tbuckley/cabot-search huggingface dataset:
Convergent Evolution of Endometrial Prolactin Expression in Primates, Mice, and Elephants Through the Independent Recruitment of Transposable Elements
Authors: Deena Emera, Claudio Casola, Vincent J. Lynch, Derek E. Wildman, Dalen Agnew, Günter P. Wagner
Journal: Molecular Biology and Evolution (2011)

Prolactin (PRL) is a multifunctional signaling molecule best known for its role in regulating lactation in mammals. Systemic PRL is produced by the anterior pituitary, but extrapituitary PRL has also been detected in many tissues including the human endometrium. Prolactin is essential for pregnancy in rodents and one of the most dramatically induced genes in the endometrium during human pregnancy. The promoter for human endometrial Prl is located about 5.8 kb upstream of the pituitary promoter and is derived from a transposable element called MER39. Although it has been shown that prolactin is expressed in the pregnant endometrium of a few mammals other than humans, MER39 has been described as primate specific. Thus, in an effort to understand mechanisms of prolactin regulatory evolution, we sought to determine how uterine prolactin is transcribed in species that lack MER39. Using a variety of complementary strategies, including reverse transcriptase-polymerase chain reaction, 5' rapid amplification of cDNA ends, and whole-transcriptome sequencing, we show that endometrial Prl expression is not a shared character of all placental mammals, as it is not expressed in rabbits, pigs, dogs, or armadillos. We show that in primates, mice, and elephants, prolactin mRNA is transcribed in the pregnant endometrium from alternative promoters, different from the pituitary promoter and different from each other. Moreover, we demonstrate that the spider monkey promoter derives from the long terminal repeat (LTR) element MER39 as in humans, the mouse promoter derives from the LTR element MER77, and the elephant promoter derives from the lineage-specific LINE retrotransposon L1-2_LA. We also find surprising variation of transcriptional start sites within these transposable elements and of Prl splice variants, suggesting a high degree of flexibility in the promoter architecture even among closely related species. Finally, the three groups shown here to express endometrial prolactin-the higher primates, the rodents, and the elephant-represent three of the four lineages that showed adaptive evolution of the Prl gene in an earlier study (Wallis M. 2000. Episodic evolution of protein hormones: molecular evolution of pituitary prolactin. J Mol Evol. 50:465-473), which supports our findings and suggests that the selective forces responsible for accelerated Prl evolution were in the endometrium. This is the first reported case of convergent evolution of gene expression through the independent recruitment of different transposable elements, highlighting the importance of transposable elements in gene regulatory, and potentially adaptive, evolution.
VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis
Authors: Steven Le Gouill, Klaus Podar, Martine Amiot, Teru Hideshima, Dharminder Chauhan, Kenji Ishitsuka, Shaji Kumar, Noopur Raje, Paul G. Richardson, Jean-Luc Harousseau, Kenneth C. Anderson
Journal: Blood (2004)
Tachykinins and airway microvascular leakage induced by HCl intra-oesophageal instillation
Authors: S. Daoui, B. D'Agostino, L. Gallelli, X. Emonds Alt, F. Rossi, C. Advenier
Journal: European Respiratory Journal (2002)

Gastro-oesophageal reflux is a common clinical disorder associated with a variety of respiratory symptoms, including chronic cough and exacerbation of asthma. In this study, the potential role of acid-induced tachykinin release was examined in guinea pigs and rabbits, by examining the effects of the tachykinin NK 1 and NK 3 receptors antagonists (SR 140333 and SR 142801, respectively) (1–10 mg·kg −1 ) on plasma protein extravasation induced in airways by hydrochloric acid (HCl) infusion in the oesophagus. Guinea pigs were anaesthetised with urethane, while rabbits were subject to neuroleptoanalgesia with hypnorm. Airway vascular leakage was evaluated by measuring extravasation of Evans blue dye. All animals were pretreated with atropine (1 mg·kg −1 i.p. ), propranolol (1 mg·kg −1 i.p. ), phosphoramidon (2.5 mg·kg −1 i.v. ) and saline or tachykinin receptor antagonists (1–10 mg·kg −1 i.p. ). Infusion of 1 N HCl into the oesophagus led to a three- and five-fold increase in plasma extravasation in the main bronchi and trachea, respectively. This increase was largely prevented by the tachykinin NK 1 and NK 3 receptor antagonists SR 140333 and SR 142801 (1–10 mg·kg −1 ). These results suggest that protein extravasation in the airways, as induced by intra-oesophageal HCl infusion, is mainly dependent on the release of tachykinins, and that both NK 1 and NK 3 tachykinin receptors are involved. The results suggest that HCl-induced sensory nerve stimulation may act in the periphery on intermediate neurons and/or ganglia where NK 3 receptors have been shown to play an important role.
Putting together the autoimmunity puzzle
Authors: Antonio La Cava
Journal: Journal of Clinical Investigation (2015)

Autoimmune diseases classically present with a complex etiology in which different factors concur in the generation and maintenance of autoreactive immune responses. Some mechanisms and pathways that lead to the development of imbalanced immune homeostasis and loss of self-tolerance have been identified as common to multiple autoimmune disorders. This Review series focuses on the general concepts of development and progression to pathogenic autoimmune phenotypes. A mechanistic discussion of the most recent advances in the field, together with related considerations of possible therapies, make this series of particular interest to both the basic and translational science communities.
The role of L-type Ca2+ current and Na+ current-stimulated Na/Ca exchange in triggering SR calcium release in guinea-pig cardiac ventricular myocytes
Authors: A.M Evans, M.B Cannell
Journal: Cardiovascular Research (1997)

Objective: This study examines the relative ability of sodium current (INa)-stimulated reverse mode Na/Ca exchange and the L-type calcium current (ICa) to trigger calcium-induced calcium release (CICR) in guinea-pig ventricular myocytes. Methods: Cytosolic Ca2+ transients were recorded from enzymatically dissociated guinea-pig ventricular mycocytes using Indo-1. Macroscopic membrane currents were simultaneously recorded using the whole-cell patch-clamp technique. Results: At room temperature (22–25°C) Ca2+ transients were associated with the activation of INa, ICa or INa plus ICa in combination. However, after ICa was blocked by verapamil (10 μM), no Ca2+ transient could be evoked by the activation of INa alone at either −40 or +5 mV. Similar results were obtained with 5 and 8 mM intracellular sodium, and when the temperature of the bathing solution was raised to 35°C and cAMP (10 μM) added to the pipette solution. Conclusions: From consideration of the relative magnitudes of the Ca2+ influx via ICa and Na/Ca exchange and thermodynamic considerations, we suggest that ICa is the major source of 'trigger' calcium for CICR (and cardiac contraction) under normal conditions. Although the Na/Ca exchanger was incapable of triggering CICR under the conditions of these experiments, we suggest that it may become more important when cytosolic Ca2+ is elevated, a condition which will also lead to decrease the amplitude of ICa.
A pilot study using carboplatin, vincristine, and temozolomide in children with progressive/symptomatic low-grade glioma: a Children's Oncology Group study
Authors: Murali Chintagumpala, Sandrah P. Eckel, Mark Krailo, Michael Morris, Adekunle Adesina, Roger Packer, Ching Lau, Amar Gajjar
Journal: Neuro-Oncology (2015)

This study was initiated to test the feasibility and toxicity of a regimen that alternates the administration of weekly carboplatin and vincristine with temozolomide in the management of children with progressive and/or symptomatic low-grade glioma. Eligible children received a 10-week induction regimen followed by six 10-week cycles of maintenance chemotherapy. Feasibility was evaluated with short-term and long-term endpoints. Short-term feasibility was evaluated by the ability to complete induction and 1 maintenance cycle in 24 weeks without >25% reduction in either carboplatin or temozolomide. Long-term feasibility was evaluated by the ability to administer induction and 4 maintenance cycles within 60 weeks without >25% reduction in either carboplatin or temozolomide. Efficacy was assessed by response to initial chemotherapy and 5-year event-free survival. Initial pathology was reviewed centrally. Sixty-six patients were enrolled on the study. It was feasible to deliver the regimen, and toxicity was acceptable. The only significant toxicities were hematologic. Both the short-term and long-term feasibility endpoints were met. The short-term feasibility success rate was 87% (95% CI: 77%–96%) and the long-term feasibility success rate was 79% (95% CI: 68%–90%). The 5-year event-free survival was 46% (95% CI: 33%–58%) and the 5-year survival was 87% (95% CI: 75%–93%). It was feasible to deliver the combination of weekly carboplatin and vincristine alternating with temozolomide to children with progressive/symptomatic low-grade glioma with acceptable toxicities. This combination appears to be effective in delaying progression. Further trials are needed to establish the relative efficacy of this regimen compared with other regimens in use.
A Randomized Trial of<i>Ex vivo</i>CD40L Activation of a Dendritic Cell Vaccine in Colorectal Cancer Patients: Tumor-Specific Immune Responses Are Associated with Improved Survival
Authors: Richard J. Barth, Dawn A. Fisher, Paul K. Wallace, Jacqueline Y. Channon, Randolph J. Noelle, Jiang Gui, Marc S. Ernstoff
Journal: Clinical Cancer Research (2010)

To determine whether an autologous dendritic cell (DC) vaccine could induce antitumor immune responses in patients after resection of colorectal cancer metastases and whether these responses could be enhanced by activating DCs with CD40L.Twenty-six patients who had undergone resection of colorectal metastases were treated with intranodal injections of an autologous tumor lysate- and control protein [keyhole limpet hemocyanin (KLH)]-pulsed DC vaccine. Patients were randomized to receive DCs that had been either activated or not activated with CD40L. All patients were followed for a minimum of 5.5 years.Immunization induced an autologous tumor-specific T-cell proliferative or IFNγ enzyme-linked immunospot response in 15 of 24 assessable patients (63%) and a tumor-specific DTH response in 61%. Patients with evidence of a vaccine-induced, tumor-specific T-cell proliferative or IFNγ response 1 week after vaccination had a markedly better recurrence-free survival (RFS) at 5 years (63% versus 18%, P = 0.037) than nonresponders. In contrast, no association was observed between induction of KLH-specific immune responses and RFS. CD40L maturation induced CD86 and CD83 expression on DCs but had no effect on immune responses or RFS.Adjuvant treatment of patients after resection of colorectal metastases with an autologous tumor lysate-pulsed, DC vaccine-induced, tumor-specific immune responses in a high proportion of patients. There was an association between induction of tumor-specific immune responses and RFS. Activation of this DC vaccine with CD40L did not lead to increased immune responses.
Beyond the Laboratory
Authors: Julian P.J. Halcox, John E. Deanfield
Journal: Circulation (2004)

Results from large-scale clinical trials of lipid lowering with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have led to a revolution in the management of atherosclerosis. In addition to their potent effect on serum lipid levels, statins influence several other cellular pathways, including those involving inflammatory, oxidative, and thrombotic processes. These effects clearly have the potential to beneficially modify the atherogenic process, and it has been suggested that they contribute to the impressive results seen in the clinical trials. We review the clinical evidence for benefits of statin therapy that are distinct from their effect on lipid biology. In particular, we address three key issues: the role of statins in diseases not traditionally associated with elevated cholesterol levels; whether clinical benefits are seen with statin therapy before an effect on lipid levels; and whether the magnitude of clinical benefit observed with statin therapy is unrelated to the degree of cholesterol reduction. At present, low-density–lipoprotein lowering seems to be the primary mechanism underlying the clinical benefits of statin therapy and should remain the focus of risk-reduction strategies in clinical practice.
Cephalometric abnormalities in non-obese and obese patients with obstructive sleep apnoea
Authors: H Sakakibara, M Tong, K Matsushita, M Hirata, Y Konishi, S Suetsugu
Journal: European Respiratory Journal (1999)

The aim of this work was to comprehensively evaluate the cephalometric features in Japanese patients with obstructive sleep apnoea (OSA) and to elucidate the relationship between cephalometric variables and severity of apnoea. Forty-eight cephalometric variables were measured in 37 healthy males and 114 male OSA patients, who were classed into 54 non-obese (body mass index (BMI) <27 kg x m(-2), apnoea-hypopnoea index (AHI)=25.3+/-16.1 events x h(-1)) and 60 obese (BMI > or = 27 kg x m(-2), AHI=45.6+/-28.0 events h(-1)) groups. Diagnostic polysomnography was carried out in all of the OSA patients and in 19 of the normal controls. The non-obese OSA patients showed several cephalometric defects compared with their BMI-matched normal controls: 1) decreased facial A-P distance at cranial base, maxilla and mandible levels and decreased bony pharynx width; 2) enlarged tongue and inferior shift of the tongue volume; 3) enlarged soft palate; 4) inferiorly positioned hyoid bone; and 5) decreased upper airway width at four different levels. More extensive and severe soft tissue abnormalities with a few defects in craniofacial bony structures were found in the obese OSA group. For the non-obese OSA group, the stepwise regression model on AHI was significant with two bony structure variables as determinants: anterior cranial base length (S-N) and mandibular length (Me-Go). Although the regression model retained only linear distance between anterior vertebra and hyoid bone (H-VL) as an explainable determinant for AHI in the obese OSA group, H-VL was significantly correlated with soft tissue measurements such as overall tongue area (Ton), inferior tongue area (Ton2) and pharyngeal airway length (PNS-V). In conclusion, Japanese obstructive sleep apnoea patients have a series of cephalometric abnormalities similar to those described in Caucasian patients, and that the aetiology of obstructive sleep apnoea in obese patients may be different from that in non-obese patients. In obese patients, upper airway soft tissue enlargement may play a more important role in the development of obstructive sleep apnoea, whereas in non-obese patients, bony structure discrepancies may be the dominant contributing factors for obstructive sleep apnoea.
Association of Obstructive Sleep Apnea in Rapid Eye Movement Sleep With Reduced Glycemic Control in Type 2 Diabetes: Therapeutic Implications
Authors: Daniela Grimaldi, Guglielmo Beccuti, Carol Touma, Eve Van Cauter, Babak Mokhlesi
Journal: Diabetes Care (2013)

Severity of obstructive sleep apnea (OSA) has been associated with poorer glycemic control in type 2 diabetes. It is not known whether obstructive events during rapid eye movement (REM) sleep have a different metabolic impact compared with those during non-REM (NREM) sleep. Treatment of OSA is often limited to the first half of the night, when NREM rather than REM sleep predominates. We aimed to quantify the impact of OSA in REM versus NREM sleep on hemoglobin A1c (HbA1c) in subjects with type 2 diabetes.All participants underwent polysomnography, and glycemic control was assessed by HbA1c.Our analytic cohort included 115 subjects (65 women; age 55.2 ± 9.8 years; BMI 34.5 ± 7.5 kg/m(2)). In a multivariate linear regression model, REM apnea-hypopnea index (AHI) was independently associated with increasing levels of HbA1c (P = 0.008). In contrast, NREM AHI was not associated with HbA1c (P = 0.762). The mean adjusted HbA1c increased from 6.3% in subjects in the lowest quartile of REM AHI to 7.3% in subjects in the highest quartile of REM AHI (P = 0.044 for linear trend). Our model predicts that 4 h of continuous positive airway pressure (CPAP) use would leave 60% of REM sleep untreated and would be associated with a decrease in HbA1c by approximately 0.25%. In contrast, 7 h of CPAP use would cover more than 85% of REM sleep and would be associated with a decrease in HbA1c by as much as 1%.In type 2 diabetes, OSA during REM sleep may influence long-term glycemic control. The metabolic benefits of CPAP therapy may not be achieved with the typical adherence of 4 h per night.
Phosphodiesterase 5 Inhibition Improves β-Cell Function in Metabolic Syndrome
Authors: Kevin D. Hill, Aaron W. Eckhauser, Annis Marney, Nancy J. Brown
Journal: Diabetes Care (2009)

This study tested the hypothesis that phosphodiesterase 5 inhibition alone or in combination with ACE inhibition improves glucose homeostasis and fibrinolysis in individuals with metabolic syndrome.Insulin sensitivity, beta-cell function, and fibrinolytic parameters were measured in 18 adults with metabolic syndrome on 4 separate days after a randomized, crossover, double-blind, 3-week treatment with placebo, ramipril (10 mg/day), tadalafil (10 mg o.d.), and ramipril plus tadalafil.Ramipril decreased systolic and diastolic blood pressure, ACE activity, and angiotensin II and increased plasma renin activity. Ramipril did not affect insulin sensitivity or beta-cell function. In contrast, tadalafil improved beta-cell function (P = 0.01). This effect was observed in women (331.9 +/- 209.3 vs. 154.4 +/- 48.0 32 micro x mmol(-1) x l(-1), respectively, for tadalafil treatment vs. placebo; P = 0.01) but not in men. There was no effect of any treatment on fibrinolysis. CONCLUSIONS Phosphodiesterase 5 inhibition may represent a novel strategy for improving beta-cell function in metabolic syndrome.
Polycythemia vera blood burst-forming units-erythroid are hypersensitive to interleukin-3.
Authors: C H Dai, S B Krantz, R T Means, S T Horn, H S Gilbert
Journal: Journal of Clinical Investigation (1991)

Because polycythemia vera (PV) is a clonal hematopoietic stem cell disease with a trilineage hyperplasia, and interleukin-3 (IL-3) stimulates trilineage hematopoiesis, we have studied the response of highly purified PV blood burst-forming units-erythroid (BFU-E) to recombinant human IL-3 (rIL-3). Whereas the growth of normal blood BFU-E in vitro rapidly declined by 40 and 60% after 24 and 48 h of incubation without 50 U/ml of rIL-3, the growth of PV BFU-E declined by only 10 and 30% under the same conditions, demonstrating a reduced dependence on rIL-3. A reduced dependence of PV BFU-E on recombinant human erythropoietin (rEP) was also present. Dose-response experiments showed a 117-fold increase in PV BFU-E sensitivity to rIL-3, and a 6.5-fold increase in sensitivity to rEP, compared to normal BFU-E, whereas blood BFU-E from patients with secondary polycythemia responded like normal BFU-E. Endogenous erythroid colony (EEC) formation, which is independent of the addition of rEP, was reduced by 50% after erythroid colony-forming cells were generated from PV BFU-E in vitro without rIL-3 for 3 d, whereas rEP-stimulated erythroid colonies were unaffected. These studies demonstrate a striking hypersensitivity of PV blood BFU-E to rIL-3, which may be the major factor in the pathogenesis of increased erythropoiesis without increased EP concentrations.
Titin Develops Restoring Force in Rat Cardiac Myocytes
Authors: Michiel Helmes, Ka´roly Trombita´s, Henk Granzier
Journal: Circulation Research (1996)

When relaxed after contraction, isolated cardiac myocytes quickly relengthen back to their slack length. The molecular basis of the force that underlies passive relengthening, known as restoring force, is not well understood. In a previous study of titin's elasticity in cardiac myocytes, we proposed that titin/connectin develops restoring force, in addition to passive force. This study tested whether titin indeed contributes to the restoring force in cardiac myocytes. Skinned rat cardiac myocytes in suspension were shortened by ≈20%, using Ca 2+ -independent shortening, followed by relaxation. Cells were observed to relengthen until they reached their original slack sarcomere length. However, the ability to relengthen was abolished after cells had been treated for 12 minutes with trypsin (0.25 μg/mL, 20°C). Gel electrophoresis showed that this treatment had degraded titin without clearly affecting other proteins, and immunoelectron microscopy revealed that the elastic segment of titin in the I band was missing from the sarcomere. Restoring force was also directly measured, before and after trypsin treatment. Restoring force of control cells was −61±20 μg (per cell) at a sarcomere length of 1.70 μm. Comparison of our results with those of activated trabeculae indicated that a large fraction of restoring force of cardiac muscle originates from within the myocyte. Restoring force of myocytes was found to be depressed after titin had been degraded with trypsin. We conclude that cardiac titin indeed develops restoring force in shortened cardiac myocytes, in addition to passive force in stretched cells, and that titin functions as a bidirectional spring. Our work suggests that at the level of the whole heart, part of the actomyosin-based active force that is developed during systole is harnessed by titin, allowing for elastic diastolic recoil and aiding in ventricular filling.
Thoracoplasty and Contralateral Pneumothorax
Authors: R. A. Smith
Journal: Thorax (1953)

In certain instances of bilateral pulmonary tuber- culosis it is a frequent practice to recommend induction of an artificial pneumothorax (A.P.) to control disease on one side when indications for thoracoplasty on the other side are clear cut.A number of writers over the last 16 years have pointed out the extra risk and added danger of operating with a contralateral A.P. present, but have not specified the nature of this increased hazard except to reaffirm the frequency of spon- taneous pneumothorax on the contralateral side.The purpose of this paper is to report a series of patients in whom spontaneous pneumothorax did not occur, to make alternative suggestions to account for the changes which undoubtedly do occur on the side of the A.P., and to state reasons for believing that the A.P. is best dispensed with.The paper is based on observations made during and after operations.This study in patients with contralateral A.P. undergoing thoracoplasty was provided by the alleged occurrence of spontaneous pneumothorax on the contralateral (A.P.) side in three consecutive patients during the first 24 hours after the first stage of the operation.It is my contention that there is no increased likelihood of spontaneous pneumo- thorax following thoracoplasty compared with its occurrence during the course of A.P. therapy "Lung compression," therefore, will be applied throughout to describe those changes seen in the on July 30, 2023 by guest.
Book Review Clone: The road to Dolly, and the path ahead By Gina Kolata. 276 pp. New York, William Morrow, 1998. $23. 0-688-15692-4 Remaking Eden: Cloning and beyond in a brave new world By Lee M. Silver. 317 pp. New York, Avon Books, 1997. $25. 0-380-97494-0
Authors: Robert S. Schwartz
Journal: New England Journal of Medicine (1998)