tbuckley/cabot-search huggingface dataset:
Is Long QT Syndrome a Disease of Abnormal Mechanical Contraction?
Authors: David S. Rosenbaum
Journal: Circulation (2010)

I t is generally assumed that long QT syndrome (LQTS) is an arrhythmic disorder that occurs in patients with normal left ventricular systolic function.The present article by Haugaa et al challenges this assumption. 1 One hundred and one patients with genetically documented LQTS were systematically compared to an age-matched unaffected control population for differences in regional contraction patterns as assessed by the speckled tracking method.Among the LQTS population, 64 had LQT1, 26 had LQT2, 1 had LQT3, 1 had LQT5, and 9 had documented Jervell and Lange Nielsen Syndrome.About half of all patients with LQTS were symptomatic.Various metrics of regional left ventricular contraction and spatial inhomogeneity of contraction were assessed.In addition to global strain, mean contraction duration measured separately in the longitudinal and circumferential directions was assessed as a mechanical counterpart to action potential duration or QT interval, dispersion of longitudinal or circumferential contraction duration served as a mechanical counterpart to regional (eg, apex versus base) dispersion of repolarization, and differences between longitudinal and circumferential contraction duration within individual regions served as a mechanical counterpart to transmural dispersion of repolarization.The latter measure was based on the assumption that longitudinal and circumferential contraction arise selectively from endocardial and midmyocardial locations, respectively, across the transmural wall.This assumption, in turn, is based on the finding that subendocardium mainly consists of longitudinal fibers, whereas midmyocardium mainly consists of circumferentially oriented fibers.
Declining Lung Cancer Rates Among Young Men and Women in the United States: A Cohort Analysis
Authors: S. S. Devesa, W. J. Blot, J. F. Fraumeni
Journal: JNCI Journal of the National Cancer Institute (1989)

Journal Article Declining Lung Cancer Rates Among Young Men and Women in the United States: A Cohort Analysis Get access Susan S. Devesa, Susan S. Devesa * Epidemiology and Biostatistics Program, Division of Cancer Etiology, National Cancer InstituteBethesda, MD *Correspondence to: Dr. Susan S. Devesa, Epidemiology and Biostatistics Program, Division of Cancer Etiology, National Cancer Institute, Executive Plaza North, Rm. 415, Bethesda, MI 20892. Search for other works by this author on: Oxford Academic PubMed Google Scholar William J. Blot, William J. Blot Epidemiology and Biostatistics Program, Division of Cancer Etiology, National Cancer InstituteBethesda, MD Search for other works by this author on: Oxford Academic PubMed Google Scholar Joseph F. Fraumeni, Jr. Joseph F. Fraumeni, Jr. Epidemiology and Biostatistics Program, Division of Cancer Etiology, National Cancer InstituteBethesda, MD Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 81, Issue 20, 18 October 1989, Pages 1568–1571, https://doi.org/10.1093/jnci/81.20.1568 Published: 18 October 1989 Article history Received: 17 May 1989 Revision received: 06 July 1989 Accepted: 07 July 1989 Published: 18 October 1989
Delayed cord clamping and improved infant outcomes
Authors: P. van Rheenen
Journal: BMJ (2011)

Enough evidence exists to encourage a routine change in practice

Cord clamping and cutting is a common procedure but little agreement exists among doctors about the optimal timing. Cord clamping takes place in the third stage of labour, which is defined as the period from expulsion of the fetus to the expulsion of the placenta. Early clamping in term babies is sometime between 10 seconds and one minute after birth, whereas delayed clamping is between two minutes after birth and cessation of cord pulsations. In the linked randomised trial (doi:10.1136/bmj.d7157), Andersson and colleagues compare the effects of early versus delayed cord clamping on infant iron status at 4 months of age in a European setting.1

Management of the third stage of labour has typically focused on women and prevention of postpartum haemorrhage. A systematic review published in 2000 found that active management involving the use of oxytocics, early cord clamping, and controlled cord traction was superior to expectant management in terms of maternal blood loss.2 For this reason, early clamping was accepted into obstetric practice without much consideration.

Another systematic review published in 2008 studied the effects of different cord clamping times …
EXUBERANT INFLAMMATORY REACTION AFTER AN INFILTRATION OF PLATELET-RICH PLASMA (PRP)
Authors: J F Kaux, J L Croisier, P Léonard, C Le Goff, J M Crielaard
Journal: British Journal of Sports Medicine (2013)

Background PRP, obtained from centrifuged autologous blood, contains a large quantity of growth factors, which may enhance tissue healing processes. Local infiltration of PRP represents a relatively new treatment for tendinopathies. To date, no side effects have been reported after infiltration of PRP to treat tendinopathy. 1 Case report A 35-year-old patient had a right upper patellar tendinopathy which was resistant to all of the conservative treatments for more than six months. The patient was a type 1 diabetic (well controlled). He benefited from an intratendinous infiltration of 6 mL of PRP (8.105 platelets/mm 3, almost no red or white blood cells) without local anaesthetic. Immediately following the infiltration, local cryotherapy was performed for 15 minutes. NSAIDs were avoided, but class-1 or -2 pain-killers were authorised if necessary. A standardised sub-maximal eccentric rehabilitation should be started 1 week after. However, the patient experienced local swelling with erythema, increased heating and pain which appeared just underneath the patella, but without biological inflammatory syndrome. A great Doppler signal in a thicker patellar tendon was observed by US, but there was no sign of local infectious disease demonstrated by either CT or MRI. However, the local inflammation did not decrease after a progressive 3-week treatment of local cryotherapy, local and oral NSAIDs and colchicine 1 mg. Thus, an insidious infection was suspected, even though there was neither evidence of biological inflammatory syndrome or sign of infectious lesion on imagery examination. An antibiotic therapy (rifampicine 600 mg+minocycline 100 mg) was initiated for 3 months. Finally, a 3-phase bone scintigraphy suggested the presence of a complex regional pain syndrome type 1 treated by a classical physical therapy and concomitant class-2 pain killers. The evolution was favourable after 6 months of symptomatic treatment, and the pain decreased to a level similar to that before the infiltration of PRP. Discussion/Conclusions This case report calls attention to potential side effects that are linked to this new therapy by infiltration of platelet rich plasma in case of tendinopathy, in particular when used in patients with type 1 diabetes. Thus, the balance between benefits and risks must be carefully evaluated before using this treatment in patients with type 1 diabetes.
γ-Secretase-Dependent Proteolysis of CD44 Promotes Neoplastic Transformation of Rat Fibroblastic Cells
Authors: Ludivine Pelletier, Patricia Guillaumot, Barbara Frêche, Céline Luquain, Dale Christiansen, Sabine Brugière, Jérome Garin, Serge N. Manié
Journal: Cancer Research (2006)

Abstract The metalloprotease-dependent extracellular domain cleavage of the adhesion molecule CD44 is frequently observed in human tumors and is thought to promote metastasis. This cleavage is followed by γ-secretase-dependent release of CD44 intracellular domain (CD44-ICD), which exhibits nuclear signaling activity. Using a reversible Ret-dependent oncogenic conversion model and a restricted proteomic approach, we identified a positive correlation between the neoplastic transformation of Rat-1 cells and the expression of standard CD44. In these transformed cells, CD44 was found to undergo a sequential metalloprotease and γ-secretase cleavage, resulting in an increase in expression of CD44-ICD. We showed that this proteolytic fragment possesses a transforming activity. In support of this role, a significant and specific reduction in Ret-induced transformation of Rat-1 cells was observed following drug-mediated inhibition of γ-secretase. Taken together, these findings suggest that the shedding of CD44 may not only modulate metastasis but also affects earlier events in tumorigenesis through the release of CD44-ICD. (Cancer Res 2006; 66(7): 3681-7)
Aldosterone Regulates Na,K-ATPase and Increases Lung Edema Clearance in Rats
Authors: WALTER G. OLIVERA, DAVID E. CICCOLELLA, NORA BARQUIN, KAREN M. RIDGE, DAVID H. RUTSCHMAN, DONOVAN B. YEATES, JACOB I. SZNAJDER
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Aldosterone increases the Na,K-ATPase function in renal cells involved in active Na+ transport. Because the alveolar type 2 (AT2) cells participate in active Na+ transport, we studied whether aldosterone regulates the Na,K-ATPase in rat AT2 cells and whether aldosterone delivered by aerosols to spontaneously breathing rats affects edema clearance in a model of isolated-perfused lungs. The AT2 cells treated with aldosterone had increased Na,K-ATPase β 1-subunit mRNA and protein, which was associated with a 4-fold increase in the Na,K-ATPase hydrolytic activity and the ouabain-sensitive 86Rb+ uptake. In physiologic experiments, 24 h after aldosterone was delivered by aerosols to the rat air spaces, the active Na+ transport and lung edema clearance increased by ∼ 53% as compared with control rats and rats in which saline aerosols were delivered. The data suggest that increased active Na+ transport and lung edema clearance induced by aldosterone is probably due to Na,K-ATPase regulation in alveolar epithelial cells. Conceivably, aldosterone may be used as a strategy to increase lung edema clearance. Olivera WG, Ciccolella DE, Barquin N, Ridge KM, Rutschman DH, Yeates DB, Sznajder JI. Aldosterone regulates Na,K-ATPase and increases lung edema clearance in rats.
Silencing <i>HoxA1</i> by Intraductal Injection of siRNA Lipidoid Nanoparticles Prevents Mammary Tumor Progression in Mice
Authors: Amy Brock, Silva Krause, Hu Li, Marek Kowalski, Michael S. Goldberg, James J. Collins, Donald E. Ingber
Journal: Science Translational Medicine (2014)

Silencing of HoxA1 with nanoparticle siRNA prevented loss of hormone receptor expression, suppressed cell proliferation, and reduced mammary tumor incidence in mice.
Isoleucine, an Essential Amino Acid, Prevents Liver Metastases of Colon Cancer by Antiangiogenesis
Authors: Kazumoto Murata, Masami Moriyama
Journal: Cancer Research (2007)

Abstract In spite of recent advances in the treatment of colon cancer, multiple liver metastases of colon cancer are still difficult to treat. Some chemotherapeutic regimens have been reported to be efficient, but there is a high risk of side effects associated with these. Here, we show that isoleucine, an essential amino acid, prevents liver metastases in a mouse colon cancer metastatic model. Because isoleucine is a strong inducer of β-defensin, we first hypothesized that it prevented liver metastases via the accumulation of dendritic cells or memory T cells through up-regulation of β-defensin. However, neither β-defensin nor immunologic responses were induced by isoleucine in both mouse livers and spleens. Furthermore, isoleucine prevented liver metastasis in nude mice, which lack T cells and natural killer T cells. Finally, we discovered a novel mechanism of isoleucine: down-regulation of angiogenesis via inhibition of vascular endothelial growth factor, partially through the mammalian target of the rapamycin pathway, independent of hypoxia-inducible factor 1-α. Importantly, isoleucine is safe for administration to humans because it does not affect cell viability. Isoleucine could be a novel prophylactic drug for the prevention of liver metastases of colon cancer. [Cancer Res 2007;67(7):3263–8]
NPV-LDE-225 (Erismodegib) inhibits epithelial mesenchymal transition and self-renewal of glioblastoma initiating cells by regulating miR-21, miR-128, and miR-200
Authors: J. Fu, M. Rodova, R. Nanta, D. Meeker, P. J. Van Veldhuizen, R. K. Srivastava, S. Shankar
Journal: Neuro-Oncology (2013)

Glioblastoma multiforme is the most common form of primary brain tumor, often characterized by poor survival. Glioblastoma initiating cells (GICs) regulate self-renewal, differentiation, and tumor initiation properties and are involved in tumor growth, recurrence, and resistance to conventional treatments. The sonic hedgehog (SHH) signaling pathway is essential for normal development and embryonic morphogenesis. The objectives of this study were to examine the molecular mechanisms by which GIC characteristics are regulated by NPV-LDE-225 (Smoothened inhibitor; (2,2'-[[dihydro-2-(4-pyridinyl)-1,3(2H,4H)-pyrimidinediyl]bis(methylene)]bis[N,N-dimethylbenzenamine).Cell viability and apoptosis were measured by XTT and annexin V-propidium iodide assay, respectively. Gli translocation and transcriptional activities were measured by immunofluorescence and luciferase assay, respectively. Gene and protein expressions were measured by quantitative real-time PCR and Western blot analyses, respectively.NPV-LDE-225 inhibited cell viability, neurosphere formation, and Gli transcriptional activity and induced apoptosis by activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase. NPV-LDE-225 increased the expression of tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-R1/DR4, TRAIL-R2/DR5, and Fas and decreased the expression of platelet derived growth factor receptor-α and Bcl2, and these effects were abrogated by Gli1 plus Gli2 short hairpin RNAs. NPV-LDE-225 enhanced the therapeutic potential of FasL and TRAIL by upregulating Fas and DR4/5, respectively. Interestingly, NPV-LDE-225 induced expression of programmed cell death 4 and apoptosis and inhibited cell viability by suppressing micro RNA (miR)-21. Furthermore, NPV-LDE-225 inhibited pluripotency-maintaining factors Nanog, Oct4, Sox2, and cMyc. The inhibition of Bmi1 by NPV-LDE-225 was regulated by induction of miR-128. Finally, NPV-LDE-225 suppressed epithelial-mesenchymal transition by upregulating E-cadherin and inhibiting N-cadherin, Snail, Slug, and Zeb1 through modulating the miR-200 family. Our data highlight the importance of the SHH pathway for self-renewal and early metastasis of GICs.
Brains, Genes, and Primates
Authors: Juan Carlos Izpisua Belmonte, Edward M. Callaway, Sarah J. Caddick, Patricia Churchland, Guoping Feng, Gregg E. Homanics, Kuo-Fen Lee, David A. Leopold, Cory T. Miller, Jude F. Mitchell, Shoukhrat Mitalipov, Alysson R. Moutri, J. Anthony Movshon, Hideyuki Okano, John H. Reynolds, Dario L. Ringach, Terrence J. Sejnowski, Afonso C. Silva, Peter L. Strick, Jun Wu, Feng Zhang
Journal: Neuron (2015)
Cytokines in chronic inflammatory arthritis. V. Mutual antagonism between interferon-gamma and tumor necrosis factor-alpha on HLA-DR expression, proliferation, collagenase production, and granulocyte macrophage colony-stimulating factor production by rheumatoid arthritis synoviocytes.
Authors: J M Alvaro-Gracia, N J Zvaifler, G S Firestein
Journal: Journal of Clinical Investigation (1990)

The effects of a broad array of cytokines, individually and in combination, were determined on separate functions (proliferation, collagenase production, and granulocyte macrophage colony-stimulating factor [GM-CSF] production) and phenotype (expression of class II MHC antigens) of cultured fibroblast-like RA synoviocytes. The following recombinant cytokines were used: IL-1 beta, IL-2, IL-3, IL-4, IFN-gamma, tumor necrosis factor (TNF)-alpha, GM-CSF, and macrophage colony-stimulating factor (M-CSF). Only IFN-gamma induced HLA-DR (but not HLA-DQ) expression. TNF-alpha inhibited IFN-gamma-mediated HLA-DR expression (46.7 +/- 4.1% inhibition) and HLA-DR mRNA accumulation. This inhibitory effect was also observed in osteoarthritis synoviocytes. Only TNF-alpha and IL-1 increased synoviocyte proliferation (stimulation index 3.60 +/- 1.03 and 2.31 +/- 0.46, respectively). IFN-gamma (but none of the other cytokines) inhibited TNF-alpha-induced proliferation (70 +/- 14% inhibition) without affecting the activity of IL-1. Only IL-1 beta and TNF-alpha induced collagenase production (from less than 0.10 U/ml to 1.10 +/- 0.15 and 0.72 +/- 0.24, respectively). IFN-gamma decreased TNF-alpha-mediated collagenase production (69 +/- 19% inhibition) and GM-CSF production but had no effect on the action of IL-1. These data demonstrate mutual antagonism between IFN-gamma and TNF-alpha on fibroblast-like synoviocytes and suggest a novel homeostatic control mechanism that might be defective in RA where very little IFN-gamma is produced.
DNA Methylation Status of Key Cell-Cycle Regulators Such as <i>CDKNA2</i>/p16 and <i>CCNA1</i> Correlates with Treatment Response to Doxorubicin and 5-Fluorouracil in Locally Advanced Breast Tumors
Authors: Jovana Klajic, Florence Busato, Hege Edvardsen, Nizar Touleimat, Thomas Fleischer, Ida Bukholm, Anne-Lise Børresen-Dale, Per Eystein Lønning, Jörg Tost, Vessela N. Kristensen
Journal: Clinical Cancer Research (2014)

To explore alterations in gene promoter methylation as a potential cause of acquired drug resistance to doxorubicin or combined treatment with 5-fluorouracil and mitomycin C in human breast cancers.Paired tumor samples from locally advanced breast cancer patients treated with doxorubicin and 5-fluorouracil-mitomycin C were used in the genome-wide DNA methylation analysis as discovery cohort. An enlarged cohort from the same two prospective studies as those in the discovery cohort was used as a validation set in pyrosequencing analysis.A total of 469 genes were differentially methylated after treatment with doxorubicin and revealed a significant association with canonical pathways enriched for immune cell response and cell-cycle regulating genes including CDKN2A, CCND2, CCNA1, which were also associated to treatment response. Treatment with FUMI resulted in 343 differentially methylated genes representing canonical pathways such as retinoate biosynthesis, gαi signaling, and LXR/RXR activation. Despite the clearly different genes and pathways involved in the metabolism and therapeutic effect of both drugs, 46 genes were differentially methylated before and after treatment with both doxorubicin and FUMI. DNA methylation profiles in genes such as BRCA1, FOXC1, and IGFBP3, and most notably repetitive elements like ALU and LINE1, were associated with TP53 mutations status.We identified and validated key cell-cycle regulators differentially methylated before and after neoadjuvant chemotherapy such as CDKN2A and CCNA1 and reported that methylation patterns of these genes may be potential predictive markers to anthracycline/mitomycine sensitivity.
Medium term functional results of single-lung transplantation for endstage obstructive lung disease.
Authors: S M Levine, A Anzueto, J I Peters, T Cronin, E Y Sako, S G Jenkinson, C L Bryan
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

Controversy has surrounded the use of single-lung transplantation (SLT) for the treatment of endstage obstructive lung disease. In recent years, several transplant centers have performed SLT for such indications. In this report, we describe functional results in patients undergoing SLT for obstructive lung disease, twenty-two followed over one year and 10 over two years. Data include pulmonary function testing, gas exchange, quantitative ventilation and perfusion to the lung graft, and results of symptom-limited graded cycle exercise testing after SLT. Our results show improvement in obstructive dysfunction FEV1 0.49 +/- 0.13 L (16 +/- 4% predicted) pre-SLT to 1.71 +/- 0.43 L (57 +/- 12% predicted) 3 mo after SLT, FEV1/FVC 0.30 +/- 0.07 pre-SLT to 0.75 +/- 0.09 3 mo after SLT, and improvement in arterial oxygenation, PaO2 58 +/- 10 mm Hg pre SLT to PaO2 86 +/- 13 mm Hg 3 mo post-SLT. In addition, these improvements were sustained up to 1 to 2 yr post-SLT. The majority of ventilation and perfusion go to the new lung graft. After SLT, patients have reduced maximum oxygen consumption (VO2max 40 to 60% predicted) but do not have ventilatory limitation to exercise and can carry out daily activities without compromise. We conclude that SLT is a viable medium-term therapeutic option for endstage obstructive lung disease. The long-term future of this technique remains to be determined.
The Relationship of Childhood Abuse to Impulsivity and Suicidal Behavior in Adults With Major Depression
Authors: B S Brodsky, M Oquendo, S P Ellis, G L Haas, K M Malone, J J Mann
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: This study investigated whether a higher frequency of reported childhood trauma would be found in depressed adults with higher levels of trait impulsivity, aggression, and suicidal behavior. METHOD: In 136 depressed adult inpatients, the authors assessed trait impulsivity, aggression history, and number of lifetime suicide attempts as well as the medical lethality and the intent to die associated with the most lethal attempt. These variables were then compared between those with and those without a reported history of childhood physical or sexual abuse. RESULTS: Subjects who reported an abuse history were more likely to have made a suicide attempt and had significantly higher impulsivity and aggression scores than those who did not report an abuse history. Impulsivity and aggression scores were significantly higher in subjects with a history of at least one suicide attempt. A logistic regression analysis revealed that abuse history remained significantly associated with suicide attempt status after adjustment for impulsivity, aggression history, and presence of borderline personality disorder. Among those who attempted suicide, there were no significant differences in severity of suicidal behavior between those with and without a childhood history of abuse. CONCLUSIONS: Abuse in childhood may constitute an environmental risk factor for the development of trait impulsivity and aggression as well as suicide attempts in depressed adults. Alternatively, impulsivity and aggression may be inherited traits underlying both childhood abuse and suicidal behavior in adulthood disorders. Additional research is needed to estimate the relative contributions of heredity and environmental experience to the development of impulsivity, aggression, and suicidal behavior.