tbuckley/cabot-search huggingface dataset:
Regulation of the Subcellular Localization of Tumor Necrosis Factor Receptor–associated Factor (TRAF)2 by TRAF1 Reveals Mechanisms of TRAF2 Signaling
Authors: Joseph R. Arron, Yael Pewzner-Jung, Matthew C. Walsh, Takashi Kobayashi, Yongwon Choi
Journal: The Journal of Experimental Medicine (2002)

Tumor necrosis factor receptor–associated factor (TRAF)2 is a critical adaptor molecule for tumor necrosis factor (TNF) receptors in inflammatory and immune signaling. Upon receptor engagement, TRAF2 is recruited to CD40 and translocates to lipid rafts in a RING finger-dependent process, which enables the activation of downstream signaling cascades including c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-κB. Although TRAF1 can displace TRAF2 and CD40 from raft fractions, it promotes the ability of TRAF2 activate signaling over a sustained period of time. Removal of the RING finger of TRAF2 prevents its translocation into detergent-insoluble complexes and renders it dominant negative for signaling. TRAF1−/− dendritic cells show attenuated responses to secondary stimulation by TRAF2-dependent factors and increased stimulus-dependent TRAF2 degradation. Replacement of the RING finger of TRAF2 with a raft-targeting signal restores JNK activation and association with the cyto-skeletal protein Filamin, but not NF-κB activation. These findings offer insights into the mechanism of TRAF2 signaling and identify a physiological role for TRAF1 as a regulator of the subcellular localization of TRAF2.
PERSONALITIES OF AMERICAN PSYCHOTHERAPISTS
Authors: MARGARET C.-L. GILDEA, EDWIN F. GILDEA
Journal: American Journal of Psychiatry (1945)

Many similarities in the development and characters of these men are evident. All were striking in appearance and unusually able through force and charm of personality to make immediate favorable contacts with people. All started life with roots in medical tradition, since all came from medical families. All were burdened by an extreme degree of responsibility beginning early and all through life. All were very sensitive and reactive. In fact the decision to work with medical, neurological and mental patients arose in part in each man as a reaction against blood and suffering, intense enough to cause each of them to veer away from the surgical approach. Each had a period of forced inactivity due to illness when he was in the very impressionable period between adolescence and young manhood. That this illness was in each case tuberculosis may have been accidental, but it is probably not accidental that this period of forced introversion brought with it the change in point of view that resulted in an intense interest in healing the mentally ill. This trend in their professional development probably sprung from a cognizance forced on them in their inactivity of mental problems in themselves. They were vigorous men capable of very hard work. But they also suffered long spells of illness and fatigue or depletion. With Mitchell we have seen that he had depressed and fatigued periods at least three times in his life and probably a great many more times to a lesser degree. Dr. Salmon was subjected to migraine headaches, and also had some episodes of depression of mood, especially during his tuberculosis cure and toward the end of his life. Dr. Riggs suffered from recurrent attacks of a tubercular condition and went through periods of fatigue and feelings of frustration and exasperation both with his bodily health and with the work he was doing. All three of these men found great relaxation and pleasure in the woods and country, and especially the water. Riggs and Salmon were enthusiastic yachtsmen. Mitchell was an ardent fisherman. All three were endowed with a high degree of controlled and directed extroversion. All had extraordinary vitality, intensity and conviction and all had great ability to focus their attention on the problem at hand, whether it was playing the traps, worrying over the problem of snake venom, struggling with a road in France or reconstructing a patient. All were strongly emphatic, were particularly able to feel into and through the problems of their patients. This talent was made effective by the ability to verbalize and by an understanding of forceful emphatic communication which enable them to express their understanding in an arresting and dramatic manner.
MicroRNA gene expression profile of hepatitis C virus-associated hepatocellular carcinoma
Authors: Heike Varnholt, Uta Drebber, Falko Schulze, Inga Wedemeyer, Peter Schirmacher, Hans‐Peter Dienes, Margarete Odenthal
Journal: Hepatology (2008)

MicroRNAs are small noncoding RNAs that regulate gene expression by targeting messenger RNAs (mRNAs) through translational repression or RNA degradation. Many fundamental biological processes are modulated by microRNAs, and an important role for microRNAs in carcinogenesis is emerging. Because understanding the pathogenesis of viral-associated hepatocellular carcinomas is important in developing effective means of classification, prognosis, and therapy, we examined the microRNA expression profiles in a large set of 52 human primary liver tumors consisting of premalignant dysplastic liver nodules and hepatocellular carcinomas by quantitative real-time polymerase chain reaction. All patients were infected with hepatitis C, and most had liver cirrhosis. Initially, the accessibility of microRNAs from formalin-fixed paraffin-embedded archival liver tissue by real-time polymerase chain reaction assays was shown. Subsequently, target parenchyma from routinely processed tissue was macrodissected, RNA was extracted, and reverse transcription followed by quantitative real-time polymerase chain reaction was performed. Relative quantification was performed by the 2−ΔΔCt method with normal livers as a calibrator. In order to obtain a comprehensive microRNA gene expression profile, 80 microRNAs were examined in a subset of tumors, which yielded 10 up-regulated and 19 down-regulated microRNAs compared to normal liver. Subsequently, five microRNAs (miR-122, miR-100, miR-10a, miR-198, and miR-145) were selected on the basis of the initial results and further examined in an extended tumor sample set of 43 hepatocellular carcinomas and 9 dysplastic nodules. miR-122, miR-100, and miR-10a were overexpressed whereas miR-198 and miR-145 were up to 5-fold down-regulated in hepatic tumors compared to normal liver parenchyma. Conclusion: A subset of microRNAs are aberrantly expressed in primary liver tumors, serving both as putative tumor suppressors and as oncogenic regulators. (HEPATOLOGY 2008.)
Pharmaceutical development of a liquid formulation for pulmonary application of a peptide
Authors: Hendrik Fischer, Rudolf Lucas, Helmut Pietschmann, Susan Tzotzos, Bernhard Fischer
Journal: European Respiratory Journal (2012)

ALI/ARDS are acute and severe conditions with mortality up to 50%. Currently, no specific drug-related treatment exists. ALI/ARDS are characterized by pulmonary oedema due to increased permeability of the endothelial/epithelial barrier. Oedema clearance is linked to Na uptake at the apical side of Type I/II alveolar cells through the amiloride-sensitive epithelial sodium channel “ENaC”. AP301, a synthetic peptide derived from the lectin-like domain of TNFα, enhances Na transport through ENaC and thus oedema clearance. As ENaC is located at the inner surface of alveoli, the water soluble AP301 is administered by inhalation of a nebulised aqueous solution. Hence, pharmaceutical development of AP301 as potent new drug for oedema resolution differs from standard orally or parenterally applied medicine and has to follow specific pharmaceutical and medicinal regulations of the Pharmacopoeia and inhalation medicine guidelines. AP301 is nebulised by a mesh-type not a jet or supersonic type nebulizer due to simplicity and effective, but gentle aerosol generation. In order to reach the alveoli the particle size of the aerosol was optimized to
Reply to M.C. Garassino et al
Authors: Giuseppe Giaccone, Sarah Temin, Vicki Leigh Keedy
Journal: Journal of Clinical Oncology (2011)

The question raised by Garassino et al whether chemotherapy should be preferred in patients with epidermal growth factor receptor (EGFR) wild-type non–small-cell lung cancer (NSCLC) is relevant, given that approximately 85% to 90% of patients belong in this category in the western world. Interestingly, gefitinib is registered in Europe only for patients with mutant EGFR NSCLC, whereas erlotinib is registered for patients with NSCLC regardless of mutation status in both Europe and United States. There is little data in support of EGFR tyrosine kinase inhibitors (TKIs) being given to patients with wildtype EGFR and some evidence that there is actually a detriment in comparison with chemotherapy in the first-line setting. There is a need to assess the value, if any, of using an EGFR TKI in any line of treatment of NSCLC in patients with wild-type EGFR. Patients with wild-type EGFR include patients whose tumor is KRAS mutant, a setting in which EGFR TKIs are essentially inactive, if not detrimental. Although it is clear that EGFR TKIs improve progression-free survival in the first-line treatment of patients with mutant EGFR, on the basis of several randomized comparisons, as delineated in the recently published American Society of Clinical Oncology provisional clinical opinion, there are insufficient data in subsequent lines of treatment. Garassino et al are to be commended, as they are in fact currently conducting a prospective randomized study in second-line treatment of advanced NSCLC, in which patients with wild-type EGFR are being randomly assigned to receive docetaxel or erlotinib (NCT00637910; Tarceva Italian Lung Optimization Trial [TAILOR] study). EGFR mutation status for patients in whom treatment has failed is often based on archival tissue available from the diagnostic specimen. Because the mutational status may change under the pressure of systemic treatment and lead to resistance, the data obtained with pretreatment archival material may not be reliable. Although there may be differences among EGFR TKIs in terms of activity on wild-type EGFR cells, these differences are trivial in comparison with presence versus absence of EGFR-activating mutations. Treating patients with advanced NSCLC with EGFR TKIs in the absence of EGFR mutation testing or in wild-type EGFR is questionable and needs to be studied more. Fortunately, we are finally in an era in the treatment of patients with NSCLC when we have TKIs that are exquisitely active in specific subsets of patients. The availability of drugs on the market that hardly have an impact on survival but may have substantial toxicity should not be a reason to treat all unselected patients until the end of their lives.
Amino acid sequence versus morphological data and the interordinal relationships of mammals.
Authors: A R Wyss, M J Novacek, M C McKenna
Journal: Molecular Biology and Evolution (1987)

To a large extent, the mutual affinities of the mammalian orders continue to puzzle systematists, even though comparative anatomy and amino acid sequencing offer a massive data base from which these relationships could potentially be adduced. In the present paper the consistency index--the number of character states less the number of characters in a data set, divided by the total number of changes in the character states on a cladogram--was used to examine the relative resolving powers of recently published morphological and molecular-sequence data. Consistency indices were calculated for previously published alpha crystallin A chain and myoglobin amino acid-sequence cladograms and for four original amino acid-sequence cladograms (alpha crystallin A, myoglobin, and alpha and beta hemoglobin); these were found to be comparable to the consistency indices of morphologically based cladograms. Qualitative comparisons between the morphologically based and molecularly based trees were also made; only moderate congruence between the two was observed. Moreover, there was a general lack of congruence between the cladograms specified by each of the four proteins. Amino acid-sequence and morphological data agreed on the placement of edentates as an early eutherian offshoot and on the grouping of hyracoids, proboscideans, and sirenians. Otherwise there was only limited congruence: morphology strongly supported the grouping of lagomorphs and rodents and the alliance of pholidotes and edentates, but sequence analyses did not. The placement of tubulidentates differed widely among proteins. Morphology indicated the close association of sirenians with proboscideans; proteins suggested a pairing of sirenians with hyracoids. Sequence data did not identify many (morphologically well-diagnosed) orders as monophyletic (e.g., Lagomorpha).(ABSTRACT TRUNCATED AT 250 WORDS)
Migration of bovine aortic smooth muscle cells after wounding injury. The role of hyaluronan and RHAMM.
Authors: R C Savani, C Wang, B Yang, S Zhang, M G Kinsella, T N Wight, R Stern, D M Nance, E A Turley
Journal: Journal of Clinical Investigation (1995)

The migration of smooth muscle cells is a critical event in the pathogenesis of vascular diseases. We have investigated the role of hyaluronan (HA) and the hyaluronan receptor RHAMM in the migration of adult bovine aortic smooth muscle cells (BASMC). Cultured BASMC migrated from the leading edge of a single scratch wound with increased velocity between 1 and 24 h. Polyclonal anti-RHAMM antisera that block HA binding with this receptor abolished smooth muscle cell migration following injury. HA stimulated the random locomotion of BASMC and its association with the cell monolayer increased following wounding injury. Immunoblot analysis of wounded monolayers demonstrated a novel RHAMM protein isoform that appeared within one hour after injury. At the time of increased cell motility after wounding, FACS analysis demonstrated an increase in the membrane localization in approximately 25% of the cell population. Confocal microscopy of injured monolayers confirmed that membrane expression of this receptor was limited to cells at the wound edge. Collectively, these data demonstrate that RHAMM is necessary for the migration of smooth muscle cells and that expression and distribution of this receptor is tightly regulated following wounding of BASMC monolayers.
Fixed Sulphonamide Eruption Simulating Early Syphilis
Authors: J. O. Doyle
Journal: BMJ (1954)

ACHLORHYDRIC ANAEMIAand my colleagues at the German Hospital and their corre- spondents for being able to use this material.November, 1936.-Thepatient was queer in the head and very forgetful (out-patient department).Complete achylia even after histamine.February, 1937.-Out-patient at Maudsley Hospital.Summer, 1942.-Still had unreality feelings (face); tongue protruded slightly to right; right plantar reflexes doubtful; spleen moderately enlarged; question of " splenic anaemia ; sternal puncture said to show a typical megaloblastic picture; C.I. usually against Addisonian anaemia.October, 1942.-Dr.Wyburn-Mason, at the National Hos- pital, Queen Square, found no definitely abnormal -physical signs in the central nervous system.The right plantar reflex was not so definitely flexor as the left, but there was no doubt that it was flexor.The only other finding was a left supinator jerk which was perhaps brisker than the right.Dr. Wyburn-Mason thought that at that time there were no definite signs of neurological disease and suggested that the mental symptoms were either connected with the anaemia or were hysterical.1942 to June, 1946.-Thepatient was treated as an out- patient and on several occasions as an in-patient for his anaemia, but on many occasions he complained of heavi- ness, etc., in his head.June to A ugust, 1946.-In-patient at Roffey Park Re- habilitation Centre.On his discharge the medical officer reported to the German Hospital that it had become apparent, during the patient's stay there, that he was suffer- ing from a paranoid schizophrenic illness.He had under- gone a course of electrical treatment which had iniproved the depressive symptoms.1946 to A pril, 1952.-Thepatient continued to attend the medical out-patient department.His anaemia appeared to remain controlled on "anahaemin" injections, 2 ml.; which towards the end of this period were given once a month.Blood count (June 1, 1950): haemoglobin, 80%; erythro-
Increased Ectonucleotidase Expression and Activity in Regulatory T Cells of Patients with Head and Neck Cancer
Authors: Magis Mandapathil, Miroslaw J. Szczepanski, Marta Szajnik, Jin Ren, Diana E. Lenzner, Edwin K. Jackson, Elieser Gorelik, Stephan Lang, Jonas T. Johnson, Theresa L. Whiteside
Journal: Clinical Cancer Research (2009)

Regulatory T cell (Treg) frequency and activity are increased in cancer patients and play a major role in tumor escape. Although disease progression is favored by the presence of Treg, mechanisms used by Treg to suppress antitumor immunity are unknown. The ectonucleotidases CD39 and CD73 are expressed in Treg and convert ATP into immunosuppressive adenosine. In this study, the involvement of the adenosinergic pathway in Treg-mediated suppression in head and neck squamous cell carcinoma (HNSCC) patients was evaluated.HNSCC patients with an active disease (n = 19) and patients with no evident disease after therapy (n = 14) were studied. Ectonucleotidase expression on CD4(+) T cells and CD4(+)CD25(high) Treg was evaluated by flow cytometry and compared with normal controls. Ectonucleotidase activity was also compared within these three groups. The data were analyzed for associations of ectonucleotidase expression/function with disease stage.The percentages and expression levels of CD39 and CD73 in CD4(+) T cells and Treg were greater in HNSCC than in normal controls and highest in patients with no evident disease. Patients' Treg hydrolyzed ATP at higher rates and produced higher levels of adenosine than normal controls' Treg. The increased frequency and enzymatic activity of CD4(+)CD39(+) cells corresponded to increased adenosine-mediated suppression of effector T cells, which was partly inhibited by ARL67156, an ectonucleotidase inhibitor, and by ZM241385, a selective A(2a)/A(2b) receptor antagonist.CD39(+) Treg frequency and adenosine-mediated suppression are significantly increased in HNSCC patients. The adenosinergic pathway is involved in Treg-mediated immunosuppression in cancer and its attenuation could be a promising immunotherapeutic strategy for patients with HNSCC.
The new microbiology of cystic fibrosis: it takes a community
Authors: John LiPuma
Journal: Thorax (2012)

For the past 40 years, the approach to studying infections in the airways of persons with cystic fibrosis (CF) has largely parallelled that taken in the study of other human infectious diseases. A microorganism (the causative agent) recovered in culture from an infected site is studied in isolation using a variety of in vitro and in vivo models intended to approximate some facet of the human infection. Although this strategy has yielded a wealth of information regarding microbial virulence factors and pathogenic mechanisms for many human infections, its limitations, when applied to the chronic, polymicrobial infections that typify CF, are becoming increasingly obvious. We now appreciate that respiratory tract infection in CF most often involves diverse communities of opportunistic bacterial species that are well adapted to the peculiarities of this niche. We have, furthermore, come to understand that species within this community are not merely living unaffected by their microbial neighbours, but rather, are actively engaged with each other. And we are steadily decoding the rules and mechanisms that govern this microbial concert.

Given this expanding understanding of infection in CF, it seems reasonable to shift our attention towards a conceptual framework that considers the airway microbial community as the ‘pathogenic unit.’ Adoption of this framework leads to several relevant but unanswered questions. How are these communities structured? Are they relatively static or dynamic? Are changes in the community stochastic or canonical? What drives changes in community structure, and how do these …
AIB1:ERα Transcriptional Activity Is Selectively Enhanced in Aromatase Inhibitor–Resistant Breast Cancer Cells
Authors: Jane O'Hara, Damir Vareslija, Jean McBryan, Fiona Bane, Paul Tibbitts, Christopher Byrne, Ronán M. Conroy, Yuan Hao, Peadar Ó Gaora, Arnold D.K. Hill, Marie McIlroy, Leonie S. Young
Journal: Clinical Cancer Research (2012)

The use of aromatase inhibitors (AI) in the treatment of estrogen receptor (ER)-positive, postmenopausal breast cancer has proven efficacy. However, inappropriate activation of ER target genes has been implicated in the development of resistant tumors. The ER coactivator protein AIB1 has previously been associated with initiation of breast cancer and resistance to endocrine therapy.Here, we investigated the role of AIB1 in the deregulation of ER target genes occurring as a consequence of AI resistance using tissue microarrays of patients with breast cancer and cell line models of resistance to the AI letrozole.Expression of AIB1 associated with disease recurrence (P = 0.025) and reduced disease-free survival time (P = 0.0471) in patients treated with an AI as first-line therapy. In a cell line model of resistance to letrozole (LetR), we found ERα/AIB1 promoter recruitment and subsequent expression of the classic ER target genes pS2 and Myc to be constitutively upregulated in the presence of both androstenedione and letrozole. In contrast, the recruitment of the ERα/AIB1 transcriptional complex to the nonclassic ER target cyclin D1 and its subsequent expression remained sensitive to steroid treatment and could be inhibited by treatment with letrozole. Molecular studies revealed that this may be due in part to direct steroid regulation of c-jun-NH(2)-kinase (JNK), signaling to Jun and Fos at the cyclin D1 promoter.This study establishes a role for AIB1 in AI-resistant breast cancer and describes a new mechanism of ERα/AIB1 gene regulation which could contribute to the development of an aggressive tumor phenotype.
Lentiviral vector integration in the human genome induces alternative splicing and generates aberrant transcripts
Authors: Arianna Moiani, Ylenia Paleari, Daniela Sartori, Riccardo Mezzadra, Annarita Miccio, Claudia Cattoglio, Fabienne Cocchiarella, Maria Rosa Lidonnici, Giuliana Ferrari, Fulvio Mavilio
Journal: Journal of Clinical Investigation (2012)

Retroviral vectors integrate in genes and regulatory elements and may cause transcriptional deregulation of gene expression in target cells. Integration into transcribed genes also has the potential to deregulate gene expression at the posttranscriptional level by interfering with splicing and polyadenylation of primary transcripts. To examine the impact of retroviral vector integration on transcript splicing, we transduced primary human cells or cultured cells with HIV-derived vectors carrying a reporter gene or a human β-globin gene under the control of a reduced-size locus-control region (LCR). Cells were randomly cloned and integration sites were determined in individual clones. We identified aberrantly spliced, chimeric transcripts in more than half of the targeted genes in all cell types. Chimeric transcripts were generated through the use of constitutive and cryptic splice sites in the HIV 5ι long terminal repeat and gag gene as well as in the β-globin gene and LCR. Compared with constitutively spliced transcripts, most aberrant transcripts accumulated at a low level, at least in part as a consequence of nonsense-mediated mRNA degradation. A limited set of cryptic splice sites caused the majority of aberrant splicing events, providing a strategy for recoding lentiviral vector backbones and transgenes to reduce their potential posttranscriptional genotoxicity.