19(52.6%) of patients that died. BRMS1 promoter methylation was associated with reduced disease-free interval (P=0.009) while a trend towards a reduced overall survival (OS) was also observed (P=0.071). Expression of BRMS1 on CTC was very heterogeneous: CTC with high BRMS1 expression were found in 7/13(53.8%) CTC positive samples while exclusively CTC with high BRMS1 were found in only 3 patients (23.0%). CTC with low BRMS1 expression were found in 3 patients. CTC negative for BRMS1 were found in 8/13(61.5%) patients. Exclusively CTC with low or negative BRMS1-expression were identified in 6/13(46.1%) patients. 4/13(30.8%) patients had both high and low or negative BRMS1 expression in their CTC. Conclusions: BRMS1 promoter methylation provides important prognostic information for disease free survival in early breast cancer patients. BRMS1 promoter methylation and protein expression were evaluated in primary tumors and corresponding CTC for the first time. BRMS1 expression in CTC was heterogeneous in individual patient samples. CTC expressing epithelial markers but no BRMS1 seem to define a worse prognosis group of patients. These results need to be further evaluated and validated in a larger cohort of breast cancer patients. Citation Format: Maria Chimonidou, Galatea Kallergi, Vasilis Georgoulias, Danny Welch, Evi Lianidou. Prognostic significance of BRMS1 promoter methylation in operable breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-283. doi:10.1158/1538-7445.AM2013-LB-283
Acquired double-barrel oesophagus in epidermolysis bullosa dystrophica.
Authors: R B Warren, T F Warner, E F Gilbert, J R Pellet
Journal: Thorax (1980)

An unusual case of epidermolysis bullosa dystrophica with extensive stenosis, high perforation, and dissection of the oesophagus forming a "double-barrel" structure is described. Gastric epithelium found in the upper oesophagus is thought to be of metaplastic origin and caused by repeated minor trauma with repair.
Asbestos-Related Diseases
Authors: B. T. Mossman, J. B. L. Gee
Journal: New England Journal of Medicine (1989)

ASBESTOS is a mineral causing much controversy in today's society. Before the passage and enactment of the Occupational Safety and Health Act of 1970, millions of Americans were exposed to relatively high concentrations of airborne asbestos in the work-place. Other citizens — including insulation installers, shipyard workers, and manufacturers of gas masks — encountered asbestos during World Wars I and II, when it was produced at an accelerated rate. Although the importation and use of asbestos have decreased in the United States since 1970, and recently the Environmental Protection Agency (EPA) has proposed a ban on its use, asbestos remains . . .
Cimetidine and ranitidine: comparison of effects on hepatic drug metabolism.
Authors: D A Henry, I A Macdonald, G Kitchingman, G D Bell, M J Langman
Journal: BMJ (1980)

Paired studies of hepatic microsomal function were conducted in eight subjects during treatment with two histamine H2 antagonists, cimetidine and ranitidine. Cimetidine but not ranitidine inhibited the metabolism of antipyrine (phenazone) and demethylation of aminopyrine (aminophenazone) as measured by breath 14CO2 production after intravenous injection of 14C-aminopyrine. These results suggest that the metabolic inhibitory actions on the liver may be separated from H2 antagonist effects, and that ranitidine has an advantage over cimetidine by not inhibiting microsomal drug oxidative function.
On Evaluating the Einthoven Triangle Theory
Authors: J. SCOTT BUTTERWORTH, JOHN J. THORPE
Journal: Circulation (1951)

The authors have attempted to treat a controversial subject in a different way by introducing a known potential into the cavity of the living human heart and determining the magnitude of this potential at the extremities. While the data may be subject to various interpretations it is suggested that this technic may be a valuable tool for further analysis of the spread of potentials in the body.
Tc-99m Labeled WBC Imaging of Lower Extremity Abscesses and Skin Necrosis Due to Skin Popping
Authors: W. GREGORY REESE, LISA M. SULLIVAN
Journal: Clinical Nuclear Medicine (1997)

Abscess formation is a common cause of hospital admission among intravenous drug abusers. As vascular access becomes more difficult secondary to venous sclerosis, subcutaneous extravasation of irritants and bacteria occurs, resulting in injection abscesses. When addicts can no longer inject drugs intravenously, they often resort to the intentional subcutaneous administration of drugs known commonly as "skin popping." These Tc-99m HMPAO labeled WBC images and lower extremity radiographs are from a 29-year-old man with a 6-month history of nonhealing ulcers and skin necrosis of both legs due to skin popping of heroin and cocaine.
Sex differences in descending pain modulatory pathways may clarify sex differences in pain
Authors: Wendy F. Sternberg
Journal: Behavioral and Brain Sciences (1997)

This commentary addresses the strength of the comparative approach to the study of sex differences in pain. Animal studies can focus our attention on mechanisms of sex differences in these clinical sex differences. Important sex differences are seen in descending pain modulation, thereby providing an explanation for the observation of sex differences in pain perception. [berkley]
A Clinical Lecture on Mediastinal Tumours: Delivered in the Western Infirmary, Glasgow
Authors: T. M. Anderson
Journal: BMJ (1894)

TIHE case which I am about to bring under your notice is one of exceptional interest from the point of view of diagnosis.The disease from which the patient suffered is very unusual in so young a woman, yet the evidence for its existence in this case appears to be practically conclusive, although it was unfortunately impossible to verify the dia- gnosis by post-mortem examination.The patient, a young woman of 20, has been seen by some of you during life.She was admitted on October 20th, 1893, complaining of swelling of the feet and legs, accompanied by palpitation and breath- lessness.These symptoms had developed four weeks before she came to the hospital.Her family history threw no light upon the case, as, with the exception of her mother, who died in childbed, all her relatives are alive and well.With regard
Risk factors for infection during treatment with peginterferon alfa and ribavirin for chronic hepatitis C
Authors: Robert Roomer, Bettina E. Hansen, Harry L. A. Janssen, Robert J. de Knegt
Journal: Hepatology (2010)

Neutropenia during treatment with peginterferon alfa and ribavirin for chronic hepatitis C virus (HCV) infection is a common cause of dose reductions of peginterferon alfa. These reductions are performed to prevent bacterial and fungal infections, which are common during HCV treatment and can be attributed to neutropenia. The aims of this study were to investigate the occurrence of infections and their relation to neutropenia and to identify potential risk factors for infections during HCV treatment. In this single-center cohort study, 2,876 visits of 321 patients treated with peginterferon alfa and ribavirin were evaluated for neutropenia, infections, dose reductions, and potential risk factors for infection during HCV treatment. The baseline mean absolute neutrophil count (ANC) was 3,420 cells/μL, and 16 patients had a baseline ANC of &lt;1,500 cells/μL. During treatment, neutropenia, which was defined as ANC &lt;750 cells/μL, was observed in 95 patients (29.7%) and ANC &lt;375/μL was observed in 16 patients (5%). Ninety-six infections were observed in 70 patients (21.8%). Thirteen infections (13.5%) were defined as severe. Infections were not correlated with neutropenia during treatment. Dose reductions did not lead to a decrease in infection rate. Multivariate logistic regression analysis revealed that age &gt;55 years (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.19-3.56, P = 0.01) and baseline hyperglycemia (OR 2.17, 95% CI 1.15-4.10, P = 0.016) were associated with an increased risk of infection during HCV treatment. Cirrhosis and chronic obstructive pulmonary disease were not risk factors for infection. Conclusion: Bacterial infections during treatment with peginterferon alfa and ribavirin are not associated with neutropenia. Older patients and patients with poorly controlled diabetes mellitus have a greater risk of developing infections during HCV treatment. (Hepatology 2010)
Discrepancies between the Doses of Cholecystokinin or Caerulein-Stimulating Exocrine and Endocrine Responses in Perfused Isolated Rat Pancreas
Authors: Makoto Otsuki, Choitsu Sakamoto, Hosai Yuu, Mitsuo Maeda, Soichiro Morita, Atsuhi Ohki, Noboru Kobayashi, Katsuhiro Terashi, Kuniyasu Okano, Shigeaki Baba
Journal: Journal of Clinical Investigation (1979)

The effects of highly purified natural porcine cholecystokinin (CCK) and synthetic caerulein on the rate of flow of pancreatic juice, the rate of output of amylase, and the rate of release of immunoreactive insulin (IRI) and immunoreactive glucagon (IRG) were simultaneously investigated in the isolated perfused rat pancreas. The maximal flow rate of pancreatic juice was obtained with concentrations of CCK ranging from 0.5 to 10 mU/ml, whereas amylase output was maximal at CCK concentrations from 1 to 10 mU/ml. Caerulein at concentrations of 0.05-1 ng/ml induced a similar maximal flow rate and amylase secretion. Supramaximal stimulatory concentrations of these peptides resulted in lower rates of release of fluid and amylase than with the maximally effective concentrations. Stimulation of IRI and IRG release was elicited only with concentrations of peptides supramaximal for effects on the exocrine responses. The demonstration of very similar discrepancies between the doses of caerulein required to elicit maximal exocrine responses and those required to elicit endocrine responses provide strong evidence that the pattern of the effect of the porcine CCK is accounted for by CCK itself. Although caerulein had no influence on IRI response when superimposed on 100 or 150 mg/100 ml glucose stimulation, preperfusion of caerulein led to a significant enhancement of IRI response to a subsequent glucose stimulation in both phases. The augmentation effect was completely separate from the direct IRI-stimulating effect of caerulein, because the CCK-like peptide requires no glucose for insulinotropic action. Because the concentrations of the peptides necessary for stimulation of endocrine responses were inhibitory in their effects on exocrine responses, it may be inferred that it is unlikely that the endocrine effect is physiologically important, though the results of caerulein for augmenting glucose-stimulated IRI release suggests a possible role for CCK in carbohydrate metabolism.
Quinacrine Effects on the Central Nervous System
Authors: George L. Engel
Journal: JAMA (1966)

<h3>To the Editor:—</h3> In the recommendation of the AMA Council on Drugs on the use of quinacrine (Atabrine) for the palliative treatment of neoplastic effusions, it is stated that adverse reactions are mild and transient.<sup>1</sup>Yet it was also noted in passing that several patients experienced transient hallucinatory episodes. These comments seriously underemphasize the potential of quinacrine to provoke grave psychotic reactions.<sup>2,3</sup> In an experimental study of its effect on the central nervous system, quinacrine in oral doses of 0.2 to 1.2 gm per day was found to act regularly as a stimulant.<sup>2</sup>Consistent symptoms of healthy volunteers included motor acceleration, heightened awareness, restlessness, sleeplessness, and disturbing dreams of a nightmarish quality. Psychologically, there was acceleration of the free flow of ideas, occasionally culminating in a disorganization of logical thinking; increased anxiety to the point of panic; excitement; aggressive outbursts; delusions; hallucinations; disordered perceptions; expansiveness; and euphoria.
Statistical Issues in Longitudinal Data Analysis for Treatment Efficacy Studies in the Biomedical Sciences
Authors: Chunyan Liu, Timothy P Cripe, Mi-Ok Kim
Journal: Molecular Therapy (2010)

Longitudinally collected outcomes are increasingly common in cell biology and gene therapy research. In this article, we review the current practice of statistical analysis of longitudinal data in these fields, and recommend the "best performing" statistical method among those available in most statistical packages. A survey of papers published in Molecular Therapy indicates that longitudinal data are only properly analyzed in a small fraction of articles, and the most popular approach was analyzing each measurement time point data separately using an analysis of variance (ANOVA) model with Tukey's post hoc tests. We show that first, such cross-sectional ANOVA approach does not utilize all the power that the longitudinal design of a study provides, and second, Tukey's post hoc tests applied at each measurement time separately could result in a false positivity rate as high as 30% using a simulation study. We recommend mixed effects model analysis instead. We also discuss the complexities of multiple comparison adjustment in the post hoc testing that result from within experimental unit correlation existing in longitudinal data. We recommend resampling as a method that readily adjusts the post hoc testing to be limited to only interesting comparisons and thereby avoids unduly sacrificing the power.