Dynamic right ventricular-pulmonary arterial uncoupling during maximum incremental exercise in exercise pulmonary hypertension and pulmonary arterial hypertension

Despite recent advances, the prognosis of pulmonary hypertension (PH) remains poor. While the initial insult in PH implicates the pulmonary vasculature, the functional state, exercise capacity, and survival of such patients are closely linked to right ventricular (RV) function. In the current study, we sought to investigate the effects of maximum incremental exercise on the matching of RV contractility and afterload (i.e. right ventricular-pulmonary arterial [RV-PA] coupling) in patients with exercise PH (ePH) and pulmonary arterial hypertension (PAH). End-systolic elastance (Ees), pulmonary arterial elastance (Ea), and RV-PA coupling (Ees/Ea) were determined using single-beat pressure-volume loop analysis in 40 patients that underwent maximum invasive cardiopulmonary exercise testing. Eleven patients had ePH, nine had PAH, and 20 were age-matched controls. During exercise, the impaired exertional contractile reserve in PAH was associated with blunted stroke volume index (SVI) augmentation and reduced peak oxygen consumption (peak VO2 %predicted). Compared to PAH, ePH demonstrated increased RV contractility in response to increasing RV afterload during exercise; however, this was insufficient and resulted in reduced peak RV-PA coupling. The dynamic RV-PA uncoupling in ePH was associated with similarly blunted SVI augmentation and peak VO2 as PAH. In conclusion, dynamic rest-to-peak exercise RV-PA uncoupling during maximum exercise blunts SV increase and reduces exercise capacity in exercise PH and PAH. In ePH, the insufficient increase in RV contractility to compensate for increasing RV afterload during maximum exercise leads to deterioration of RV-PA coupling. These data provide evidence that even in the early stages of PH, RV function is compromised.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Developments in the negative-U modelling of the cuprate HTSC systems

The paper deals with the many stands that go into creating the unique and complex nature of the HTSC cuprates above Tc as below. Like its predecessors it treats charge, not spin or lattice, as prime mover, but thus taken in the context of the chemical bonding relevant to these copper oxides. The crucial shell filling, negative-U, double-loading fluctuations possible there require accessing at high valent local environment as prevails within the mixed valent, inhomogeneous two sub-system circumstance of the HTSC materials. Close attention is paid to the recent results from Corson, Demsar, Li, Johnson, Norman, Varma, Gyorffy and colleagues.Comment: 44 pages:200+ references. Submitted to J.Phys.:Condensed Matter, Sept 7 200

Constant slip‐rate on the Doruneh strike‐slip fault, Iran, averaged over Late Pleistocene, Holocene, and decadal timescales

Varying estimates of both present‐day strain accumulation and long‐term slip‐rate on the Doruneh left‐lateral strike‐slip fault, NE Iran, have led to suggestions that it exhibits large along‐strike and/or temporal changes in activity. In this paper, we make and compare estimates of slip‐rate measured using both geodesy and geomorphology, and spanning time periods ranging from decadal to 100 ka. To image the present‐day accumulation of strain we process seven years (2003‐2010) of data from six ENVISAT tracks covering the fault, with interferograms produced for 400 km‐long strips of data in order to image the long‐wavelength signals associated with interseismic strain accumulation across the locked fault. Our analysis shows that less than 4 mm/yr – and likely only 1‐3 mm/yr ‐ of slip accumulates across the fault. Using high‐resolution optical satellite imagery we make reconstructions of displacement across six alluvial fans whose surfaces cross the fault, in four separate river catchments. We determine the ages of these fans using infra‐red‐stimulated luminescence dating combined with U‐series dating of pedogenic carbonates. The six fans vary in age from ∼10‐100 kyr, and a regression line fitted to four of these yields a slip rate of 2.5 ± 0.3 mm/yr. We conclude that within the uncertainty of our measurements the slip‐rate has remained constant over the last ∼100 ka and is representative of the strain accumulation at the present‐day. The slip‐rate that we measure is consistent with the E‐W left‐lateral Doruneh fault accommodating N‐S right‐lateral faulting by 'bookshelf' faulting, with clockwise rotation about a vertical axis

Structural matters in HTSC; the origin and form of stripe organization and checker boarding

The paper deals with the controversial charge and spin self-organization phenomena in the HTSC cuprates, of which neutron, X-ray, STM and ARPES experiments give complementary, sometimes apparently contradictory glimpses. The examination has been set in the context of the boson-fermion, negative-U understanding of HTSC advocated over many years by the author. Stripe models are developed which are 2q in nature and diagonal in form. For such a geometry to be compatible with the data rests upon both the spin and charge arrays being face-centred. Various special doping concentrations are closely looked at, in particular p = 0.1836 or 9/49, which is associated with the maximization of the superconducting condensation energy and the termination of the pseudogap regime. The stripe models are dictated by real space organization of the holes, whereas the dispersionless checkerboarding is interpreted in terms of correlation driven collapse of normal Fermi surface behaviour and response functions. The incommensurate spin diffraction below the resonance energy is seen as in no way expressing spin-wave physics or Fermi surface nesting, but is driven by charge and strain (Jahn-Teller) considerations, and it stands virtually without dispersion. The apparent dispersion comes from the downward dispersion of the resonance peak, and the growth of a further incoherent commensurate peak ensuing from the falling level of charge stripe organization under excitation.Comment: 49 pages with 8 figure

Intra- and Inter-Tumor Heterogeneity of BRAFV600EMutations in Primary and Metastatic Melanoma

The rationale for using small molecule inhibitors of oncogenic proteins as cancer therapies depends, at least in part, on the assumption that metastatic tumors are primarily clonal with respect to mutant oncogene. With the emergence of BRAFV600E as a therapeutic target, we investigated intra- and inter-tumor heterogeneity in melanoma using detection of the BRAFV600E mutation as a marker of clonality. BRAF mutant-specific PCR (MS-PCR) and conventional sequencing were performed on 112 tumors from 73 patients, including patients with matched primary and metastatic specimens (n = 18). Nineteen patients had tissues available from multiple metastatic sites. Mutations were detected in 36/112 (32%) melanomas using conventional sequencing, and 85/112 (76%) using MS-PCR. The better sensitivity of the MS-PCR to detect the mutant BRAFV600E allele was not due to the presence of contaminating normal tissue, suggesting that the tumor was comprised of subclones of differing BRAF genotypes. To determine if tumor subclones were present in individual primary melanomas, we performed laser microdissection and mutation detection via sequencing and BRAFV600E-specific SNaPshot analysis in 9 cases. Six of these cases demonstrated differing proportions of BRAFV600Eand BRAFwild-type cells in distinct microdissected regions within individual tumors. Additional analyses of multiple metastatic samples from individual patients using the highly sensitive MS-PCR without microdissection revealed that 5/19 (26%) patients had metastases that were discordant for the BRAFV600E mutation. In conclusion, we used highly sensitive BRAF mutation detection methods and observed substantial evidence for heterogeneity of the BRAFV600E mutation within individual melanoma tumor specimens, and among multiple specimens from individual patients. Given the varied clinical responses of patients to BRAF inhibitor therapy, these data suggest that additional studies to determine possible associations between clinical outcomes and intra- and inter-tumor heterogeneity could prove fruitful

Osteopontin induces growth of metastatic tumors in a preclinical model of non-small lung cancer

Osteopontin (OPN), also known as SPP1 (secreted phosphoprotein), is an integrin binding glyco-phosphoprotein produced by a variety of tissues. In cancer patients expression of OPN has been associated with poor prognosis in several tumor types including breast, lung, and colorectal cancers. Despite wide expression in tumor cells and stroma, there is limited evidence supporting role of OPN in tumor progression and metastasis. Using phage display technology we identified a high affinity anti-OPN monoclonal antibody (hereafter AOM1). The binding site for AOM1 was identified as SVVYGLRSKS sequence which is immediately adjacent to the RGD motif and also spans the thrombin cleavage site of the human OPN. AOM1 efficiently inhibited OPNa binding to recombinant integrin αvβ3 with an IC50 of 65 nM. Due to its unique binding site, AOM1 is capable of inhibiting OPN cleavage by thrombin which has been shown to produce an OPN fragment that is biologically more active than the full length OPN. Screening of human cell lines identified tumor cells with increased expression of OPN receptors (αvβ3 and CD44v6) such as mesothelioma, hepatocellular carcinoma, breast, and non-small cell lung adenocarcinoma (NSCLC). CD44v6 and αvβ3 were also found to be highly enriched in the monocyte, but not lymphocyte, subset of human peripheral blood mononuclear cells (hPBMCs). In vitro, OPNa induced migration of both tumor and hPBMCs in a transwell migration assay. AOM1 significantly blocked cell migration further validating its specificity for the ligand. OPN was found to be enriched in mouse plasma in a number of pre-clinical tumor model of non-small cell lung cancers. To assess the role of OPN in tumor growth and metastasis and to evaluate a potential therapeutic indication for AOM1, we employed a KrasG12D-LSLp53fl/fl subcutaneously implanted in vivo model of NSCLC which possesses a high capacity to metastasize into the lung. Our data indicated that treatment of tumor bearing mice with AOM1 as a single agent or in combination with Carboplatin significantly inhibited growth of large metastatic tumors in the lung further supporting a role for OPN in tumor metastasis and progression

Six RNA Viruses and Forty-One Hosts: Viral Small RNAs and Modulation of Small RNA Repertoires in Vertebrate and Invertebrate Systems

We have used multiplexed high-throughput sequencing to characterize changes in small RNA populations that occur during viral infection in animal cells. Small RNA-based mechanisms such as RNA interference (RNAi) have been shown in plant and invertebrate systems to play a key role in host responses to viral infection. Although homologs of the key RNAi effector pathways are present in mammalian cells, and can launch an RNAi-mediated degradation of experimentally targeted mRNAs, any role for such responses in mammalian host-virus interactions remains to be characterized. Six different viruses were examined in 41 experimentally susceptible and resistant host systems. We identified virus-derived small RNAs (vsRNAs) from all six viruses, with total abundance varying from “vanishingly rare” (less than 0.1% of cellular small RNA) to highly abundant (comparable to abundant micro-RNAs “miRNAs”). In addition to the appearance of vsRNAs during infection, we saw a number of specific changes in host miRNA profiles. For several infection models investigated in more detail, the RNAi and Interferon pathways modulated the abundance of vsRNAs. We also found evidence for populations of vsRNAs that exist as duplexed siRNAs with zero to three nucleotide 3′ overhangs. Using populations of cells carrying a Hepatitis C replicon, we observed strand-selective loading of siRNAs onto Argonaute complexes. These experiments define vsRNAs as one possible component of the interplay between animal viruses and their hosts

Ventricular Geometry From Non-contrast Non-ECG-gated CT Scans:An Imaging Marker of Cardiopulmonary Disease in Smokers

Cardiovascular disease is a major cause of morbidity in smokers, and as much as 50% of the estimated 24 million patients in the United States with chronic obstructive pulmonary disease (COPD) die of cardiovascular causes (1,2). Although echocardiography and cardiac magnetic resonance imaging (MRI) are often used to study cardiac structure and function in COPD (3), these are not routinely deployed in all smokers. Computed tomographic (CT) imaging of the chest is broadly used in clinical care and is increasingly used for lung cancer screening in high-risk smokers (4). Assessment of cardiac structure on those CT scans may help identify patients with COPD at greater risk of developing cardiac dysfunction. Rapid, noninvasive assessments of cardiac morphology and a better understanding of the functional interdependence of heart and lung may improve healthcare outcomes through early detection and initiation of treatment

Retinoic Acids Potentiate BMP9-Induced Osteogenic Differentiation of Mesenchymal Progenitor Cells

As one of the least studied bone morphogenetic proteins (BMPs), BMP9 is one of the most osteogenic BMPs. Retinoic acid (RA) signaling is known to play an important role in development, differentiation and bone metabolism. In this study, we investigate the effect of RA signaling on BMP9-induced osteogenic differentiation of mesenchymal progenitor cells (MPCs).Both primary MPCs and MPC line are used for BMP9 and RA stimulation. Recombinant adenoviruses are used to deliver BMP9, RARalpha and RXRalpha into MPCs. The in vitro osteogenic differentiation is monitored by determining the early and late osteogenic markers and matrix mineralization. Mouse perinatal limb explants and in vivo MPC implantation experiments are carried out to assess bone formation. We find that both 9CRA and ATRA effectively induce early osteogenic marker, such as alkaline phosphatase (ALP), and late osteogenic markers, such as osteopontin (OPN) and osteocalcin (OC). BMP9-induced osteogenic differentiation and mineralization is synergistically enhanced by 9CRA and ATRA in vitro. 9CRA and ATRA are shown to induce BMP9 expression and activate BMPR Smad-mediated transcription activity. Using mouse perinatal limb explants, we find that BMP9 and RAs act together to promote the expansion of hypertrophic chondrocyte zone at growth plate. Progenitor cell implantation studies reveal that co-expression of BMP9 and RXRalpha or RARalpha significantly increases trabecular bone and osteoid matrix formation.Our results strongly suggest that retinoid signaling may synergize with BMP9 activity in promoting osteogenic differentiation of MPCs. This knowledge should expand our understanding about how BMP9 cross-talks with other signaling pathways. Furthermore, a combination of BMP9 and retinoic acid (or its agonists) may be explored as effective bone regeneration therapeutics to treat large segmental bony defects, non-union fracture, and/or osteoporotic fracture