tbuckley/cabot-search huggingface dataset:
Cisplatin Mimics ARF Tumor Suppressor Regulation of RelA (p65) Nuclear Factor-κB Transactivation
Authors: Kirsteen J. Campbell, James M. Witty, Sonia Rocha, Neil D. Perkins
Journal: Cancer Research (2006)

Abstract The RelA (p65) nuclear factor-κB (NF-κB) subunit can contribute towards tumor cell survival through inducing the expression of a variety of antiapoptotic genes. However, the NF-κB response can show great diversity and is not always antiapoptotic. Here, we find that cisplatin, a DNA cross-linking agent and commonly used anticancer compound, does not affect RelA nuclear translocation but modulates its transcriptional activity. Similar to other genotoxic agents, such as daunorubicin and UV light, cisplatin treatment in the U-2 OS osteosarcoma cell line represses RelA activity and inhibits expression of the NF-κB antiapoptotic target gene Bcl-xL. The mechanism through which cisplatin achieves these effects is different to daunorubicin and UV light but shows great similarity to the RelA regulatory pathway induced by the ARF tumor suppressor: cisplatin regulation of RelA requires ATR/Chk1 activity, represses Bcl-xL but not XIAP expression, and results in phosphorylation of RelA at Thr505. In contrast to these results, another chemotherapeutic drug etoposide activates NF-κB and induces expression of these target genes. Thus, within a single tumor cell line, there is great heterogeneity in the NF-κB response to different, commonly used chemotherapeutic drugs. These observations suggest that it might be possible to minimize the ability of RelA to inhibit cancer therapy by diagnostically predicting the type of chemotherapeutic drug most compatible with NF-κB functionality in a tumor cell type. Moreover, our data indicate that at least with respect to RelA, cisplatin functions as an ARF mimic. Other drugs capable of mimicking this aspect of ARF function might therefore have therapeutic potential. (Cancer Res 2006; 66(2): 929-35)
Why don't chimps talk and humans sing like canaries?
Authors: Sverker Johansson, Jordan Zlatev, Peter Gärdenfors
Journal: Behavioral and Brain Sciences (2006)

We focus on two problems with the evolutionary scenario proposed: (1) It bypasses the question of the origins of the communicative and semiotic features that make language distinct from, say, pleasant but meaningless sounds. (2) It does little to explain the absence of language in, for example, chimpanzees: Most of the selection pressures invoked apply just as strongly to chimps. We suggest how these problems could possibly be amended.
HLA-derived peptides which inhibit T cell function bind to members of the heat-shock protein 70 family.
Authors: E Nossner, J E Goldberg, C Naftzger, S C Lyu, C Clayberger, A M Krensky
Journal: The Journal of Experimental Medicine (1996)

Synthetic peptides corresponding to sequences of HLA class I molecules have inhibitory effects on T cell function. The peptides investigated in this study have sequences corresponding to the relatively conserved region of the alpha 1 helix of HLA class I molecules that overlaps the "public epitope" Bw4/Bw6. These HLA-derived peptides exhibit inhibitory effects on T lymphocytes and have beneficial effects on the survival of allogenic organ transplants in mice and rats. Peptides corresponding to the Bw4a epitope appear most potent as they inhibit the differentiation of T cell precursors into mature cytotoxic T lymphocytes (CTL) and target cell lysis by established CTL lines and clones. To elucidate the mechanism through which these peptides mediate their inhibitory effect on T lymphocytes, peptide binding proteins were isolated from T cell lysates. We show that the inhibitory Bw4a peptide binds two members of the heat-shock protein (HSP) 70 family, constitutively expressed HSC70 and heat-inducible HSP70. Peptide binding to HSC/HSP70 is sequence specific and follows the rules defined by the HSC70 binding motif. Most intriguing, however, is the strict correlation of peptide binding to HSC/HSP70 and the functional effects such that only inhibitory peptides bind to HSC70 and HSP70 whereas noninhibitory peptides do not bind. This correlation suggests that small molecular weight HLA-derived peptides may modulate T cell responses by directly interacting with HSPs. In contrast to numerous reports of HSP70 expression at the surface of antigen-presenting cells and some tumor cells, we find no evidence that HSC/HSP70 are expressed at the surface of the affected T cells. Therefore, we believe that the peptides' immunodulatory effects are not mediated through a signaling event initiated by interaction of peptide with surface HSP, but favor a model similar to the action of other immunomodulatory compounds, FK506 and cyclosporin A, with a role for HSC/HSP70 similar to that for immunophilins, FKBPs and CyP40.
External Beam Radiation of Tumors Alters Phenotype of Tumor Cells to Render Them Susceptible to Vaccine-Mediated T-Cell Killing
Authors: Mala Chakraborty, Scott I. Abrams, C. Norman Coleman, Kevin Camphausen, Jeffrey Schlom, James W. Hodge
Journal: Cancer Research (2004)

Local radiation is an established therapy for human tumors. Radiation also has been shown to alter the phenotype of target tissue, including gene products that may make tumor cells more susceptible to T-cell-mediated immune attack. We demonstrate a biological synergy between local radiation of tumor and active vaccine therapy. The model used consisted of mice transgenic for human carcinoembryonic antigen (CEA) and a murine carcinoma cell line transfected with CEA. The vaccine regimen consisted of a prime and boost strategy using vaccinia and avipox recombinants expressing CEA and three T-cell costimulatory molecules. One dose of 8-Gy radiation to tumor induced up-regulation of the death receptor Fas in situ for up to 11 days. However, neither radiation at this dose nor vaccine therapy was capable of inhibiting growth of 8-day established tumor. When vaccine therapy and local radiation of tumor were used in combination, dramatic and significant cures were achieved. This was mediated by the engagement of the Fas/Fas ligand pathway because Ag-bearing tumor cells expressing dominant-negative Fas were not susceptible to this combination therapy. Following the combination of vaccine and local radiation, tumors demonstrated a massive infiltration of T cells not seen with either modality alone. Mice cured of tumors demonstrated CD4(+) and CD8(+) T-cell responses specific for CEA but also revealed the induction of high levels of T-cell responses to two other antigens (gp70 and p53) overexpressed in tumor, indicating the presence of a consequential antigen cascade. Thus, these studies demonstrate a new paradigm for the use of local tumor irradiation in combination with active specific vaccine therapy to elicit durable antitumor responses of established tumors.
Evolution of eutherian cytochrome c oxidase subunit II: heterogeneous rates of protein evolution and altered interaction with cytochrome c
Authors: R. M. Adkins, R. L. Honeycutt, T. R. Disotell
Journal: Molecular Biology and Evolution (1996)

Cytochrome c oxidase subunit II (COII), encoded by the mitochondrial genome, exhibits one of the most heterogeneous rates of amino acid replacement among placental mammals. Moreover, it has been demonstrated that cytochrome c oxidase has undergone a structural change in higher primates which has altered its physical interaction with cytochrome c. We collected a large data set of COII sequences from several orders of mammals with emphasis on primates, rodents, and artiodactyls. Using phylogenetic hypotheses based on data independent of the COII gene, we demonstrated that an increased number of amino acid replacements are concentrated among higher primates. Incorporating approximate divergence dates derived from the fossil record, we find that most of the change occurred independently along the New World monkey lineage and in a rapid burst before apes and Old World monkeys diverged. There is some evidence that Old World monkeys have undergone a faster rate of nonsynonymous substitution than have apes. Rates of substitution at four-fold degenerate sites in primates are relatively homogeneous, indicating that the rate heterogeneity is restricted to nondegenerate sites. Excluding the rate acceleration mentioned above, primates, rodents, and artiodactyls have remarkably similar nonsynonymous replacement rates. A different pattern is observed for transversions at four-fold degenerate sites, for which rodents exhibit a higher rate of replacement than do primates and artiodactyls. Finally, we hypothesize specific amino acid replacements which may account for much of the structural difference in cytochrome c oxidase between higher primates and other mammals.
A proinflammatory peptide from Helicobacter pylori activates monocytes to induce lymphocyte dysfunction and apoptosis
Authors: Åsa Betten, Johan Bylund, Thierry Cristophe, François Boulay, Ana Romero, Kristoffer Hellstrand, Claes Dahlgren
Journal: Journal of Clinical Investigation (2001)

Infection with Helicobacter pylori causes chronic gastritis, which is characterized by a dense mucosal infiltration by inflammatory cells such as monocytes/macrophages. H. pylori–induced inflammation is a risk factor for the development of gastric adenocarcinoma, but the mechanisms involved in H. pylori–associated carcinogenesis are poorly understood. A cecropin-like H. pylori peptide, Hp(2-20), was found to be a monocyte chemoattractant and activated the monocyte NADPH-oxidase to produce oxygen radicals. The receptors mediating monocyte activation were identified as FPRL1 and the monocyte-specific orphan receptor FPRL2. Hp(2-20)–activated monocytes inhibited lymphocytes with antitumor properties, such as CD56+ natural killer (NK) cells and CD3ε+ T cells. The changes observed in NK cells and T cells — a reduced antitumor cytotoxicity, downregulation of CD3ζ expression, and apoptosis — were mediated by Hp(2-20)–induced oxygen radicals. Histamine, a gastric mucosal constituent, rescued NK cells and T cells from inhibition and apoptosis by suppressing Hp(2-20)–induced oxygen radical formation. We conclude that H. pylori expression of this monocyte-activating peptide contributes to its ability to attract and activate monocytes and reduces the function and viability of antineoplastic lymphocytes. These novel mechanisms may be subject to local, histaminergic regulation in the gastric mucosa.
Macrophages eliminate circulating tumor cells after monoclonal antibody therapy
Authors: Nuray Gül, Liane Babes, Kerstin Siegmund, Rianne Korthouwer, Marijn Bögels, Rens Braster, Gestur Vidarsson, Timo L.M. ten Hagen, Paul Kubes, Marjolein van Egmond
Journal: Journal of Clinical Investigation (2014)

The use of monoclonal antibodies (mAbs) as therapeutic tools has increased dramatically in the last decade and is now one of the mainstream strategies to treat cancer. Nonetheless, it is still not completely understood how mAbs mediate tumor cell elimination or the effector cells that are involved. Using intravital microscopy, we found that antibody-dependent phagocytosis (ADPh) by macrophages is a prominent mechanism for removal of tumor cells from the circulation in a murine tumor cell opsonization model. Tumor cells were rapidly recognized and arrested by liver macrophages (Kupffer cells). In the absence of mAbs, Kupffer cells sampled tumor cells; however, this sampling was not sufficient for elimination. By contrast, antitumor mAb treatment resulted in rapid phagocytosis of tumor cells by Kupffer cells that was dependent on the high-affinity IgG-binding Fc receptor (FcγRI) and the low-affinity IgG-binding Fc receptor (FcγRIV). Uptake and intracellular degradation were independent of reactive oxygen or nitrogen species production. Importantly, ADPh prevented the development of liver metastases. Tumor cell capture and therapeutic efficacy were lost after Kupffer cell depletion. Our data indicate that macrophages play a prominent role in mAb-mediated eradication of tumor cells. These findings may help to optimize mAb therapeutic strategies for patients with cancer by helping us to aim to enhance macrophage recruitment and activity.
How living wills can help doctors and patients talk about dying
Authors: L. Emanuel
Journal: BMJ (2000)

Papers p 1640 

Many people are unaware of living wills but are highly interested once they hear about them. In this week's BMJ Schiff et al (p 1640) find that elderly inpatients are confused by the term living will, but most would welcome the chance to discuss issues about facing the end of life, and many would want to limit their health care if they were terminally ill.1 An assessment of the understanding of living wills in the United States some time ago found a similar state of affairs.2 This juxtaposition of ignorance and interest raises an important question: what is this apparent appetite to discuss and prepare for dying?

When lawyer Louis Kutner proposed the notion of a living will in 1969, he was responding to the fear that technology was driving doctors to impose life sustaining treatment on patients who might not want it. The living will was seen as a simple device to allow patients to say no, even if they were too ill to …
Transcriptional regulation of the Vascular Endothelial Growth Factor gene?a concert of activating factors
Authors: G PAGES, J POUYSSEGUR
Journal: Cardiovascular Research (2004)

The vascular endothelial growth factor A (VEGF-A) is essential during embryonic development as inactivation of only one allele of its gene results in embryonic lethality. Up-regulation of VEGF under physiological situations allows for adaptation to hypoxic stress, to transient inflammatory processes, and to wounding. Its expression also increases all along the process of neovascularization of solid and hematological tumors. The object of this article is to focus on the transcriptional regulation of its gene. The major cis-acting sequences and trans-activating factors will be described as well as the physiological and pathological situations leading to the intervention of such sequences and factors. We will also focus on two transcription factors essential to VEGF gene transcription: the hypoxia-inducible factor-1, which is responsible for its increased by hypoxia, as well as Sp1, which is implicated in the response to various extracellular stimuli.
Aspects of the Management of Shock
Authors: Kenneth I. Shine, Marie Kuhn, Lowell S. Young, Jan H. Tillisch
Journal: Annals of Internal Medicine (1980)

Shock is a state of systemic imbalance between supply and demand for oxygenated blood. We discuss here management of shock states not primarily of cardiac origin. Inadequacy or maldistribution of blood volume is important in the pathogenesis of most forms of shock. The Military Anti-Shock Trouser (MAST) suit assists the redistribution of blood from the periphery to the central circulation. Normal saline and Ringer's lactate solution may be used interchangeably for acute volume replacement. Colloid replacement requires smaller volumes but carries a higher risk of pulmonary edema, whereas crystalloid replacement requires larger volumes and leads to more systemic edema. Myocardial injury may contribute notably to the transition from reversible to irreversible shock. Naloxone, lidocaine, and indomethacin have improved survival in animal models of endotoxin shock, but proof of efficacy in humans is lacking. A role for corticosteroid administration in shock remains to be defined. Effective antibiotic therapy is the best treatment for septic shock; antisera against endotoxic antigens may develop as important adjunctive therapy.
Cardiac remodelling and dysfunction in children with obstructive sleep apnoea: a community based study
Authors: J Y S Chan, A M Li, C-T Au, A F C Lo, S-K Ng, V J Abdullah, C Ho, C-M Yu, T-F Fok, Y-K Wing
Journal: Thorax (2008)

<h3>Background:</h3> Childhood obstructive sleep apnoea (OSA) is suggested to be associated with cardiac structural abnormalities and dysfunction but existing evidence is limited and the treatment effect on echocardiographic outcome remains controversial. <h3>Objective:</h3> To examine the presence of subclinical cardiac abnormalities in childhood OSA and the effects of treatment on cardiac changes. <h3>Methods:</h3> Polysomnography (PSG) and echocardiographic examinations were performed in 101 children aged between 6 and 13 years who were invited from a community based questionnaire survey. They were classified into a reference group (apnoea–hypopnoea index (AHI) &lt;1, n = 35), mild OSA group (AHI 1–5, n = 39) and moderate to severe group (AHI &gt;5, n = 27) based on the PSG results. Treatments, including adenotonsillectomy or nasal steroids, were offered to the mild and moderate to severe OSA groups. <h3>Results:</h3> The moderate to severe OSA group had greater right ventricular (RV) systolic volume index (RVSVI), lower RV ejection fraction (RVEF) and higher RV myocardial performance index (RVMPI) than the reference group. They also had more significant left ventricular (LV) diastolic dysfunction and remodelling with larger interventricular septal thickness index (IVSI) and relative wall thickness than those with lower AHI values. The moderate to severe OSA group had an increased risk of abnormal LV geometry compared with the reference group (odds ratio 4.21 (95% CI 1.35 to 13.12)). Log transformed AHI was associated with RVSVI (p = 0.0002), RVEF (p = 0.0001) and RVMPI (p&lt;0.0001), independent of the effect of obesity. Improvement in RVMPI, IVSI and E/e′ were observed in those with a significant reduction in AHI (&gt;50%) comparing 6 month with baseline data. <h3>Conclusions:</h3> OSA is an independent risk factor for subclinical RV and LV dysfunction, and improvement in AHI is associated with reversibility of these abnormalities.
Management of dysfunctional breathlessness (DYB) – A retrospective service evaluation
Authors: Akshay Dwarakanath, Vera Davidson, Claire Taylor, Anthony Fennerty
Journal: European Respiratory Journal (2011)

Introduction:  DYB has an incidence of about 10% and may pose a diagnostic and therapeutic challenge.We have established a physiotherapist run clinic to mange this condition.   Aim:  To evaluate the outcome of a physiotherapist run DYB clinic.   Method:  The diagnosis of DYB was made on the basis of exclusion with a normal clinical examination,lung function and echocardiogram,or with symptoms disproportionate to measurements of severity of their respiratory illness.Patients were assessed by the physiotherapist with regard to their breathing pattern and the Nijmegen (Ni) score,with a score over 23 being regarded as diagnostic of DYB.Consecutive patients referred to the clinic over 24 months were reviewed.The following parameters were analysed-underlying respiratory illness,breathing pattern,Ni score (Pre and Post Intervention),HAD scores and the interventional modalities.   Results:  51 patients (males-20) were referred to the clinic in 24 months.The mean age was 60.2 (range, 20-84).26/51 patients had chronic cardio respiratory illness.28/51 patients had an abnormal breathing pattern.  37 patients had a pre intervention Ni score over 23 (mean-29, range, 23-42). Interventions included patient education, cognitive behaviour therapy, breathing exercises and training. Post intervention the Ni score fell below the diagnostic threshold in 29/37 patients (mean reduction-14, range, 3-22). HAD scores was used to assess the degree of mood impairment and there was no linear correlation with the pre intervention Ni score.   Conclusion:  A clinically significant improvement in symptoms as measured by the Ni score was achieved in 78% of the patients referred to our DYB clinic. There was poor correlation between HAD score and the Ni score.
Schizophrenia, an Illness and a metaphor: Analysis of the use of the term ‘schizophrenia’ in the UK national newspapers
Authors: Arun K Chopra, Gillian A Doody
Journal: Journal of the Royal Society of Medicine (2007)

Objective To determine whether schizophrenia is a commonly used ‘illness as metaphor‘, to compare the use of schizophrenia and cancer as illnesses as metaphor, and to determine if there is a difference in such usage between the UK and USA. Design An examination of articles published in the British press. Setting 600 articles from six British newspapers: the Times, the Daily Telegraph, the Guardian, the Mirror, the Sun and the Daily Mail. Main outcome measures Use of schizophrenia and cancer as metaphors. Results Schizophrenia was more likely to be metaphorized than cancer (P&lt;50.001) in the UK press, but was less likely to be used as metaphor in the UK press than in the US press (P&lt;50.001). 11% of articles containing the term schizophrenia used the word as a metaphor. Conclusions Clinicians need to be aware that patients, carers and the public might have a different understanding of the word we use as a diagnosis.
Randomized Controlled Trial of Physician-directed versus Respiratory Therapy Consult Service-directed Respiratory Care to Adult Non-ICU Inpatients
Authors: JAMES K. STOLLER, EDWARD J. MASCHA, LUCY KESTER, DAVID HANEY
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Although current evidence suggests that respiratory care protocols can enhance allocation of respiratory care services while conserving costs, a randomized trial is needed to address shortcomings of available studies. We therefore conducted a randomized controlled trial comparing respiratory care for adult non-ICU inpatients directed by a Respiratory Therapy Consult Service (RTCS) versus respiratory care by managing physicians. Eligible subjects were adult non-ICU inpatients whose physicians had prescribed specific respiratory care services. Consecutive eligible patients were approached for consent, after which a blocked randomization strategy was used to assign patients to (1) Physician-directed respiratory care, in which the prescribed physician respiratory care orders were maintained (n = 74), or (2) RTCS-directed respiratory care, in which the physician's respiratory care orders were preempted by a respiratory care plan generated by the RTCS (n = 71). Specifically, these patients were evaluated by an RTCS therapist evaluator whose respiratory care plan was based on sign/symptom-based algorithms drafted to comply with the American Association for Respiratory Care (AARC) Clinical Practice Guidelines. Appropriateness of respiratory care orders was assessed as agreement between the prescribed respiratory care plan and an algorithm-based “standard care plan” generated by an expert therapist who was blind to the patient's actual orders. The compared groups were similar at baseline regarding demographic features, admission diagnostic category, smoking status, and Triage Score (mean, 3.8 ± 0.9 SD [RTCS] versus 3.7 ± 1.0). Similarly, no differences were observed between RTCS-directed and physician-directed respiratory care regarding hospital mortality rate (5.7 versus 5.6%), hospital length of stay (7.9 ± 9.0 versus 7.7 ± 7.3 d), total number of respiratory care treatments delivered (30.3 ± 30 versus 31.6 ± 30.5), or days requiring respiratory care (4.2 ± 5.2 versus 4.1 ± 3.6). Notably, using both a stringent (S) and a liberal (L) criterion for agreement, RTCS-directed respiratory care demonstrated better agreement with the “standard care plan” (82 ± 17% [S] and 86 ± 16% [L]) than did physician-directed respiratory care (64 ± 21% [S] and 72 ± 23% [L]) (p < 0.001). Finally, the true cost of respiratory care treatments was slightly lower with RTCS-directed respiratory care (mean, $235.70 versus $255.70/pt, p = 0.61). We conclude that (1) compared with physician-directed respiratory care, the RTCS prescribed a similar number and duration of respiratory care services at a slight savings (that did not achieve statistical significance) and without any increased adverse events; and (2) compared with physician-directed respiratory care, RTCS-directed respiratory care showed greater agreement with Clinical Practice Guideline-based algorithms.