tbuckley/cabot-search huggingface dataset:
Transpleural ventilation of explanted human lungs
Authors: C. K Choong, P. T Macklem, J. A Pierce, S. S Lefrak, J. C Woods, M. S Conradi, D. A Yablonskiy, J. C Hogg, K. Chino, J. D Cooper
Journal: Thorax (2007)

<b>Background:</b> The hypothesis that ventilation of emphysematous lungs would be enhanced by communication with the parenchyma through holes in the pleural surface was tested. <b>Methods:</b> Fresh human lungs were obtained from patients with emphysema undergoing lung transplantation. Control human lungs were obtained from organ donors whose lungs, for technical reasons, were not considered suitable for implantation. Lungs were ventilated through the bronchial tree or transpleurally via a small hole communicating with the underlying parenchyma over which a flanged silicone tube had been cemented to the surface of the lung (spiracle). Measurements included flow-volume-time curves during passive deflation via each pathway; volume of trapped gas recovered from lungs via spiracles when no additional gas was obtainable passively from the airways; and magnetic resonance imaging assessment of spatial distribution of hyperpolarised helium (<sup>3</sup>He) administered through either the airways or spiracles. <b>Results:</b> In emphysematous lungs, passively expelled volumes at 20 s were 94% greater through spiracles than via the airways. Following passive deflation from the airways, an average of 1.07 litres of trapped gas volume was recoverable via spiracles. Regions were ventilated by spiracles that were less well ventilated via bronchi. <b>Conclusions:</b> Because of the extensive collateral ventilation present in emphysematous lungs, direct communication with the lung parenchyma through non-anatomical pathways has the potential to improve the mechanics of breathing and hence ventilation.
Can dopamine agonists reduce the incidence and severity of OHSS in IVF/ICSI treatment cycles? A systematic review and meta-analysis
Authors: M. A. F. M. Youssef, M. van Wely, M. A. Hassan, H. G. Al-Inany, M. Mochtar, S. Khattab, F. van der Veen
Journal: Human Reproduction Update (2010)

Recently, dopamine agonists were proposed as a prophylactic treatment for ovarian hyperstimulation syndrome (OHSS) in women at high risk in IVF/ICSI treatment cycles. We conducted a systematic review and meta-analysis of randomized trials comparing the prophylactic effect of the dopamine agonist, cabergoline, versus no treatment in IVF/ICSI cycles. Primary outcome was OHSS incidence per randomized woman. Secondary outcomes were live birth rate, ongoing pregnancy rate, clinical pregnancy rate and miscarriage rate. Searches (until September 2009) were conducted in MEDLINE, EMBASE, Science Direct, Cochrane Library and databases of abstracts. Four randomized trials entailing 570 women were included. There was evidence of a statistically significant reduction in the incidence of OHSS in the cabergoline group (OR 0.41, 95% CI 0.25–0.66) with an absolute risk reduction of 12% (95% CI 6.1–18.2%), but there was no statistically significant evidence of a reduction in severe OHSS (OR 0.50, 95% CI 0.20–1.26). There was no evidence for a difference in clinical pregnancy rate (OR 1.07, 95% CI 0.70–1.62) and miscarriage rate (OR 0.31, 95% CI 0.03–3.07). Prophylactic treatment with the dopamine agonist, cabergoline, reduces the incidence, but not the severity of OHSS, without compromising pregnancy outcomes.
Reconstruction of the Patterns of Gene Expression in the Developing Mouse Heart Reveals an Architectural Arrangement That Facilitates the Understanding of Atrial Malformations and Arrhythmias
Authors: Alexandre T. Soufan, Maurice J.B. van den Hoff, Jan M. Ruijter, Piet A.J. de Boer, Jaco Hagoort, Sandra Webb, Robert H. Anderson, Antoon F.M. Moorman
Journal: Circulation Research (2004)

Firm knowledge about the formation of the atrial components and of the variations seen in congenital cardiac malformations and abnormal atrial rhythms is fundamental to our understanding of the normal structure of the definitive atrial chambers. The atrial region is relatively inaccessible and has continued to be the source of disagreement. Seeking to resolve these controversies, we made three-dimensional reconstructions of the myocardial components of the developing atrium, identifying domains on the basis of differential expression of myocardial markers, connexin40, and natriuretic precursor peptide A. These reconstructions, made from serial sections of mouse embryos, show that from the outset of atrial development, the systemic and pulmonary veins are directly connected to the atrium. Relative to the systemic junctions, however, the pulmonary venous junction appears later. Our experience shows that three-dimensional reconstructions have three advantages. First, they provide clear access to the combined morphological and molecular data, allowing clarification and verification of morphogenetic concepts for nonmorphological experts and setting the scene for further discussion. Second, they demonstrate that, from the outset, the myocardium surrounding the pulmonary veins is distinct from that clothing the systemic venoatrial junctions. Third, they reveal an anatomical and molecular continuity between the entrance of the systemic venous tributaries, the internodal atrial myocardium, and the atrioventricular region. All these regions are derived from primary myocardium, providing a molecular basis for the observed nonrandom distribution of focal right atrial tachycardias.
<i>Notch4</i> Normalization Reduces Blood Vessel Size in Arteriovenous Malformations
Authors: Patrick A. Murphy, Tyson N. Kim, Gloria Lu, Andrew W. Bollen, Chris B. Schaffer, Rong A. Wang
Journal: Science Translational Medicine (2012)

Abnormally enlarged blood vessels underlie many life-threatening disorders including arteriovenous (AV) malformations (AVMs). The core defect in AVMs is high-flow AV shunts, which connect arteries directly to veins, "stealing" blood from capillaries. Here, we studied mouse brain AV shunts caused by up-regulation of Notch signaling in endothelial cells (ECs) through transgenic expression of constitutively active Notch4 (Notch4*). Using four-dimensional two-photon imaging through a cranial window, we found that normalizing Notch signaling by repressing Notch4* expression converted large-caliber, high-flow AV shunts to capillary-like vessels. The structural regression of the high-flow AV shunts returned blood to capillaries, thus reversing tissue hypoxia. This regression was initiated by vessel narrowing without the loss of ECs and required restoration of EphB4 receptor expression by venous ECs. Normalization of Notch signaling resulting in regression of high-flow AV shunts, and a return to normal blood flow suggests that targeting the Notch pathway may be useful therapeutically for treating diseases such as AVMs.
Clinical, Pharmacodynamic, and Pharmacokinetic Evaluation of BNC105P: A Phase I Trial of a Novel Vascular Disrupting Agent and Inhibitor of Cancer Cell Proliferation
Authors: Danny Rischin, David C. Bibby, Geoff Chong, Gabriel Kremmidiotis, Annabell F. Leske, Clayton A. Matthews, Shirley S. Wong, Mark A. Rosen, Jayesh Desai
Journal: Clinical Cancer Research (2011)

Abstract Purpose: To determine the recommended phase II dose and evaluate the safety and toxicity profile and pharmacokinetic (PK) and pharmacodynamic (PD) effects of BNC105P, an inhibitor of tubulin polymerization that has vascular disrupting and antiproliferative effects. Experimental Design: BNC105P was administered as a 10-minute infusion on days 1 and 8 of a 21-day cycle in a first-in-human phase I study. A dynamic accelerated dose titration method was used for dose escalation. Plasma concentrations of BNC105P (phosphate prodrug) and BNC105 (active agent) were determined. PD assessments were carried out using dynamic contrast enhanced (DCE)-MRI and analysis of a blood-borne biomarker. Results: Twenty-one subjects with advanced solid tumors were enrolled on 6 dose levels (range: 2.1–18.9 mg/m2). The recommended dose level was 16 mg/m2 and was well tolerated. BNC105P (prodrug) rapidly converted to BNC105 with a half-life of 0.13 hours. Plasma concentrations of BNC105 generally increased in proportion to dose with a half-life of 0.57 hours. Pharmacodymanically active plasma levels were obtained with a dose dependant reduction in the levels of polymerized tubulin (on-target action) being observed in PBMCs. DCE-MRI also indicated blood flow changes in the tumor lesions of a number of subjects. Conclusions: BNC105P has a favorable toxicity profile at the recommended dose of 16 mg/m2 and is associated with PD changes consistent with its known mechanism of action. Phase II studies in renal cancer and mesothelioma have commenced. Clin Cancer Res; 17(15); 5152–60. ©2011 AACR.
Comprehensive volumetric optical microscopy in vivo
Authors: Seok H. Yun, Guillermo J. Tearney, Benjamin J. Vakoc, Milen Shishkov, Wang-Yuhl Oh, Adrien E. Desjardins, Melissa J. Suter, Raymond C. Chan, John A. Evans, Ik-Kyung Jang, Norman S. Nishioka, Johannes F. de Boer, Brett E. Bouma
Journal: Nature Medicine (2006)
A Risk Score for Predicting Incident Diabetes in the Thai Population
Authors: Wichai Aekplakorn, Pongamorn Bunnag, Mark Woodward, Piyamitr Sritara, Sayan Cheepudomwit, Sukit Yamwong, Tada Yipintsoi, Rajata Rajatanavin
Journal: Diabetes Care (2006)

OBJECTIVE—The objective of this study was to develop and evaluate a risk score to predict people at high risk of diabetes in Thailand. RESEARCH DESIGN AND METHODS—A Thai cohort of 2,677 individuals, aged 35–55 years, without diabetes at baseline, was resurveyed after 12 years. Logistic regression models were used to identify baseline risk factors that predicted the incidence of diabetes; a simple model that included only those risk factors as significant (P &amp;lt; 0.05) when adjusted for each other was developed. The coefficients from this model were transformed into components of a diabetes score. This score was tested in a Thai validation cohort of a different 2,420 individuals. RESULTS—A total of 361 individuals developed type 2 diabetes in the exploratory cohort during the follow-up period. The significant predictive variables in the simple model were age, BMI, waist circumference, hypertension, and history of diabetes in parents or siblings A cutoff score of 6 of 17 produced the optimal sum of sensitivity (77%) and specificity (60%). The area under the receiver-operating characteristic curve (AUC) was 0.74. Adding impaired fasting glucose or impaired glucose tolerance status to the model slightly increased the AUC to 0.78; adding low HDL cholesterol and/or high triglycerides barely improved the model. The validation cohort demonstrated similar results. CONCLUSIONS—A simple diabetes risk score, based on a set of variables not requiring laboratory tests, can be used for early intervention to delay or prevent the disease in Thailand. Adding impaired fasting glucose or impaired glucose tolerance or triglyceride and HDL cholesterol status to this model only modestly improves the predictive ability.
Sleep and Sleep-disordered Breathing in Adults with Predominantly Mild Obstructive Airway Disease
Authors: Mark H. Sanders, Anne B. Newman, Catherine L. Haggerty, Susan Redline, Michael Lebowitz, Jonathan Samet, George T. O'Connor, Naresh M. Punjabi, Eyal Shahar
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Neither the association between obstructive airways disease (OAD) and sleep apnea–hypopnea (SAH) nor the sleep consequences of each disorder alone and together have been characterized in an adult community setting. Our primary aims were (1) to determine if there is an association between OAD and SAH and (2) identify predictors of oxyhemoglobin desaturation during sleep in persons having OAD with and without SAH. Polysomnography and spirometry results from 5,954 participants in the Sleep Heart Health Study were analyzed. OAD was defined by a FEV1/FVC value less than 70%. Assessment of SAH prevalence in OAD was performed using thresholds of respiratory disturbance index (RDI) greater than 10 and greater than 15. A total of 1,132 participants had OAD that was predominantly mild (FEV1/FVC 63.81 ± 6.56%, mean ± SD). SAH was not more prevalent in participants with OAD than in those without OAD (22.32 versus 28.86%, with and without OAD, respectively, at RDI threshold values greater than 10; and 13.97 versus 18.63%, with and without OAD, respectively, at RDI threshold value greater than 15). In the absence of SAH, the adjusted odds ratio for sleep desaturation (> 5% total sleep time with saturation < 90%) was greater than 1.9 when FEV1/FVC was less than 65%. Participants with both OAD and SAH had greater sleep perturbation and desaturation than those with one disorder. Generally mild OAD alone was associated with minimally altered sleep quality. We conclude that (1) there is no association between generally mild OAD and SAH; (2) exclusive of SAH and after adjusting for demographic factors and awake oxyhemoglobin saturation, an FEV1/FVC value less than 65% is associated with increased risk of sleep desaturation; (3) desaturation is greater in persons with both OAD and SAH compared with each of these alone; and (4) individuals with generally mild OAD and without SAH in the community have minimally perturbed sleep.
Analysis of sustained-release tablet film coats using terahertz pulsed imaging
Authors: L. Ho, R. Müller, M. Römer, K.C. Gordon, J. Heinämäki, P. Kleinebudde, M. Pepper, T. Rades, Y.C. Shen, C.J. Strachan, P.F. Taday, J.A. Zeitler
Journal: Journal of Controlled Release (2007)
The Helix–Loop–Helix Factors Id3 and E47 Are Novel Regulators of Adiponectin
Authors: Amanda C. Doran, Nahum Meller, Alexis Cutchins, Hamid Deliri, R. Parker Slayton, Stephanie N. Oldham, Jae B. Kim, Susanna R. Keller, Coleen A. McNamara
Journal: Circulation Research (2008)

Adiponectin is an adipocyte-derived cytokine with beneficial effects on insulin sensitivity and the development of atherosclerosis. Id3 is a helix–loop–helix factor that binds to E-proteins such as E47 and inhibits their binding to DNA. Although the helix–loop–helix factor sterol regulatory element binding protein (SREBP)-1c is a known activator of adiponectin transcription, this study provides the first evidence of a role for Id3 and E47 in adiponectin expression. Decreased Id3 in differentiating adipocytes correlates with increased adiponectin expression and forced expression of Id3 inhibits adiponectin expression. Moreover, Id3-null mice have increased adiponectin expression in visceral fat tissue and in serum. We demonstrate that E47 potentiates SREBP-1c–mediated adiponectin promoter activation and that Id3 can dose-dependently inhibit this action via interaction with E47. Mutation of a consensus E47 binding site results in nearly complete loss of promoter activation. Furthermore, we demonstrate E47 binding to the endogenous adiponectin promoter both in vitro and in vivo by chromatin immunoprecipitation analysis. Binding is not detected in undifferentiated cells which express Id3 but peaks during differentiation in parallel with Id3 decline. This promoter binding can be completely abolished by the overexpression of Id3 and is enhanced in adipose tissue null for Id3. These data establish Id3 and E47 as novel regulators of SREBP-1c–mediated adiponectin expression in differentiating adipocytes and provide evidence that Id3 regulates adiponectin expression in vivo.
Expression and sub-cellular localization of an epigenetic regulator, co-activator arginine methyltransferase 1 (CARM1), is associated with specific breast cancer subtypes and ethnicity
Authors: Melissa B Davis, Xinyu Liu, Shiyao Wang, Jaxk Reeves, Andrey Khramtsov, Dezheng Huo, Olufunmilayo I Olopade
Journal: Molecular Cancer (2013)

Co-Activator Arginine Methyltransferase 1(CARM1) is an Estrogen Receptor (ER) cofactor that remodels chromatin for gene regulation via methylation of Histone3. We investigated CARM1 levels and localization across breast cancer tumors in a cohort of patients of either European or African ancestry. We analyzed CARM1 levels using tissue microarrays with over 800 histological samples from 549 female cancer patients from the US and Nigeria, Africa. We assessed associations between CARM1 expression localized to the nucleus and cytoplasm for 11 distinct variables, including; ER status, Progesterone Receptor status, molecular subtypes, ethnicity, HER2+ status, other clinical variables and survival. We found that levels of cytoplasmic CARM1 are distinct among tumor sub-types and increased levels are associated with ER-negative (ER-) status. Higher nuclear CARM1 levels are associated with HER2 receptor status. EGFR expression also correlates with localization of CARM1 into the cytoplasm. This suggests there are distinct functions of CARM1 among molecular tumor types. Our data reveals a basal-like subtype association with CARM1, possibly due to expression of Epidermal Growth Factor Receptor (EGFR). Lastly, increased cytoplasmic CARM1, relative to nuclear levels, appear to be associated with self-identified African ethnicity and this result is being further investigated using quantified genetic ancestry measures. Although it is known to be an ER cofactor in breast cancer, CARM1 expression levels are independent of ER. CARM1 has distinct functions among molecular subtypes, as is indicative of its sub-cellular localization and it may function in subtype etiology. These sub-cellular localization patterns, indicate a novel role beyond its ER cofactor function in breast cancer. Differential localization among ethnic groups may be due to ancestry-specific polymorphisms which alter the gene product.
Epigenetic Modifiers: Basic Understanding and Clinical Development
Authors: Richard L. Piekarz, Susan E. Bates
Journal: Clinical Cancer Research (2009)

More than 60 years after the first description of differentiation in cell culture and 40 years after the synthesis of 5-azacytidine, epigenetic therapies have been added to the anticancer armamentarium. DNA methyltransferase (DNMT) inhibitors such as 5-aza-2'-deoxycytidine or 5-azacytidine have been approved in myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML), whereas the histone deacetylase inhibitors (HDIs) including vorinostat, romidepsin, panobinostat, belinostat, and entinostat have been shown to be active in cutaneous and peripheral T-cell lymphoma. Although the range of malignancies in which monotherapy with DNMT inhibitors or HDIs are effective has been limited to date, the possibility remains that a broader spectrum of activity will be identified as combination studies are completed. Meanwhile, basic science has provided a steadily increasing understanding of the complexity of the epigenome, including the histone code and triggers for aberrant methylation, and their contribution to oncogenesis. As our basic understanding of the epigenetics of cancer increases, the number of potential therapeutic targets will also increase, offering more hope in the quest to treat cancer by normalizing the epigenome. This issue of CCR Focus is dedicated to understanding the clinical and translational aspects of epigenetics research.
Tomato profilin Lyc e 1: IgE cross‐reactivity and allergenic potency
Authors: S. Westphal, W. Kempf, K. Foetisch, M. Retzek, S. Vieths, S. Scheurer
Journal: Allergy (2004)

Background: To date, very little data are available about the nature of tomato allergens. Immunoglobulin E (IgE) cross‐reactive profilins have been suggested to account for allergic symptoms in patients suffering from tomato allergy. Methods: The cDNA of tomato profilin was amplified by reversely transcribed polymerase chain reaction (RT‐PCR) from total RNA extracted from ripe tomato fruit. The gene was cloned into the pET101D expression plasmid and the protein was produced in Escherichia coli BL21. Purification was performed via poly‐ l ‐proline (PLP) affinity chromatography. IgE reactivity of recombinant tomato profilin was investigated by immunoblot and enzyme‐linked immunosorbent assay. IgE‐inhibition studies were performed to analyse cross‐reactivity with other profilins. To determine the allergenic activity of the recombinant protein, basophil histamine release assays using sera of patients with adverse reactions to tomato were performed. Results: Profilin was identified as a new minor allergen in tomato fruits. The recombinant tomato profilin comprises 131 amino acids and high sequence identity to other allergenic food and pollen profilins. It was shown to be IgE‐reactive with a prevalence of 22% (11/50) in tomato‐allergic patients. In patients with tomato allergy and multiple sensitization to other foods and birch pollen, IgE directed against tomato profilin showed a strong cross‐reactivity with profilins from plant food sources and birch pollen. The tomato profilin was able to induce mediator release from human basophils. Conclusion: The tomato profilin is a minor allergen in tomato fruit. Thus, it shows biological activity, as confirmed by in vitro histamine release assays with human basophils and thereby has the potential to account for clinical symptoms in tomato‐allergic patients.
The beneficial effects of thyroxine on nephrotoxic acute renal failure in the rat.
Authors: U F Michael, J L Logan, L A Meeks
Journal: Journal of the American Society of Nephrology (1991)

We were able to confirm previous studies demonstrating that administration of thyroxine is capable of ameliorating the severity of acute nephrotoxic renal failure in the rat. Nephrotoxic acute renal failure was induced by the subcutaneous injection of potassium dichromate (6.25 mg/kg) into Sprague-Dawley rats. Twenty-four hours after this injection, rats received an intraperitoneal injection of either thyroxine (80 micrograms/kg body wt) or normal saline. Forty-eight hours after the potassium dichromate injection, renal clearance studies were performed. Inulin clearance was significantly higher in the thyroxine-treated than in the saline-treated acute renal failure rats: 1.12 +/- 0.13 (SEM) mL/g versus 0.75 +/- 0.07 mL/min/g kidney wt (P = 0.025). Thyroxine treatment also effected an increase of p-aminohippuric acid extraction from 0.23 +/- 0.03 to 0.33 +/- 0.02 (P = 0.011) and a decrease in the fractional excretion of sodium from 0.38 +/- 0.21 to 0.11 +/- 0.03% (P = 0.037 by Mann-Whitney U test). In order to investigate one potential mechanism of the beneficial effect of thyroxine we studied renal tubular regeneration in this model of acute renal failure. Renal cortical uptake of labeled thymidine into DNA was significantly increased 48 h after the injection of potassium dichromate, and thyroxine administration further enhanced this repair process: 53.9 +/- 3.6 versus 81.4 +/- 5.3 dpm/200 pg of DNA (P = 0.0033).