tbuckley/cabot-search huggingface dataset:
Prognostic Biomarkers in Diffuse Large B-Cell Lymphoma
Authors: Izidore S. Lossos, Daniel Morgensztern
Journal: Journal of Clinical Oncology (2006)

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. Although it represents a curable disease, less than half of the patients are cured with conventional chemotherapy. The highly variable outcome reflects a heterogeneous group of tumors, with different genetic abnormalities and response to therapy. The International Prognostic Index (IPI) is useful in predicting the outcome of DLBCL patients. However, patients with identical IPI still exhibit marked variability in survival, suggesting the presence of significant residual heterogeneity within each IPI category. The discovery of specific genetic alterations and the assessment of protein expression led to the identification of multiple novel single molecular markers capable of predicting the outcome of DLBCL patients independently of clinical variables. The recent application of DNA microarrays and tissue array technologies allowed a better understanding of the biology of lymphoma and the development of novel diagnostic tools capable of improving the current models for outcome prediction. However, much confusion exists in the literature regarding the importance of different prognostic biomarkers and their applicability in routine practice. This review summarizes the recent advances in our understanding of prognostic biomarkers in DLBCL and discusses whether this is the right time for biomarkers-guided risk-adjusted therapy.
Design and evaluation of a novel transdermal patch containing diclofenac and teriflunomide for rheumatoid arthritis therapy
Authors: Yuxiu Zhang, Dongmei Cun, Xin Kong, Liang Fang
Journal: Asian Journal of Pharmaceutical Sciences (2014)

The aim of this study was to design a compound transdermal patch containing diclofenac (DA) and teriflunomide (TEF) for the treatment of rheumatoid arthritis (RA). The various organic amines salts of DA were prepared and their forming was confirmed using DSC and FTIR. The percutaneous permeation of organic amines salt of DA was investigated in vitro using a two-chamber diffusion cell with excised rabbit skin as transdermal barrier. The formulation of the patch was optimized in terms of the concentration of percutaneous permeation enhancer and the loading dose of drugs. The pharmacokinetic behavior of the optimal formulation was studies in rabbits and the anti-inflammatory and analgesic effects of the optimal patch were evaluated with the adjuvant arthritis model in rats and the pain model in mice, respectively. The result showed that skin penetration of diclofenac-triethylamine (DA-TEtA) salt was better than other organic amine salts. Based on previous study of our laboratory, teriflunomide-triethylamine (TEF-TEtA) significantly enhanced the skin permeation of TEF. 10% of azone (AZ) was the best enhancer for the two drugs. The optimal patch formulation was composed of 2% of TEF-TEtA, 6% of DA-TEtA and 10% of AZ. The cumulative permeated amount of DA-TEtA in vitro was comparable with that of the commercial diclofenac-diethylamine (DA-DEtA) patch. The absolute bioavailability of TEF-TEtA was 42%, which could achieve the therapeutic drug levels. In animal study, the optimized compound patch containing DA-TEtA and TEF-TEtA displayed significant anti-inflammatory and analgesic effect, which indicated the potential of the compound patch.
Sympathetic Control of Renin Release
Authors: J Torretti
Journal: The Annual Review of Pharmacology and Toxicology (1982)

Sympathetic outflow influences the renal release of renin through modifications of the tonic activity of the renal nerves and the plasma concentration of catecholamines. These influences may initiate changes in the rate of renin secretion or modulate the response initiated by another of the mechanisms that control renin release. Beta-adrenoceptor mediated stimulation of renin release has been demonstrated in vivo, in the isolated perfused kidney and in preparation in vitro. Likewise an array of evidence has accumulated pointing to the existence of alpha-adrenoceptor mediated inhibition of renin release. However, the cellular location, the physiological significance, and even the existence of these alpha-adrenoceptors is still disputed. Receptors sensitive to alterations in the vascular volume have been identified in areas of low and high pressure of the circulation. There is evidence that input from both types of receptors may cancel each other, and that to demonstrate experimentally the effects on renin release of the low pressure cardiopulmonary receptors it is necessary to avoid changes in the input from the high pressure arterial receptors, and vice versa. Again there are dissenting voices that disclaim a tonic inhibitory effect of cardiopulmonary receptor initiated impulses on renin release. The majority of the pharmacological evidence identifies the beta-adrenoceptors in JG cells as of the beta 1-subtype. However, some species may make exception to this generalization. As in other tissues, beta-adrenoceptor mediated influences appear to relate to activation of adenylcyclase in the cell membrane. Considerable interest in the role of calcium in the process of activation of renin release has met with some unexpected, though consistent, experimental findings.
Impact of statins and angiotensin-converting enzyme inhibitors on mortality of subjects hospitalised with pneumonia
Authors: E. M. Mortensen, M. J. Pugh, L. A. Copeland, M. I. Restrepo, J. E. Cornell, A. Anzueto, J. A. Pugh
Journal: European Respiratory Journal (2007)

Recent studies suggest that statins and angiotensin-converting enzyme (ACE) inhibitors may have beneficial effects for some types of infections. The present study aimed to examine the association of outpatient use of these medications on 30-day mortality for subjects aged &gt;65 yrs and hospitalised with community-acquired pneumonia. A retrospective national cohort study was conducted using the Department of Veterans Affairs administrative data including subjects aged ≥65 yrs hospitalised with community-acquired pneumonia, and having ≥1 yr of prior Veterans Affairs outpatient care. In total, 8,652 subjects were identified with a mean age of 75 yrs, 98.6% were male, and 9.9% of subjects died within 30 days of presentation. In this cohort, 18.1% of subjects were using statins and 33.9% were using ACE inhibitors. After adjusting for potential confounders, current statin use (odds ratio (OR) 0.54, 95% confidence interval (CI) 0.42–0.70) and ACE inhibitor use (OR 0.80, 95% CI 0.68–0.89) were significantly associated with decreased 30-day mortality. Use of statins and angiotensin-converting enzyme inhibitors prior to admission is associated with decreased mortality in subjects hospitalised with community-acquired pneumonia. Randomised controlled trials are needed to examine whether the use of these medications in patients hospitalised with community-acquired pneumonia may be beneficial.
Haplotype-specific suppression of antibody responses in vitro. I. Generation of genetically restricted suppressor T cells by neonatal treatment with semiallogeneic spleen cells
Authors: CM Sorensen, CW Pierce
Journal: The Journal of Experimental Medicine (1981)

C57BL/10 mice were injected with semiallogeneic (B10.D2 X C57BL/10)F(1) spleen cells via the anterior facial vein within 24 h of birth to induce tolerance to B10.D2 (H-2(d)) alloantigens. Spleen cells from these mice as adults developed reduced, but significant, mixed lymphocyte and cytotoxic lymphocyte responses in vitro to H-2(d) stimulator cells and these treated mice rejected first-set B10.D2 skin grafts within a normal time-course, indicating that at best only a state of partial tolerance had been induced. Spleen cells from these mice failed to develop antibody responses to a variety of antigens in vitro when H-2(d) macrophages were in the cultures. Partially purified T cells from these neonatally treated mice suppressed primary antibody responses by normal syngeneic spleen cells in the presence of H-2(d) but not other allogeneic macrophages. These radiosensitive, haplotype-specific suppressor T (Ts) cells inhibited primary antibody responses by blocking initiation of the response, but failed to suppress secondary antibody responses and mixed lymphocyte or cytotoxic lymphocyte responses by appropriate responding spleen cells. To activate H-2(d) haplotype-specific Ts cells, stimulation with IA(d) subregion antigen(s) was necessary and sufficient; syngenicity at the I-A subregion of H-2 between the activated Ts cells and target responding spleen cell populations was also necessary and sufficient to achieve suppression. Comparable results have been obtained with spleen cells from BALB/c mice injected as neonates with (B10.D2 × C57BL/10)F(1) spleen cells where IA(b) antigens activate the haplotype-specific Ts cells. Implications for the significance of this population of haplotype-specific Ts cells in immune regulation are discussed and the properties of these Ts cells are compared and contrasted with other antigen-specific and nonspecific Ts cells whose activity is restricted by I- region products.
Elongation Factor 1 alpha interacts with phospho-Akt in breast cancer cells and regulates their proliferation, survival and motility
Authors: Luisa Pecorari, Oriano Marin, Chiara Silvestri, Olivia Candini, Elena Rossi, Clara Guerzoni, Sara Cattelani, Samanta A Mariani, Francesca Corradini, Giovanna Ferrari-Amorotti, Laura Cortesi, Rita Bussolari, Giuseppe Raschellà, Massimo R Federico, Bruno Calabretta
Journal: Molecular Cancer (2009)

Akt/PKB is a serine/threonine kinase that has attracted much attention because of its central role in regulating cell proliferation, survival, motility and angiogenesis. Activation of Akt in breast cancer portends aggressive tumour behaviour, resistance to hormone-, chemo-, and radiotherapy-induced apoptosis and it is correlated with decreased overall survival. Recent studies have identified novel tumor-specific substrates of Akt that may provide new diagnostic and prognostic markers and serve as therapeutic targets. This study was undertaken to identify pAkt-interacting proteins and to assess their biological roles in breast cancer cells.We confirmed that one of the pAkt interacting proteins is the Elongation Factor EF1alpha. EF1alpha contains a putative Akt phosphorylation site, but is not phosphorylated by pAkt1 or pAkt2, suggesting that it may function as a modulator of pAkt activity. Indeed, downregulation of EF1alpha expression by siRNAs led to markedly decreased expression of pAkt1 and to less extent of pAkt2 and was associated with reduced proliferation, survival and invasion of HCC1937 cells. Proliferation and survival was further reduced by combining EF1alpha siRNAs with specific pAkt inhibitors whereas EF1alpha downregulation slightly attenuated the decreased invasion induced by Akt inhibitors.We show here that EF1alpha is a pAkt-interacting protein which regulates pAkt levels. Since EF1alpha is often overexpressed in breast cancer, the consequences of EF1alpha increased levels for proliferation, survival and invasion will likely depend on the relative concentration of Akt1 and Akt2.
Does Memory of a Traumatic Event Increase the Risk for Posttraumatic Stress Disorder in Patients With Traumatic Brain Injury? A Prospective Study
Authors: Sharon Gil, Yael Caspi, Irit Zilberman Ben-Ari, Danny Koren, Ehud Klein
Journal: American Journal of Psychiatry (2005)

The present study examined prospectively the relationship between memory of the traumatic event and subsequent development of posttraumatic stress disorder (PTSD). More specifically, the aims of this study were to 1) investigate the possibility that lack of memory of the traumatic event might be a protective factor; 2) assess whether memory of the traumatic event equally affects the three symptom clusters of PTSD: reexperiencing, avoidance, and hyperarousal; and 3) explore the predictive value of memory of the traumatic event for the development of subsequent PTSD in the immediate aftermath of the event.One hundred twenty subjects with mild traumatic brain injury who were hospitalized for observation were assessed immediately after the trauma and followed up 1 week, 3 months, and 6 months later. All participants underwent psychiatric evaluation and self-assessment of their memory of the traumatic event.Overall, 17 (14%) of the participants met full criteria for PTSD at 6 months. Subjects with memory of the traumatic event were significantly more likely to develop PTSD than those without memory of the traumatic event; the difference between the groups resulted primarily from the reexperiencing cluster. Logistic regression analysis revealed that memory of the traumatic event within the first 24 hours is a strong predictor of PTSD 6 months after the event.Our study indicated that memory of a traumatic event is a strong predictor and a potential risk factor for subsequent development of PTSD. Future studies are needed to show whether these findings can be generalized to other traumatic conditions.
Animal studies and HIV research
Authors: R. Greek
Journal: BMJ (2002)

Editor—As Yamey et al highlighted, HIV will have killed 55 million people by the year 2010.1 Now, 20 years since the first appearance of the virus, is a good time to review the advances to date and identify promising avenues for future research.

To estimate the amount of money spent on research on HIV and, within that, the amount spent on animal studies is difficult. Assessments of the efficacy of animal studies in HIV research are, however, easier to come by.

Thomas Insel, former director of the Yerkes Regional Primate Center in Georgia, said: “[An animal model] that takes 12-14 years to develop doesn't sound to me to be ideal . . . I can't tell you what it is that those studies [with chimpanzees] have given us that has really made a difference in the way we approach people with this disease.”2 Animal models of HIV have been notoriously inaccurate for two reasons.

Firstly, the immune response is intensely complicated and there are many disparities between the human immune response and those of other animals. Secondly, viruses are usually species specific.

In terms of treatment, the efficacy of zidovudine—originally an anticancer drug—was shown in 1985 from the results of in vitro studies rather than animal research. Similarly, combination antiretroviral therapy was developed using in vitro methods, rational drug design, and clinical research.

In vitro research has also enabled other advances in understanding and potentially treating HIV. These include elucidating the structure of the virus (and recently the rare b12 antibody), finding that an HIV-1 entry inhibitor could prevent HIV from fusing with the cell membrane,3 and discovering that certain strains of HIV do not use the normal 2-receptor binding process but bind directly to T helper cells via the CD8 receptor.4 Epidemiological studies determined the routes of HIV transmission. Gene variants that influence HIV progression were identified using longitudinal epidemiological cohort studies, high throughput genotyping and polymorphism discovery methods, and computational algorithms to detect gene associations in cohorts with the disease.5

The fact that 20 years on there is still no cure or vaccine for HIV is surely partly because too much money, time, and effort have been invested in animal research which has produced little, if nothing, in return. To make any impact on this global pandemic during the next 20 years, funding needs to be concentrated on research methods that have come up with the goods.
Twenty four hour oesophageal acidity in achalasia before and after pneumatic dilatation.
Authors: H L Smart, P N Foster, D F Evans, B Slevin, M Atkinson
Journal: Gut (1987)

Radiotelemetric ambulatory 24 hour oesophageal pH measurement was carried out in 17 patients with symptomatic manometrically proven achalasia before and after pneumatic dilatation. Before dilatation an abnormally high percentage acid exposure time was present but typical episodes of gastro-oesophageal reflux occurred in only one patient. In nine patients who had a oesophageal food residue these values were significantly greater than those found in the remaining patients without retained food. Analysis of oesophageal food residues revealed that the low pH was predominantly caused by lactic acid. These findings indicate that preoperative oesophageal pH studies do not offer a valid means of selection of patients in whom an antireflux procedure should be combined with cardiomyotomy. Repeat studies one week after pneumatic dilatation showed a fall in the acid exposure time in patients with initial food residue presumably resulting from improved oesophageal emptying after treatment. A significant rise in acid exposure time after dilatation was seen in those patients without initial food residue presumably resulting from gastro-oesophageal reflux after therapeutic disruption of the lower oesophageal sphincter. Troublesome symptoms of gastro-oesophageal reflux were, however, uncommon after bag dilatation.
Azithromycin Reverses Airflow Obstruction in Established Bronchiolitis Obliterans Syndrome
Authors: Bryan Yates, Desmond M. Murphy, Ian A. Forrest, Chris Ward, Robert M. Rutherford, Andrew J. Fisher, James L. Lordan, John H. Dark, Paul A. Corris
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Introduction: A recent pilot study noted clinical benefit of macrolide therapy in the management of six lung transplant recipients with bronchiolitis obliterans syndrome (BOS), a condition previously regarded as irreversible. Objective: To examine the effect of low-dose macrolides on lung function in lung allograft recipients with established BOS and to assess whether this benefit is sustained. Methods: We retrospectively evaluated the effect of azithromycin (250 mg alternate days) on clinical status and lung function in 20 allograft recipients with established BOS, confirmed by decline in FEV1 or FEF25–75; consistent high-resolution computed tomography findings; and exclusion of acute rejection, infection, or anastomatic complications. Azithromycin was introduced at mean 82 months after transplantation. BOS staging at initiation of treatment was BOS 3 (10), BOS 2 (2), BOS 1 (6), and BOS0-p (2). All patients were on maintenance immunosuppression comprising cell-cycle inhibitor, oral corticosteroids, and calcineurin inhibitor. Results: There was a significant increase in FEV1 of median 110 ml (range, −70 to 730 ml) between baseline and 3 months of azithromycin therapy (p = 0.002). This improvement was sustained beyond 3 months in the majority of patients, who had initially benefited from azithromycin (up to 11 months follow up). Conclusions: This case series confirms the benefit of azithromycin in not only halting, but reversing the declining lung function seen in patients with BOS. This benefit appears to be maintained over time. Low-dose macrolides offer a new and exciting therapeutic strategy for the treatment of progressive BOS, and further clinical and translational mechanistic studies are required.
Biased T Cell Receptor Usage Directed against Human Leukocyte Antigen DQ8-Restricted Gliadin Peptides Is Associated with Celiac Disease
Authors: Sophie E. Broughton, Jan Petersen, Alex Theodossis, Stephen W. Scally, Khai Lee Loh, Allan Thompson, Jeroen van Bergen, Yvonne Kooy-Winkelaar, Kate N. Henderson, Travis Beddoe, Jason A. Tye-Din, Stuart I. Mannering, Anthony W. Purcell, James McCluskey, Robert P. Anderson, Frits Koning, Hugh H. Reid, Jamie Rossjohn
Journal: Immunity (2012)
Biological background of pediatric medulloblastoma and ependymoma: A review from a translational research perspective
Authors: Judith M. de Bont, Roger J. Packer, Erna M. Michiels, Monique L. den Boer, Rob Pieters
Journal: Neuro-Oncology (2008)

Survival rates of pediatric brain tumor patients have significantly improved over the years due to developments in diagnostic techniques, neurosurgery, chemotherapy, radiotherapy, and supportive care. However, brain tumors are still an important cause of cancer-related deaths in children. Prognosis is still highly dependent on clinical characteristics, such as the age of the patient, tumor type, stage, and localization, but increased knowledge about the genetic and biological features of these tumors is being obtained and might be useful to further improve outcome for these patients. It has become clear that the deregulation of signaling pathways essential in brain development, for example, sonic hedgehog (SHH), Wnt, and Notch pathways, plays an important role in pathogenesis and biological behavior, especially for medulloblastomas. More recently, data have become available about the cells of origin of brain tumors and the possible existence of brain tumor stem cells. Newly developed array-based techniques for studying gene expression, protein expression, copy number aberrations, and epigenetic events have led to the identification of other potentially important biological abnormalities in pediatric medulloblastomas and ependymomas.
Regulatory mechanisms of hemoglobin oxygen affinity in acidosis and alkalosis
Authors: A. J. Bellingham, J. C. Detter, C. Lenfant
Journal: Journal of Clinical Investigation (1971)

The recent reports of the effect of 2,3-diphosphoglycerate (2,3-DPG) on hemoglobin affinity for oxygen suggested that this substance may play a role in man's adaptation to acidosis and alkalosis.A study of the effect of induced acidosis and alkalosis on the oxyhemoglobin dissociation curve of normal man was therefore carried out, and the mechanisms involved in the physiological regulation of hemoglobin oxygen affinity examined.In acute changes of plasma pH there was no alteration in red cell 2,3-DPG content. However, there were changes in hemoglobin oxygen affinity and these correlated with changes in mean corpuscular hemoglobin concentration (MCHC). With maintained acidosis and alkalosis, red cell 2,3-DPG content was altered and correlated with the changes in hemoglobin oxygen affinity. Both of these mechanisms shift the hemoglobin oxygen dissociation curve opposite to the direct pH (Bohr) effect, and providing the rate of pH change is neither too rapid nor too large, they counteract the direct pH effect and the in vivo hemoglobin oxygen affinity remains unchanged. It is also shown that approximately 35% of the change in hemoglobin oxygen affinity resulting from an alteration in red cell 2,3-DPG, is explained by effect of 2,3-DPG on the red cell pH.