tbuckley/cabot-search huggingface dataset:
Dobutamine stress for evaluation of right ventricular reserve in pulmonary arterial hypertension
Authors: Tripura Sharma, Edmund M.T. Lau, Preeti Choudhary, Paul J. Torzillo, Phillip A. Munoz, Lisa R. Simmons, Robert Naeije, David S. Celermajer
Journal: European Respiratory Journal (2014)

Right ventricular contractile response to pharmacological stress in pulmonary arterial hypertension (PAH) has not been characterised. We evaluated right ventricular contractile reserve in adults with PAH using dobutamine stress echocardiography. 16 PAH patients and 18 age-matched controls underwent low-dose dobutamine stress echocardiography. Contractile reserve was assessed by the change (Δ; peak stress minus rest value) in tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular systolic velocity (S′). A subgroup of 13 PAH patients underwent treadmill cardiopulmonary exercise testing for peak oxygen uptake ( V ′ O 2 peak ). At rest, TAPSE and S′ were reduced in the PAH group compared with controls (1.7±0.4 versus 2.4±0.2 cm and 9.7±2.6 versus 12.5±1.2 cm·s −1 , respectively; p&lt;0.05). Contractile reserve was markedly attenuated in PAH compared to controls (ΔTAPSE 0.1±0.2 versus 0.6±0.3 cm and ΔS′ 4.6±2.8 versus 11.2±3.6 cm·s −1 ; p&lt;0.0001). In the sub-group of PAH patients with preserved right ventricular systolic function at rest, contractile reserve remained depressed compared to controls. V ′ O 2 peak was significantly correlated with ΔS′ (r=0.87, p=0.0003) and change in stroke volume (r=0.59, p=0.03). Dobutamine stress can reveal sub-clinical reduction in right ventricular contractile reserve in patients with PAH. A correlation with exercise capacity suggests potential clinical value beyond resting measurements.
Oncogenic PI3K Mutations Lead to NF-κB–Dependent Cytokine Expression following Growth Factor Deprivation
Authors: Jessica E. Hutti, Adam D. Pfefferle, Sean C. Russell, Mayukh Sircar, Charles M. Perou, Albert S. Baldwin
Journal: Cancer Research (2012)

Abstract The phosphoinositide 3-kinase (PI3K) pathway is one of the most commonly misregulated signaling pathways in human cancers, but its impact on the tumor microenvironment has not been considered as deeply as its autonomous impact on tumor cells. In this study, we show that NF-κB is activated by the two most common PI3K mutations, PIK3CA E545K and H1047R. We found that markers of NF-κB are most strongly upregulated under conditions of growth factor deprivation. Gene expression analysis conducted on cells deprived of growth factors identified the repertoire of genes altered by oncogenic PI3K mutations following growth factor deprivation. This gene set most closely correlated with gene signatures from claudin-low and basal-like breast tumors, subtypes frequently exhibiting constitutive PI3K/Akt activity. An NF-κB–dependent subset of genes driven by oncogenic PI3K mutations was also identified that encoded primarily secreted proteins, suggesting a paracrine role for this gene set. Interestingly, while NF-κB activated by oncogenes such as Ras and EGF receptor leads to cell-autonomous effects, abrogating NF-κB in PI3K-transformed cells did not decrease proliferation or induce apoptosis. However, conditioned media from PI3K mutant-expressing cells led to increased STAT3 activation in recipient THP-1 monocytes or normal epithelial cells in a NF-κB and interleukin-6–dependent manner. Together, our findings describe a PI3K-driven, NF-κB–dependent transcriptional profile that may play a critical role in promoting a microenvironment amenable to tumor progression. These data also indicate that NF-κB plays diverse roles downstream from different oncogenic signaling pathways. Cancer Res; 72(13); 3260–9. ©2012 AACR.
Computed Tomography Radiation Dose in Patients With Suspected Urolithiasis
Authors: Rebecca Smith-Bindman, Michelle Moghadassi, Richard T. Griffey, Carlos A. Camargo, John Bailitz, Michael Beland, Diana L. Miglioretti
Journal: JAMA Internal Medicine (2015)

metrics to evaluate the progress of obesity-prevention strategies toward sustainable implementation.Delivering these strategies is a priority to counter the burden of obesity on contemporary and future generations.
Intravenous Immunoglobulins Modulate Neutrophil Activation and Vascular Injury Through FcγRIII and SHP-1
Authors: Jung-Eun Jang, Andrés Hidalgo, Paul S. Frenette
Journal: Circulation Research (2012)

Intravascular neutrophil recruitment and activation are key pathogenic factors that contribute to vascular injury. Intravenous immunoglobulin (IVIG) has been shown to have a beneficial effect in systemic inflammatory disorders; however, the mechanisms underlying IVIG's inhibitory effect on neutrophil recruitment and activation are not understood.We studied the mechanisms by which IVIG exerts protection from neutrophil-mediated acute vascular injury.We examined neutrophil behavior in response to IVIG in vivo, using real-time intravital microscopy. We found that an antibody that blocks both FcγRIII and its inhibitory receptor counterpart, FcγRIIB, abrogated the inhibitory effect of IVIG on leukocyte recruitment and heterotypic red blood cell (RBC) interactions with adherent leukocytes in wild-type mice. In the context of sickle cell disease, the blockade of both FcγRIIB and III abrogated the protective effect of IVIG on acute vaso-occlusive crisis caused by neutrophil recruitment and activation. Analysis of FcγRIIB- and FcγRIII-deficient mice revealed the predominant expression of FcγRIII on circulating neutrophils. FcγRIII mediated IVIG-triggered inhibition of leukocyte recruitment, circulating RBC capture, and enhanced Mac-1 activity, whereas FcγRIIB was dispensable. In addition, FcγRIII-induced IVIG anti-inflammatory activity in neutrophils was mediated by recruitment of Src homology 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1). Indeed, the protective effect of IVIG on leukocyte recruitment and activation was abrogated in SHP-1-mutant mice.FcγRIII, a classic activating receptor, has an unexpected inhibitory role on neutrophil adhesion and activation via recruitment of SHP-1 in response to IVIG. Our results identify SHP-1 as a therapeutic target in neutrophil-mediated vascular injury.
Deletions of chromosomal regulatory boundaries are associated with congenital disease
Authors: Jonas Ibn-Salem, Sebastian Köhler, Michael I Love, Ho-Ryun Chung, Ni Huang, Matthew E Hurles, Melissa Haendel, Nicole L Washington, Damian Smedley, Christopher J Mungall, Suzanna E Lewis, Claus-Eric Ott, Sebastian Bauer, Paul N Schofield, Stefan Mundlos, Malte Spielmann, Peter N Robinson
Journal: Genome biology (2014)

Abstract Background Recent data from genome-wide chromosome conformation capture analysis indicate that the human genome is divided into conserved megabase-sized self-interacting regions called topological domains. These topological domains form the regulatory backbone of the genome and are separated by regulatory boundary elements or barriers. Copy-number variations can potentially alter the topological domain architecture by deleting or duplicating the barriers and thereby allowing enhancers from neighboring domains to ectopically activate genes causing misexpression and disease, a mutational mechanism that has recently been termed enhancer adoption. Results We use the Human Phenotype Ontology database to relate the phenotypes of 922 deletion cases recorded in the DECIPHER database to monogenic diseases associated with genes in or adjacent to the deletions. We identify combinations of tissue-specific enhancers and genes adjacent to the deletion and associated with phenotypes in the corresponding tissue, whereby the phenotype matched that observed in the deletion. We compare this computationally with a gene-dosage pathomechanism that attempts to explain the deletion phenotype based on haploinsufficiency of genes located within the deletions. Up to 11.8% of the deletions could be best explained by enhancer adoption or a combination of enhancer adoption and gene-dosage effects. Conclusions Our results suggest that enhancer adoption caused by deletions of regulatory boundaries may contribute to a substantial minority of copy-number variation phenotypes and should thus be taken into account in their medical interpretation.
TFE3 Fusions Activate MET Signaling by Transcriptional Up-regulation, Defining Another Class of Tumors as Candidates for Therapeutic MET Inhibition
Authors: Masumi Tsuda, Ian J. Davis, Pedram Argani, Neerav Shukla, Gael G. McGill, Makoto Nagai, Tsuyoshi Saito, Marick Laé, David E. Fisher, Marc Ladanyi
Journal: Cancer Research (2007)

Abstract Specific chromosomal translocations encoding chimeric transcription factors are considered to play crucial oncogenic roles in a variety of human cancers but the fusion proteins themselves seldom represent suitable therapeutic targets. Oncogenic TFE3 fusion proteins define a subset of pediatric renal adenocarcinomas and one fusion (ASPL-TFE3) is also characteristic of alveolar soft part sarcoma (ASPS). By expression profiling, we identified the MET receptor tyrosine kinase gene as significantly overexpressed in ASPS relative to four other types of primitive sarcomas. We therefore examined MET as a direct transcriptional target of ASPL-TFE3. ASPL-TFE3 binds to the MET promoter and strongly activates it. Likewise, PSF-TFE3 and NONO-TFE3 also bind this promoter. Induction of MET by ASPL-TFE3 results in strong MET autophosphorylation and activation of downstream signaling in the presence of hepatocyte growth factor (HGF). In cancer cell lines containing endogenous TFE3 fusion proteins, inhibiting MET by RNA interference or by the inhibitor PHA665752 abolishes HGF-dependent MET activation, causing decreased cell growth and loss of HGF-dependent phenotypes. MET is thus a potential therapeutic target in these cancers. Aberrant transcriptional up-regulation of MET by oncogenic TFE3 fusion proteins represents another mechanism by which certain cancers become dependent on MET signaling. The identification of kinase signaling pathways transcriptionally up-regulated by oncogenic fusion proteins may reveal more accessible therapeutic targets in this class of human cancers. [Cancer Res 2007;67(3):919–29]
Circulating Levels of Adipocyte and Epidermal Fatty Acid–Binding Proteins in Relation to Nephropathy Staging and Macrovascular Complications in Type 2 Diabetic Patients
Authors: Dennis C.Y. Yeung, Aimin Xu, Annette W.K. Tso, W.S. Chow, Nelson M.S. Wat, Carol H.Y. Fong, Sidney Tam, Pak C. Sham, Karen S.L. Lam
Journal: Diabetes Care (2008)

To investigate the relationships of serum adipocyte fatty acid-binding protein (A-FABP) and epidermal fatty acid-binding protein (E-FABP) with renal dysfunction and macrovascular complications in type 2 diabetic patients.The associations of serum A-FABP and E-FABP with markers of renal function, nephropathy staging, and macrovascular complications were examined in 237 type 2 diabetic patients.Serum A-FABP and E-FABP correlated significantly with serum creatinine, mean albumin excretion rate, and glomerular filtration rate (all P < 0.001) and were independently associated with diabetic nephropathy staging (P = 0.001 and P < 0.05, respectively). Circulating levels of both types of FABP were increased (P < 0.01) in subjects with macrovascular complications. Serum A-FABP was independently associated with macrovascular complications (odds ratio 2.92 [95% CI 1.42-6.01]; P = 0.004).Serum A-FABP and E-FABP might be novel serum biomarkers for evaluating the progression of nephropathy and its cardiovascular risk in type 2 diabetic patients.
Structure/Function Relationships of Apolipoprotein A-I Mimetic Peptides
Authors: Wilissa D'Souza, John A. Stonik, Andrew Murphy, Steven J. Demosky, Amar A. Sethi, Xiao L. Moore, Jaye Chin-Dusting, Alan T. Remaley, Dmitri Sviridov
Journal: Circulation Research (2010)

Rationale : Apolipoprotein (apoA)-I mimetic peptides are a promising type of antiatherosclerosis therapy, but how the structural features of these peptides relate to the multiple antiatherogenic functions of HDL is poorly understood. Objective : To establish structure/function relationships of apoA-I mimetic peptides with their antiatherogenic functions. Methods and Results : Twenty-two bihelical apoA-I mimetic peptides were investigated in vitro for the capacity and specificity of cholesterol efflux, inhibition of inflammatory response of monocytes and endothelial cells, and inhibition of low-density lipoprotein (LDL) oxidation. It was found that mean hydrophobicity, charge, size of hydrophobic face, and angle of the link between the helices are the major factors determining the efficiency and specificity of cholesterol efflux. The peptide with optimal parameters was more effective and specific toward cholesterol efflux than human apoA-I. Charge and size of hydrophobic face were also the major factors affecting antiinflammatory properties, and the presence of cysteine and histidine residues was the main factor determining antioxidant properties. There was no significant correlation between capacities of the peptides to support individual functions; each function had its own optimal set of features. Conclusions : None of the peptides was equally effective in all the antiatherogenic functions tested, suggesting that different functions of HDL may have different mechanisms and different structural requirements. The results do suggest, however, that rationalizing the design of apoA-I mimetic peptides may improve their therapeutic value and may lead to a better understanding of mechanisms of various antiatherogenic functions of HDL.
Alternative Splicing of Fibroblast Growth Factor Receptor 3 Produces a Secreted Isoform That Inhibits Fibroblast Growth Factor–Induced Proliferation and Is Repressed in Urothelial Carcinoma Cell Lines
Authors: Darren C. Tomlinson, Corine G. L'Hôte, Wendy Kennedy, Eva Pitt, Margaret A. Knowles
Journal: Cancer Research (2005)

Abstract Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that play key roles in proliferation, differentiation, and tumorigenesis. FGFR3 was identified as the major family member expressed in both normal human urothelium and cultured normal human urothelial (NHU) cells and was expressed as the IIIb isoform. We also identified a splice variant, FGFR3 Δ8-10, lacking exons encoding the COOH-terminal half of immunoglobulin-like domain III and the transmembrane domain. Previous reports have assumed that this is a cancer-specific splice variant. We showed that FGFR3 Δ8-10 is a normal transcript in NHU cells and is translated, N-glycosylated, and secreted. Primary urothelium expressed high levels of FGFR3 transcripts. In culture, levels were reduced in actively proliferating cells but increased at confluence and as cells approached senescence. Cells overexpressing FGFR3 IIIb showed FGF1-induced proliferation, which was inhibited by the addition of FGFR3 Δ8-10. In bladder tumor cell lines derived from aggressive carcinomas, there were significant alterations in the relative expression of isoforms including an overall decrease in the proportion of FGFR3 Δ8-10 and predominant expression of FGFR3 IIIc in some cases. In summary, alternative splicing of FGFR3 IIIb in NHU cells represents a normal mechanism to generate a transcript that regulates proliferation and in bladder cancer, the ratio of FGFR3 isoforms is significantly altered.
Opa1 Overexpression Ameliorates the Phenotype of Two Mitochondrial Disease Mouse Models
Authors: Gabriele Civiletto, Tatiana Varanita, Raffaele Cerutti, Tatiana Gorletta, Serena Barbaro, Silvia Marchet, Costanza Lamperti, Carlo Viscomi, Luca Scorrano, Massimo Zeviani
Journal: Cell Metabolism (2015)

Highlights•Opa1 overexpression improves the phenotype of Ndufs4−/− and Cox15sm/sm mice•O2 consumption rate and respiratory chain activities are increased in double mutants•Mitochondrial ultrastructure is corrected by Opa1 overexpression in Cox15sm/sm•Respiratory complexes and supercomplexes are stabilized in Cox15sm/sm::Opa1tgSummaryIncreased levels of the mitochondria-shaping protein Opa1 improve respiratory chain efficiency and protect from tissue damage, suggesting that it could be an attractive target to counteract mitochondrial dysfunction. Here we show that Opa1 overexpression ameliorates two mouse models of defective mitochondrial bioenergetics. The offspring from crosses of a constitutive knockout for the structural complex I component Ndufs4 (Ndufs4−/−), and of a muscle-specific conditional knockout for the complex IV assembly factor Cox15 (Cox15sm/sm), with Opa1 transgenic (Opa1tg) mice showed improved motor skills and respiratory chain activities compared to the naive, non-Opa1-overexpressing, models. While the amelioration was modest in Ndufs4−/−::Opa1tg mice, correction of cristae ultrastructure and mitochondrial respiration, improvement of motor performance and prolongation of lifespan were remarkable in Cox15sm/sm::Opa1tg mice. Mechanistically, respiratory chain supercomplexes were increased in Cox15sm/sm::Opa1tg mice, and residual monomeric complex IV was stabilized. In conclusion, cristae shape amelioration by controlled Opa1 overexpression improves two mouse models of mitochondrial disease.Graphical abstract
Clinical assessment of a rebreathing method for measuring pulmonary gas transfer.
Authors: N J Russell, L R Bagg, J Dobrzynski, D T Hughes
Journal: Thorax (1983)

A rebreathing method for measuring carbon monoxide transfer factor (TLCO) and transfer coefficient (KCO) is evaluated. The test was performed on 42 subjects. Seventeen of these had normal lung function while the remainder suffered from various conditions, most having fibrosing alveolitis. No patients with severe airways obstruction were included in the group. The results were compared with single-breath measurements and close correlations were found between single-breath KCO and rebreathing KCO (r = 0.78, p less than 0.001) and between single-breath TLCO and rebreathing TLCO (r = 0.97, p less than 0.001). The reasons for discrepancies between single-breath and rebreathing values are discussed. It is concluded that measurement of rebreathing gas transfer is a useful supplement to routine tests of lung function, particularly in breathless patients with a small vital capacity.
Standardisation in clinical laboratory medicine: an ethical reflection
Authors: X. Bossuyt, C. Louche, A. Wiik
Journal: Annals of the Rheumatic Diseases (2008)

Many efforts have been undertaken to standardise diagnostic tests. For example, the introduction of CRM-470, an international reference preparation for proteins in human serum1 has reduced the among-laboratory variance of protein quantification.2 (The examples provided are from the field of Clinical Laboratory Immunology and Protein Chemistry.) The Dutch Red Cross Institute together with the World Health Organization (WHO) prepared an international standard for quantification of antibodies to double-stranded DNA.3 The International Union of Immunological Societies (IUIS), together with the American Arthritis Foundation and the Centers of Disease Control (CDC), made available reference sera selected by the International Committee on Autoantibody Testing in Rheumatic Diseases and Related Disorders for detecting anti-nuclear antibodies.4 These initiatives improved worldwide harmonisation of laboratory test results.

However, despite efforts to harmonise laboratory tests, reference reagents are still lacking for many tests. For example, standardisation is unsatisfactory for IgG subclass determination.5

A number of promising new laboratory tests have recently become available, such as the determination of antibodies to (a) tissue transglutaminase, (b) Saccharomyces cerevisiae and (c) (cyclic) citrullinated peptides (CCP) and proteins (anti-citrullinated protein antibodies (ACPA)). These tests have been introduced without standardisation.6–8 Results obtained in different laboratories or in different clinical studies are not interchangeable, which impairs evidence-based medicine. In spite of this, there are encouraging initiatives, as more reference reagents are being prepared at this moment.9 A new reference reagent for anti-CCP antibody quantification is being prepared by the IUIS Autoantibody Standardization Committee. If the material is appropriate, it will become available as a standard through CDC. New reagents for standardisation of proteinase 3 anti-neutrophil cytoplasmic autoantibodies (ANCA) and myeloperoxidase ANCA have recently been made ready for use through CDC

The implementation of standards lags behind the development and implementation of new technologies.10 This …
RAD001 (Everolimus) Improves the Efficacy of Replicating Adenoviruses that Target Colon Cancer
Authors: Krisztian Homicsko, Alexander Lukashev, Richard D. Iggo
Journal: Cancer Research (2005)

Abstract Selectively replicating adenoviruses have the potential to cure cancer but have shown little efficacy in clinical trials. We have tested the ability of the mTOR kinase inhibitor RAD001 (everolimus) to enhance the response of xenografts to an oncolytic adenovirus. The virus has Tcf sites inserted in the early viral promoters and replicates selectively in cells with activation of the Wnt signaling pathway. To enhance tumor cell infection, an integrin targeting peptide (CDCRGDCFC) was inserted into the fiber gene of the virus. RAD001 combines three useful properties: it inhibits tumor cell growth directly, blocks angiogenesis, and suppresses the immune response. RAD001 does not block viral protein expression, DNA replication, or cytopathic effect in tumor cells in vitro. After 6 weeks of daily RAD001 treatment, ongoing viral DNA replication could be detected in tumor xenografts, showing that RAD001 does not inhibit virus replication in vivo. I.v. injection of virus alone produced a small delay in xenograft growth, whereas combination therapy substantially prolonged the survival of the mice. We suggest that collapsing the tumor vasculature after the initial infection traps the virus and facilitates local spread within the tumor. Unlike conventional drugs, which require continued access to the tumor through the vascular system, oncolytic viruses are in principle less sensitive to late reductions in perfusion because they are produced locally within the tumor.
Oral Tetra-Arsenic Tetra-Sulfide Formula Versus Intravenous Arsenic Trioxide As First-Line Treatment of Acute Promyelocytic Leukemia: A Multicenter Randomized Controlled Trial
Authors: Hong-Hu Zhu, De-Pei Wu, Jie Jin, Jian-Yong Li, Jun Ma, Jian-Xiang Wang, Hao Jiang, Sai-Juan Chen, Xiao-Jun Huang
Journal: Journal of Clinical Oncology (2013)

This randomized, multicenter, phase III noninferiority trial was designed to test the efficacy and safety of an oral tetra-arsenic tetra-sulfide (As4S4) -containing formula named the Realgar-Indigo naturalis formula (RIF) compared with intravenous arsenic trioxide (ATO) as both induction and maintenance therapies for newly diagnosed acute promyelocytic leukemia (APL).In all, 242 patients with APL were randomly assigned (1:1) to oral RIF (60 mg/kg) or ATO (0.16 mg/kg) combined with all-trans retinoic acid (ATRA; 25 mg/m(2)) during induction therapy. After achieving complete remission (CR), all patients received three courses of consolidation chemotherapy and maintenance treatment with sequential ATRA followed by either RIF or ATO for 2 years. The primary end point was the rate of disease-free survival (DFS) at 2 years, which was assessed for noninferiority with a 10% noninferiority margin.The median follow-up time was 39 months. DFS at 2 years was 98.1% (106 of 108) in the RIF group and 95.5% (107 of 112) in the ATO group. The DFS difference was 2.6% (95% CI, -3.0% to 8.0%). The lower limit of the 95% CI of DFS difference was greater than the -10% noninferiority margin, confirming noninferiority (P < .001). No significant differences were noted between the RIF and ATO groups with regard to the CR rate (99.1% v 97.2%; P = .62) or the overall survival at 3 years (99.1% v 96.6%; P = .18). The rates of adverse events were similar in the two groups.Oral RIF plus ATRA is not inferior to intravenous ATO plus ATRA as first-line treatment of APL and may be considered as a routine treatment option for appropriate patients.