tbuckley/cabot-search huggingface dataset:
Identification of an Astrocyte Cell Population from Human Brain that Expresses Perforin, a Cytotoxic Protein Implicated in Immune Defense
Authors: Philippe Gasque, Jane Jones, Sim K. Singhrao, B. Morgan
Journal: The Journal of Experimental Medicine (1998)

The brain is an immunoprivileged organ isolated from the peripheral immune system. However, it has been shown that resident cells, notably astrocytes and microglia, can express numerous innate immune molecules, providing the capacity to generate a local antipathogen system. Perforin is a cytolytic protein present in the granules of cytotoxic T lymphocytes and natural killer cells. Expression in cells other than those of the hemopoetic lineage has not been described. We report here that fetal astrocytes in culture (passages 2 to 15), astrocytoma, and adult astrocytes expressed perforin. Reverse transcriptase polymerase chain reaction followed by Southern blot was carried out using multiple specific primers and all cDNAs were cloned and sequenced. Human fetal astrocyte perforin cDNA sequence was ∼100% identical to the reported perforin cDNA cloned from T cells. Western blot analysis using monoclonal and polyclonal antiperforin peptide antibodies revealed a protein of 65 kD in both human fetal astrocyte and rat natural killer cell lysates (n = 4). Immunostaining followed by FACS® and confocal and electron microscopy analysis revealed that perforin was expressed by 40–50% of glial fibrillary acidic protein positive cells present in the fetal brain culture (n = 11). Perforin was not localized to granules in astrocytes but was present throughout the cytoplasm, probably in association with the endoplasmic reticulum. Perforin was not detected in normal adult brain tissue but was present in and around areas of inflammation (white and grey matter) in multiple sclerosis and neurodegenerative brains. Perforin-positive cells were identified as reactive astrocytes. These findings demonstrate that perforin expression is not unique to lymphoid cells and suggest that perforin produced by a subpopulation of astrocytes plays a role in inflammation in the brain.
A gene expression profile of stem cell pluripotentiality and differentiation is conserved across diverse solid and hematopoietic cancers
Authors: Nathan P Palmer, Patrick R Schmid, Bonnie Berger, Isaac S Kohane
Journal: Genome biology (2012)

Abstract Background Understanding the fundamental mechanisms of tumorigenesis remains one of the most pressing problems in modern biology. To this end, stem-like cells with tumor-initiating potential have become a central focus in cancer research. While the cancer stem cell hypothesis presents a compelling model of self-renewal and partial differentiation, the relationship between tumor cells and normal stem cells remains unclear. Results We identify, in an unbiased fashion, mRNA transcription patterns associated with pluripotent stem cells. Using this profile, we derive a quantitative measure of stem cell-like gene expression activity. We show how this 189 gene signature stratifies a variety of stem cell, malignant and normal tissue samples by their relative plasticity and state of differentiation within Concordia, a diverse gene expression database consisting of 3,209 Affymetrix HGU133+ 2.0 microarray assays. Further, the orthologous murine signature correctly orders a time course of differentiating embryonic mouse stem cells. Finally, we demonstrate how this stem-like signature serves as a proxy for tumor grade in a variety of solid tumors, including brain, breast, lung and colon. Conclusions This core stemness gene expression signature represents a quantitative measure of stem cell-associated transcriptional activity. Broadly, the intensity of this signature correlates to the relative level of plasticity and differentiation across all of the human tissues analyzed. The fact that the intensity of this signature is also capable of differentiating histological grade for a variety of human malignancies suggests potential therapeutic and diagnostic implications.
Oesophageal manometry in the evaluation of megacolon with onset in adult life.
Authors: G Basilisco, P Velio, P A Bianchi
Journal: Gut (1997)

BACKGROUND: Oesophageal motility is often impaired in patients with megaduodenum and other forms of intestinal pseudo-obstruction in which a visceral myopathy or neuropathy may be present. Idiopathic longstanding megacolon with onset in adult life is still a poorly defined entity, which may also be part of a more widespread motility disorder but in which oesophageal motility has not been yet systematically studied. AIMS: To assess oesophageal motility in patients with longstanding idiopathic megacolon with onset in adult life. PATIENTS: 14 consecutive subjects with idiopathic megacolon whose symptoms began after the age of 10 and a clinical history of 2-22 years. METHODS: Standard barium enema, water perfused oesophageal manometry, and also anorectal manometry. RESULTS: Oesophageal motility was impaired in five patients (36%; 95% confidence intervals 16 to 61%). Normal peristalsis was substituted by low amplitude multiple peaked simultaneous contractions in four subjects and by undetectable contractions in one. In three of them the lower oesophageal sphincter did not relax after swallows; in the same patients anal relaxation after rectal distension was also undetectable. All five patients with impaired oesophageal motility had a colonic dilatation sparing the rectum. Three of them reported constipation and a history of pesudo-obstruction and the other two only abdominal distension. CONCLUSIONS: Oesophageal manometry should be performed in patients with longstanding idiopathic megacolon with onset in adult life, in particular if the rectum is not dilated and even in absence of pseudo-obstruction. This simple test may disclose a more widespread visceral neuropathy or myopathy. Such a diagnosis helps to better understand the cause of the colonic dilatation and may be clinically relevant for treatment of the patients.
Acute upper gastrointestinal bleeding: identifying low risk patients
Authors: Richard F A Logan, Sarah Hearnshaw, Derek Lowe, Simon P L Travis, M Stephen Murphy, Kel R Palmer
Journal: Gut (2012)

We thank Chakrabaty and colleagues for their letter.1 As they mention, the full Rockall score was designed (and has been validated) for use in identifying patients at risk of death from acute upper gastrointestinal bleeding (AUGIB),2 ,3 and we believe this is the best use of the score. It has also recently been shown to be comparable with the Glasgow Blatchford Score …
Traumatic grief: a case of loss-induced trauma [clinical conference]
Authors: H G Prigerson, M K Shear, E Frank, L C Beery, R Silberman, J Prigerson, C F Reynolds
Journal: American Journal of Psychiatry (1997)

A 59-year-old widow came for treatment of her depressive symptoms in response to a media announcement recruiting subjects for bereavement research. The patient described a series of difficulties and symptoms that had begun when her husband became terminally ill and that had persisted during the 8 years since his death. Despite this patient’s claim that “grieving is for other people, not for me,” shortly after her husband’s death she became depressed, with symptoms of low mood, anhedonia, poor sleep, poor appetite, 15-lb. weight loss, low energy, and poor concentration— symptoms for which a psychiatrist treated her with fluoxetine. After several months of taking fluoxetine, the patient’s depressive symptoms remitted. She then discontinued the medication and moved across the country to begin a business venture that seemed promising to her at the time. She used nearly all of the money that her husband had left to her to open this franchise with the expectation that she would become financially successful on her own and would be able to assume the provider role that had formerly been her husband’s. The patient described how the franchise was “taken from” her; she told convincingly of how she had been the victim of fraud. She provided a summation of the loss of her business by stating simply, “They robbed me of everything.” During this particularly stressful and upsetting period for the patient, her problems were compounded when her apartment was robbed. Many of her most valuable and cherished possessions were stolen, including a pearl necklace that her husband had given to her. Because she was having difficulty coping with these anxiety-provoking events, the patient sought help from a psychologist for symptoms of posttraumatic stress disorder (PTSD). The patient received sertraline and an unspecified psychotherapy. Although she experienced some improvement with this combination therapy, she still remained quite symptomatic. With her finances decimated and a lawsuit pending, the patient decided to return to her hometown, where most of her family still resided. Despite a strong wish to be independent and to maintain the role of a competent and giving matriarch who provided for her family, she was forced to “live off their charity.” The dependence and insecurity she felt as a result of her impoverishment both enraged and depressed her. She complained of feeling victimized, bitter, and helpless. Her confidence was shattered, and she felt unable to care for herself, much less provide for others.
Cardiopulmonary exercise testing following bilateral thoracoscopic sympathicolysis in patients with essential hyperhidrosis.
Authors: M Noppen, P Herregodts, P Dendale, J D'Haens, W Vincken
Journal: Thorax (1995)

BACKGROUND--Essential hyperhidrosis is characterised by an overactivity of the sympathetic fibres passing through the upper dorsal sympathetic ganglia D2-D3. Anatomical interruption at the D2-D3 level is a highly effective treatment for essential hyperhidrosis but also causes (partial) cardiac denervation and, after surgical sympathicolysis, important impairment of cardiopulmonary exercise function has been observed. The purpose of this study was to compare the results of cardiopulmonary exercise testing between patients with essential hyperhidrosis and a normal control population, and to examine the effects of thoracoscopic D2-D3 sympathicolysis on cardiopulmonary exercise capacity in patients with essential hyperhidrosis. METHODS--maximal, symptom limited incremental exercise tests were performed in 26 patients with severe essential hyperhidrosis one week before and one month after D2-D3 thoracoscopic sympathicolysis, and in 14 age and sex matched healthy volunteers. D2-D3 thoracoscopic sympathicolysis was performed using a simplified one stage bilateral procedure. RESULTS--Palmar hyperhidrosis was relieved in every patient, confirming the D2-D3 denervation. A higher peak heart rate (7%) was seen in the patient group than in the normal subjects, but ll other cardiovascular, metabolic, and respiratory parameters were similar. After D2-D3 thoracoscopic sympathicolysis, heart rate at rest (13%) and at peak exercise (7%) were reduced, together with an increase in oxygen pulse. All other parameters remained unchanged. CONCLUSIONS--Sympathetic overactivity relevant to cardiovascular function in essential hyperhidrosis is evident only during sympathetic stimulation. D2-D3 thoracoscopic sympathicolysis causes a small and asymptomatic reduction in maximal and resting heart rate and is not associated with a decrease in exercise capacity, in contrast with the detrimental effects on exercise capacity of open surgical sympathectomy.
Observations ON TRENCH NEPHRITIS, ITS LATER STAGES AND TREATMENT
Authors: J. M. Clarke
Journal: BMJ (1917)

THIs paper deals witlh cases of nepliritis in a base hospital, tlle initial stage being over.Allthe patients came frQm France, except about six from Salonica, who showed no special features.The cases were taken in order of admission witlhout selection.Tlley were all under my imme- diate observation, and eighty cases seemed a sufficiently large number to represent the chief features of the disease.The occurrence of neplhritis on the large scale of the present war lhas afforded an opportunity of studying the first attack of the primary disease in young adults, wlich rarely occurs in civil hospitals, because in them the majoritv of cases of nephritis are exacerbations of a pre- existing disease.One wouLld therefore be prepared for possible variations in the ecLrse: and syrmiptoms of the disease from those met witlh in civil practice, and possibly even for a new clinical type of nepliritis, eitlher as the result of the unprecedented physical conditions under wlicll the men were placed and of a diet wlicli mostly' contained a relative exce%s of protein, or as the result of infection by a specific micro-organisna At the stage in wlhiclh these cases were -seen -it--seemed too late to make- it wortlh wlhile to carry out bacteriological investigations.The general result seems to point to a diffLse nepliritis, chiefly affecting tlle convoluted tubules,l focal in distribu- tion in tlle kidney, and presenting a corresponding clinical syndrome with somue special btut no absolutely distinctive features.In view of the youth of, most of-tle patients, it might-be- expected that some cases classed as nepbritis would in reality turn out to be examples of "functional albu- minuria" or " albuminuria of adolescents," but this was not the case, anid, speaking generally, this formu of albuminuria has-hardly been seen at this. hlospital through- out the: war.-Taking the 80 cases admitted to tlhe hospital witih the label "neplhritis," there were only 6 in wllich tlho
Expression Signature Developed from a Complex Series of Mouse Models Accurately Predicts Human Breast Cancer Survival
Authors: Mei He, David P. Mangiameli, Stefan Kachala, Kent Hunter, John Gillespie, Xiaopeng Bian, H.-C. Jennifer Shen, Steven K. Libutti
Journal: Clinical Cancer Research (2009)

The capability of microarray platform to interrogate thousands of genes has led to the development of molecular diagnostic tools for cancer patients. Although large-scale comparative studies on clinical samples are often limited by the access of human tissues, expression profiling databases of various human cancer types are publicly available for researchers. Given that mouse models have been instrumental to our current understanding of cancer progression, we aimed to test the hypothesis that novel gene signatures possessing predictability in clinical outcome can be derived by coupling genomic analyses in mouse models of cancer with publicly available human cancer data sets.We established a complex series of syngeneic metastatic animal models using a murine breast cancer cell line. Tumor RNA was hybridized on Affymetrix MouseGenome-430A2.0 GeneChips. With the use of Venn logic, gene signatures that represent metastatic competency were derived and tested against publicly available human breast and lung cancer data sets.Survival analyses showed that the spontaneous metastasis gene signature was significantly associated with metastasis-free and overall survival (P < 0.0005). Consequently, the six-gene model was determined and showed statistical predictability in predicting survival in breast cancer patients. In addition, the model was able to stratify poor from good prognosis for lung cancer patients in most data sets analyzed.Together, our data support that novel gene signature derived from mouse models of cancer can be used for predicting human cancer outcome. Our approaches set precedence that similar strategies may be used to decipher novel gene signatures for clinical utility.
HDAC2 mediates therapeutic resistance of pancreatic cancer cells via the BH3-only protein NOXA
Authors: P Fritsche, B Seidler, S Schuler, A Schnieke, M Gottlicher, R M Schmid, D Saur, G Schneider
Journal: Gut (2009)

<h3>Background:</h3> Although histone deacetylase inhibitors (HDACi) are promising cancer therapeutics regulating proliferation, differentiation and apoptosis, molecular pathways engaged by specific HDAC isoenzymes in cancer are ill defined. <h3>Results:</h3> In this study we demonstrate that HDAC2 is highly expressed in pancreatic ductal adenocarcinoma (PDAC), especially in undifferentiated tumours. We show that HDAC2, but not HDAC1, confers resistance towards the topoisomerase II inhibitor etoposide in PDAC cells. Correspondingly, the class I selective HDACi valproic acid (VPA) synergises with etoposide to induce apoptosis of PDAC cells. Transcriptome profiling of HDAC2-depleted PDAC cells revealed upregulation of the BH3-only protein NOXA. We show that the epigenetically silenced NOXA gene locus is opened after HDAC2 depletion and that NOXA upregulation is sufficient to sensitise PDAC cells towards etoposide-induced apoptosis. <h3>Conclusions:</h3> In summary, our data characterise a novel molecular mechanism that links the epigenetic regulator HDAC2 to the regulation of the pro-apoptotic BH3-only protein NOXA in PDAC. Targeting HDAC2 will therefore be a promising strategy to overcome therapeutic resistance of PDAC against chemotherapeutics that induce DNA damage.
Steroids Produced in Vitro by Adrenal Glands of Normal and Arteriosclerotic Rats During and After Drug-Induced Myocardial Necrosis
Authors: BERNARD C. WEXLER, GEORGE W. KITTINGER, Joan E. Schreiber
Journal: Circulation Research (1965)

The subcutaneous injection of the potent catecholamine, isoproterenol, on two consecutive days causes active and massive myocardial necrosis in rats. Infarctoid myocardial necrosis was produced in male and female virgin rats free of arterial disease, in male breeder rats which have microscopic arteriosclerosis only, and in female breeder rats having early or advanced gross arteriosclerosis. During the active development of myocardial necrosis and heart failure, an apparent shift in distribution of body fluid produced systemic dehydration, pulmonary edema, and hydrothorax. Animals which survived the myocardial destruction showed gradual reduction of the congestive heart failure and beginning myocardial repair. Virgin animals with no pre-existing arterial disease developed more severe signs of shock and congestive heart failure than breeder rats with pre-existing arteriosclerosis. In vitro estimation of the adrenal steroids produced by the animals with myocardial necrosis indicated intense in vivo stimulation of adrenocorticoid production coincident with the increasing severity of the myocardial necrosis. Steroid production returned to normal during progressive myocardial repair. Virgin rats showed a very prompt adrenal response to the stress of myocardial destruction but breeder rats, which also have pre-existing reduced adrenal function, showed a lag in the response of their adrenal glands. Chemical and histological analyses of the adrenal glands indicated a pronounced increase of aldoster-one production during the experiment, this increase being associated with loss of fluid and electrolytes from the vascular space. The production of aldosterone appears to be vital to the physiological adjustments needed by these animals during heart failure because the production of aldosterone seems to occur at the expense of the other adrenal steroids, e.g., corticosterone, 18-hydroxy-deoxycorticoster-one and total steroid. These comparative studies suggest that adrenal responsiveness during the stress of myocardial infarctoid necrosis is quantitatively different in animals free of previous arterial disease from that found in animals with pre-existing microscopic or grossly visible arteriosclerosis. The specific kind and the amount of adrenal steroid produced during myocardial destruction may be of vital importance for survival.
Kinase-Inactive Glycogen Synthase Kinase 3β Promotes Wnt Signaling and Mammary Tumorigenesis
Authors: Marganit Farago, Isabel Dominguez, Esther Landesman-Bollag, Xin Xu, Andrea Rosner, Robert D. Cardiff, David C. Seldin
Journal: Cancer Research (2005)

Abstract Recent studies have implicated ectopic activation of the Wnt pathway in many human cancers, including breast cancer. β-catenin is a critical coactivator in this signaling pathway and is regulated in a complex fashion by phosphorylation, degradation, and nuclear translocation. Glycogen synthase kinase 3β (GSK3β) phosphorylation of the NH2-terminal domain of β-catenin targets it for ubiquitination and proteosomal degradation. We hypothesized that expression of kinase-inactive GSK3β (KI-GSK3β) in mammary glands would function in a dominant-negative fashion by antagonizing the endogenous activity of GSK3β and promoting breast cancer development. Consistent with this, we find that KI-GSK3β stabilizes β-catenin expression, catalyzes its localization to the nucleus, and up-regulates the downstream target gene, cyclin D1, in vitro. In vivo, transgenic mice overexpressing the KI-GSK3β under the control of the mouse mammary tumor virus-long terminal repeat develop mammary tumors with overexpression of β-catenin and cyclin D1. Thus, antagonism of GSK3β activity is oncogenic in the mammary epithelium; mutation or pharmacologic down-regulation of GSK3β could promote mammary tumors.
Lymphocytotoxic antibody is a predictor of response to random donor platelet transfusion
Authors: Donna E. Hogge, Janice P. Dutcher, Joseph Aisner, Charles A. Schiffer
Journal: American Journal of Hematology (1983)

Abstract The transfusion records of 189 patients with acute leukemia were analyzed to correlate lymphocytotoxic antibody (LCTAb) levels with response to a series of random‐donor platelet transfusions (Tx). Twenty‐one patients were studied twice at times of different LCTAb levels. All transfusions were given when patients were clinically stable without disseminated intravascular coagulation, bleeding, temperature &gt; 101°F, or splenomegaly. The mean 1‐hr and 24‐hr corrected count increments (CCI) for all patients with negative LCTAb were 16,100 and 12,000, and values for patients with positive LCTAb were 5,600 and 2,600 (P &lt; 0.0005). Thirteen patients had intermediate LCTAb (10–20%) and a variable response to Tx. Of the 137 patients with negative LCTAb levels 106 (77%) had good mean CCI of &gt; 10,000 at 1 hr and &gt; 7,500 at 24 hr following transfusion. In contrast of 60 patients with positive LCTAb (&gt; 20% cytotoxicity), 53 (88%) had poor CCI of &lt; 10,000 at 1 hr and &lt; 7,500 at 24 hr after transfusion. Only 4 patients with positive LCTAb had a good response to random donor platelets at both 1 and 24 hrs. Eighteen patients had negative LCTAb with a high 1‐hr and low 24‐hr CCI. Thirteen of these had a history of positive LCTAb and in 9 there was an anamnestic rise following transfusion. Nine of 137 patients had negative LCTAb with low 1‐hr and 24‐hr CCI. LCTAb is highly predictive of response to random donor platelets. Cytotoxicity to &gt; 20% of tested lymphocytes virtually precludes a good CCI at 1 and 24 hr.