tbuckley/cabot-search huggingface dataset:
Pim kinases in hematological malignancies: where are we now and where are we going?
Authors: Patrizia Mondello, Salvatore Cuzzocrea, Michael Mian
Journal: Journal of Hematology & Oncology (2014)

The proviral insertion in murine (PIM) lymphoma proteins are a serine/threonine kinase family composed of three isoformes: Pim-1, Pim-2 and Pim-3. They play a critical role in the control of cell proliferation, survival, homing and migration. Recently, overexpression of Pim kinases has been reported in human tumors, mainly in hematologic malignancies. In vitro and in vivo studies have confirmed their oncogenic potential. Indeed, PIM kinases have shown to be involved in tumorgenesis, to enhance tumor growth and to induce chemo-resistance, which is why they have become an attractive therapeutic target for cancer therapy. Novel molecules inhibiting Pim kinases have been evaluated in preclinical studies, demonstrating to be effective and with a favorable toxicity profile. Given the promising results, some of these compounds are currently under investigation in clinical trials. Herein, we provide an overview of the biological activity of PIM-kinases, their role in hematologic malignancies and future therapeutic opportunities.
<b> <i>p73</i> </b> G4C14-to-A4T14 Polymorphism and Risk of Lung Cancer
Authors: Guojun Li, Li-E Wang, Robert M. Chamberlain, Christopher I. Amos, Margaret R. Spitz, Qingyi Wei
Journal: Cancer Research (2004)

Genetic variants in genes controlling cellular processes such as cell cycle, DNA repair, and apoptosis may modulate lung cancer risk. p73 has some p53-like activity and plays an important role in modulating these processes. The noncoding region of exon 2 of the p73 gene has two polymorphisms that are in complete linkage disequilibrium with one another, which may alter translation efficiency of the p73 protein. To test the hypothesis that this p73 polymorphism plays a role in the etiology of lung cancer, we conducted a hospital-based case-control study of 1054 patients newly diagnosed with lung cancer and 1139 cancer-free controls and evaluated the association between the p73 variant AT allele and risk of lung cancer. Cancer-free controls were frequency matched to the cases by age (+/-5 years), sex, and smoking status, and all subjects were non-Hispanic whites. The variant AT allele and genotypes were more common among the cases than among the controls (P = 0.0007 and P < 0.001, respectively). Compared with the GC/GC genotype, the variant GC/AT and AT/AT genotypes were associated with a statistically significantly increased risk for lung cancer [adjusted odds ratio (OR) = 1.32, 95% confidence interval (CI), 1.10-1.59 and OR = 1.54, 95% CI, 1.05-2.26, respectively] in an allele dose-effect relationship (trend test: P < 0.001). The risk associated with the AT allele (GC/AT+AT/AT) was more pronounced in younger (</=50 years) individuals (OR = 1.53, 95% CI, 1.00-2.37), men (OR = 1.61, 95% CI, 1.26-2.06), light smokers (OR = 1.58, 95% CI, 1.17-2.14), and squamous cell lung carcinoma (OR = 1.79, 95% CI, 1.32-2.42). These results suggest that this p73 polymorphism may be a marker for susceptibility to lung cancer.
Evaluation of the buccal component of systemic absorption with inhaled fluticasone propionate
Authors: O. J Dempsey, W. J R Coutie, A. M Wilson, P. Williams, B. J Lipworth
Journal: Thorax (1999)

<h3>BACKGROUND</h3> Inhaled corticosteroids have dose related systemic effects determined by oral (swallowed or oropharyngeal absorption) and lung bioavailability. A study was undertaken to evaluate the significance of oropharyngeal absorption for fluticasone propionate. <h3>METHODS</h3> Sixteen healthy volunteers of mean age 29.3 years were studied using an open randomised, placebo controlled, four way crossover design. Treatments were: (a) fluticasone metered dose inhaler (pMDI) 250 μg, 8 puffs; (b) fluticasone pMDI 250 μg, 8 puffs + mouth rinsing/gargling (water); (c) fluticasone pMDI 250 μg, 8 puffs + mouth rinsing/gargling (charcoal); and (d) placebo pMDI, 8 puffs + mouth rinsing/gargling (water). Overnight (ONUC) and early morning (EMUC) urinary cortisol/creatinine ratios and 8 am serum cortisol (SC) levels were measured. <h3>RESULTS</h3> Significant (p&lt;0.05) suppression of ONUC, EMUC, and SC occurred with each active treatment compared with placebo. The mean values (95% CI for difference from placebo) were: (a) ONUC (nmol/mmol): fluticasone (2.8, 95% CI 3.6 to 7.9), fluticasone + water (3.1, 95% CI 3.3 to 7.7), fluticasone + charcoal (2.3, 95% CI 4.1 to 8.5); placebo (8.6); (b) EMUC (nmol/mmol): fluticasone (5.6, 95% CI 8.4 to 24.5), fluticasone + water (7.6, 95% CI 6.6 to 22.4); fluticasone + charcoal (5.6, 95% CI 8.7 to 24.5); placebo (22.1). There were no significant differences between active treatments. The numbers of subjects with an overnight urinary cortisol of &lt;20 nmol/10 hours were 0 (placebo), 11 (fluticasone), 12 (fluticasone + water), and 13 (fluticasone + charcoal). <h3>CONCLUSIONS</h3> Oropharyngeal absorption of fluticasone does not significantly contribute to its overall systemic bioactivity as assessed by sensitive measures of adrenal suppression. In view of almost complete hepatic first pass inactivation with fluticasone, there is no rationale to employ mouth rinsing to reduce its systemic effects although it may be of value for reducing oral candidiasis.
Structural and Functional Implications of an Unusual Foraminiferal β-Tubulin
Authors: Andrea Habura, Laura Wegener, Jeffrey L. Travis, Samuel S. Bowser
Journal: Molecular Biology and Evolution (2005)

We have obtained sequence data for β-tubulin genes from eight species of Foraminifera (forams) and α-tubulin sequences from four species, sampling major taxonomic groups from a wide range of environments. Analysis of the β-tubulin sequences demonstrates that foram β-tubulins possess the highest degree of divergence of any tubulin gene sequenced to date and represent a novel form of the protein. In contrast, foram α-tubulin genes resemble the conventional α-tubulins seen in other organisms. Partition homogeneity analysis shows that the foraminiferal β-tubulin gene has followed an evolutionary path that is distinct from that of all other organisms. Our findings indicate that positive selective pressure occurred on the β-tubulin subunit in ancestral forams prior to their diversification. The specific substitutions observed have implications for microtubule (MT) assembly dynamics. The regions most strongly affected are implicated in lateral contacts between protofilaments and in taxol binding. We predict that these changes strengthen lateral contacts between adjacent dimers in a manner similar to that induced by taxol binding, thus allowing the formation of the tubulin "helical filaments" observed in forams by electron microscopy. Our results also indicate that substantial changes to these portions of the β-tubulin molecule can be made without sacrificing essential MT functions.
Postprandial Hypotension: Epidemiology, Pathophysiology, and Clinical Management
Authors: Rene W. M. M. Jansen
Journal: Annals of Internal Medicine (1995)

Objective: To show the clinical relevance of postprandial hypotension and to review its pathophysiology and management. Data Sources: Articles on postprandial hypotension were identified through MEDLINE and bibliographies of relevant articles. Study Selection: All articles and case reports describing meal-related hypotension in the elderly and in patients with autonomic failure. Data Synthesis: Postprandial hypotension, defined as a decrease in systolic blood pressure of 20 mm Hg or more, may result in syncope, falls, dizziness, weakness, angina pectoris, and stroke. Postprandial hypotension is distinct from and probably more common than orthostatic hypotension. Because meal-related hypotension is particularly common in older hypertensive patients, it has important implications for the evaluation and management of hypertension. The mechanism of postprandial hypotension is not fully understood. Possible contributors include inadequate sympathetic nervous system compensation for meal-induced splanchnic blood pooling; impairments in baroreflex function; inadequate postprandial increases in cardiac output; and impaired peripheral vasoconstriction, insulin-induced vasodilation, and release of vasodilatory gastrointestinal peptides. Although caffeine is often recommended as treatment for postprandial hypotension, available data do not support its use. Octreotide, a somatostatin analog, has been shown to be effective, but it is expensive and must be given parenterally. Conclusion: All physicians caring for elderly patients should be aware of the hypotensive effects of food intake and should consider postprandial hypotension in the evaluation of syncope, falls, dizziness, and other cerebral ischemic symptoms.
Nedocromil sodium in adults with asthma dependent on inhaled corticosteroids: a double blind, placebo controlled study.
Authors: M F Bone, M M Kubik, N P Keaney, G D Summers, C K Connolly, P S Burge, R G Dent, G W Allan
Journal: Thorax (1989)

Eighty nine adults with asthma who were receiving inhaled corticosteroid and bronchodilator treatment took part in a double blind, randomised, placebo controlled trial of nedocromil sodium, 4 mg four times daily by inhalation. During a run in period of two to four weeks corticosteroid treatment was reduced when possible to produce a comparable level of symptoms across the trial population. The test treatment was then taken for four weeks, with the severity of asthma recorded daily by patients and assessed at two weekly hospital visits. There was an improvement in symptoms in the patients taking nedocromil sodium by comparison with those having the placebo, the differences being significant for diary card PEF readings, asthma symptom scores, and bronchodilator usage at night. The mean difference between the two groups was 18 l/min for PEF, 0.42 for daytime asthma score, and 1.73 puffs in 24 hours for bronchodilator usage. These results suggest that asthmatic patients who require inhaled steroids show better control of their asthma with the addition of nedocromil sodium than of placebo over a four week period after reduction of the dosage of their inhaled steroids.
p38 Kinase Is a Negative Regulator of Angiotensin II Signal Transduction in Vascular Smooth Muscle Cells
Authors: Masatoshi Kusuhara, Eiichi Takahashi, Timothy E. Peterson, Jun-ichi Abe, Mari Ishida, Jiahuai Han, Richard Ulevitch, Bradford C. Berk
Journal: Circulation Research (1998)

Abstract —Activation of the Na + /H + exchanger isoform-1 (NHE-1) by angiotensin II is an early signal transduction event that may regulate vascular smooth muscle cell (VSMC) growth and migration. Many signal transduction events stimulated by angiotensin II are mediated by the mitogen-activated protein (MAP) kinases. To define their roles in angiotensin II–mediated NHE-1 activity, VSMCs were treated with angiotensin II and the activities of p38, c-Jun N -terminal kinase (JNK), and extracellular signal–regulated kinases 1 and 2 (ERK1/2) were measured. Angiotensin II rapidly (peak, 5 minutes) activated p38 and ERK1/2, whereas JNK was activated more slowly (peak, 30 minutes). Because angiotensin II stimulated Na + /H + exchange within 5 minutes, the effects of p38 and ERK1/2 antagonists on Na + /H + exchange were studied. The MEK-1 inhibitor PD98059 decreased ERK1/2 activity and Na + /H + exchange stimulated by angiotensin II. In contrast, the specific p38 antagonist SKF-86002 increased Na + /H + exchange. Two mechanisms were identified that may mediate the effects of p38 and SKF-86002 on angiotensin II–stimulated Na + /H + exchange. First, angiotensin II activation of ERK1/2 was increased 1.5- to 2.5-fold (depending on assay technique) in the presence of SKF-86002, demonstrating that p38 negatively regulates ERK1/2. Second, the ability of angiotensin II–stimulated MAP kinases to phosphorylate a glutathione S -transferase fusion protein containing amino acids 625 to 747 of NHE-1 in vitro was analyzed. The relative activities of endogenous immunoprecipitated p38, ERK1/2, and JNK were 1.0, 2.0, and 0.05 versus control, respectively suggesting that p38 and ERK1/2, but not JNK, may phosphorylate NHE-1 in VSMC. These data indicate important roles for p38 and ERK1/2 in angiotensin II–mediated regulation of the Na + /H + exchanger in VSMC.
Continuous-Flow Cell Saver Reduces Cognitive Decline in Elderly Patients After Coronary Bypass Surgery
Authors: George Djaiani, Ludwik Fedorko, Michael A. Borger, Robin Green, Jo Carroll, Michael Marcon, Jacek Karski
Journal: Circulation (2007)

Background— Cerebral microembolization during cardiopulmonary bypass may lead to cognitive decline after cardiac surgery. Transfusion of the unprocessed shed blood (major source of lipid microparticulates) into the patient during cardiopulmonary bypass is common practice to reduce blood loss and blood transfusion. Processing of shed blood with cell saver before transfusion may limit cerebral microembolization and reduce cognitive decline after surgery. Methods and Results— A total of 226 elderly patients were randomly allocated to either cell saver or control groups. Anesthesia and surgical management were standardized. Epiaortic scanning of the proximal thoracic aorta was performed in all patients. Transcranial Doppler was used to measure cerebral embolic rates. Standardized neuropsychological testing was conducted 1 week before and 6 weeks after surgery. The raw scores for each test were converted to Z scores, and then a combined Z score of 10 main variables was calculated for both study groups. The primary analysis was based on dichotomous composite cognitive outcome with a 1-SD rule. Cognitive dysfunction was present in 6% (95% confidence interval, 1.3% to 10.7%) of patients in the cell saver group and 15% (95% confidence interval, 8% to 22%) of patients in the control group 6 weeks after surgery ( P =0.038). The severity of aortic atheroma and cerebral embolic count were similar between the 2 groups. Conclusions— The present report demonstrates that processing of shed blood with cell saver results in clinically significant reduction in postoperative cognitive dysfunction after cardiac surgery. These findings emphasize the clinical importance of lipid embolization in contributing to postoperative cognitive decline in patients exposed to cardiopulmonary bypass.
Offer regular HIV tests to high risk groups to reduce late diagnoses, says public health agency
Authors: M. Limb
Journal: BMJ (2012)

The number of HIV diagnoses in the United Kingdom among men who have sex with men reached its highest level in 2011, the Health Protection Agency has said.

The agency’s annual report on HIV in the UK shows that 6280 people were given new diagnoses of HIV in 2011: 4470 men and 1810 women.1

New diagnoses among men who have sex with men surpassed the number of diagnoses made among people who contracted the virus through heterosexual sex for the first time since 1999, accounting for almost half of new diagnoses in 2011 (3010). In 2010 there were 3000 new diagnoses among men who have sex with men , which was at the time the highest level recorded in one year.

In the UK overall one in 20 men who have sex with men now have …
Ambient Air Pollution and Depressive Symptoms in Older Adults: Results from the MOBILIZE Boston Study
Authors: Yi Wang, Melissa N. Eliot, Petros Koutrakis, Alexandros Gryparis, Joel D. Schwartz, Brent A. Coull, Murray A. Mittleman, William P. Milberg, Lewis A. Lipsitz, Gregory A. Wellenius
Journal: Environmental Health Perspectives (2014)

Exposure to ambient air pollution, particularly from traffic, has been associated with adverse cognitive outcomes, but the association with depressive symptoms remains unclear. We investigated the association between exposure to ambient air and traffic pollution and the presence of depressive symptoms among 732 Boston-area adults ≥ 65 years of age (78.1 ± 5.5 years, mean ± SD). We assessed depressive symptoms during home interviews using the Revised Center for Epidemiological Studies Depression Scale (CESD-R). We estimated residential distance to the nearest major roadway as a marker of long-term exposure to traffic pollution and assessed short-term exposure to ambient fine particulate matter (PM2.5), sulfates, black carbon (BC), ultrafine particles, and gaseous pollutants, averaged over the 2 weeks preceding each assessment. We used generalized estimating equations to estimate the odds ratio (OR) of a CESD-R score ≥ 16 associated with exposure, adjusting for potential confounders. In sensitivity analyses, we considered CESD-R score as a continuous outcome and mean annual residential BC as an alternate marker of long-term exposure to traffic pollution. We found no evidence of a positive association between depressive symptoms and long-term exposure to traffic pollution or short-term changes in pollutant levels. For example, we found an OR of CESD-R score ≥ 16 of 0.67 (95% CI: 0.46, 0.98) per interquartile range (3.4 μg/m(3)) increase in PM2.5 over the 2 weeks preceding assessment. We found no evidence suggesting that ambient air pollution is associated with depressive symptoms among older adults living in a metropolitan area in attainment of current U.S. regulatory standards.
Symptom triggered pharmacotherapy for acute unplanned alcohol withdrawal can be both clinically and cost-effective in a hospital setting: experience from a specialist hepatology unit
Authors: L. Glover, P. Collins, F. Gordon, H. Karen, V. Hunt, J. Portal, S. Saleem, C. A. McCune
Journal: Gut (2011)

<h3>Introduction</h3> In recent guidance, NICE (2010) recommend a symptom-triggered (STW) pharmacological dosing regimen to treat AAW as both clinically and cost effective.1 Supporting evidence is from a small number of studies largely undertaken in specialised addiction units and a paucity of published evidence from other settings remains. With this in mind our liver unit formulated and piloted a STW regimen using chlordiazepoxide (CDP). Our aim was to evaluate STW and explore potential cost savings. <h3>Methods</h3> The STW regimen allowed a maximum daily dose of 240 mg CDP without specialist review. Pharmacotherapy was tailored to the patient9s requirements as determined by the severity of their withdrawal signs and symptoms using a designated questionnaire (modified CIWA-AD2). Patients were scored hourly or 4 hourly according to protocol score. Data was collected prospectively over a 10-month period (Nov 09 – Aug 10) and case note review undertaken in those previously admitted with AAW (all managed on a fixed dose regimen). <h3>Results</h3> 135 individuals had STW, each consuming a mean of 28 units of alcohol/day. Most (n= 78, 58%) were admitted with uncomplicated AAW, although over a third had significant liver disease (n=51, 38%). 6 (4%) had no significant liver disease but other serious co-morbidity requiring admission. 41 (30.4%) were previously admitted with AAW. The mean total dose of CDP prescribed during STW was 70.6 mg c.f. 541.6 mg on a fixed dose regimen. A significant number (n= 53, 39%) of STW patients did not require CDP at all, allowing early discharge. Patients on STW required CPD on average for shorter duration (3.11 days vs 7.52 days for fixed dose regimen). In the group admitted with uncomplicated AAW, we estimate within one ward cost savings of at least £220k per annum in bed days alone. Nursing staff welcomed the STW protocol, citing improved patient care and a reduction in violence and aggressive behaviour on the ward. <h3>Conclusion</h3> Our results support the recommendations made by NICE (2010) that symptom-triggered regimens are associated with lower doses of benzodiazepines, shorter treatment duration and cost-savings, especially in those with uncomplicated AAW. Designated questionnaires (such as CIWR-AD) are a useful adjunct to clinical experience.
Epidermal Growth Factor Activates Store-Operated Calcium Channels in Human Glomerular Mesangial Cells
Authors: RONG MA, STEVEN C. SANSOM
Journal: Journal of the American Society of Nephrology (2001)

Abstract. A cellular influx of Ca 2+ is critical for initiating and maintaining growth in a variety of cell types. Experiments were performed to determine whether epidermal growth factor (EGF), which is known to initiate a proliferative response in mesangial cells, could regulate by intracellular signal transduction the store-operated Ca 2+ channels (SOC) of human mesangial cells (HMC) in culture. The cell-attached patch configuration was used to monitor the activity of SOC, with 90 mM Ba 2+ in the pipette and physiologic saline solution in the bath. Under control conditions, the mean NP o value was 1.06 at a holding potential of -80 mV. When 100 nM EGF was added to the bath, SOC were activated by 53%. The EGF-evoked response was dose-dependent, with a half-maximal activation concentration of 4.8 nM. An inhibitor of tyrosine kinase, i.e. , tyrphostin A23 (100 μM), completely abolished EGF-evoked channel activation. EGF combined with the inactive control compound tyrphostin A1 (100 μM) elicited significant (85%) activation of SOC. Calphostin C, an inhibitor of protein kinase C (PKC), did not affect the baseline activity of SOC but abolished the EGF-evoked enhancement of SOC activity. The PKC activator phorbol-12-myristate-13-acetate (PMA) significantly activated SOC. However, the effects of PMA were duplicative rather than additive or potentiating with maximal concentrations (100 nM) of EGF, suggesting that PMA and EGF activate SOC through a common PKC pathway. In addition, downregulation of PKC via incubation of HMC with PMA for 1 to 20 h depressed both basal activity and EGF-induced activation of SOC. It is concluded that EGF stimulates SOC in HMC through an intracellular signaling mechanism involving tyrosine kinase and PKC.
Impact of Substance Use Disorders on Recovery From Episodes of Depression in Bipolar Disorder Patients: Prospective Data From the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)
Authors: Michael J. Ostacher, Roy H. Perlis, Andrew A. Nierenberg, Joseph Calabrese, Jonathan P. Stange, Ihsan Salloum, Roger D. Weiss, Gary S. Sachs
Journal: American Journal of Psychiatry (2009)

Objective Bipolar disorder is highly comorbid with substance use disorders, and this comorbidity may be associated with a more severe course of illness, but the impact of comorbid substance abuse on recovery from major depressive episodes in these patients has not been adequately examined. The authors hypothesized that comorbid drug and alcohol use disorders would be associated with longer time to recovery in patients with bipolar disorder. Method Subjects (N=3,750) with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were followed prospectively for up to 2 years. Prospectively observed depressive episodes were identified for this analysis. Subjects with a past or current drug or alcohol use disorder were compared with those with no history of drug or alcohol use disorders on time to recovery from depression and time until switch to a manic, hypomanic, or mixed episode. Results During follow up, 2,154 subjects developed a new-onset major depressive episode; of these, 457 subjects switched to a manic, hypomanic, or mixed episode prior to recovery. Past or current substance use disorder did not predict time to recovery from a depressive episode relative to no substance use comorbidity. However, those with current or past substance use disorder were more likely to experience switch from depression directly to a manic, hypomanic, or mixed state. Conclusions Current or past substance use disorders were not associated with longer time to recovery from depression but may contribute to greater risk of switch into manic, mixed, or hypomanic states. The mechanism conferring this increased risk merits further study.