247 research outputs found
Supplemental material for Hematopoietic stem cell transplantation alters susceptibility to pulmonary hypertension in <i>Bmpr2</i>-deficient mice
No full textSupplemental material for Hematopoietic stem cell transplantation alters susceptibility to pulmonary hypertension in Bmpr2-deficient mice by Alexi Crosby, Mark R. Toshner, Mark R. Southwood, Elaine Soon, Benjamin J. Dunmore, Emily Groves, Stephen Moore, Penny Wright, Katrin Ottersbach, Cavan Bennett, Jose Guerrero, Cedric Ghevaert and Nicholas W. Morrell in Pulmonary Circulation</p
Espressione della proteina AKT nelle neoplasie mammarie del cane e del gatto.
No full textPTEN/AKT pathway is highly involved in tumor development and growth. PTEN is a tumor suppressor protein that negatively regulates the develop of this pathway and neoplastic cells proliferation inhibiting AKT production. The role of these two molecules has been commonly investigated in human mammary tumors. The aim of this study is to evaluate by immunohistochemistry the role of PTEN and AKT in canine and feline mammary cancer and their interaction.
Thirty-nine canine mammary tumors (7 adenomas and 32 carcinomas) and 30 feline mammary carcinomas were submitted to immunohistochemistry for the evaluation of PTEN and AKT expression. Subjects bearing mammary carcinoma were also submitted to a 2-year follow-up study to compare overall survival with PTEN and AKT expression.
All the canine mammary adenomas were PTEN-positive and AKT-negative, while 22/32 (69%) of canine carcinomas expressed PTEN and 10/32 (31%) AKT. A statical correlation was observed between AKT positivity and canine mammary carcinomas (P <0.05)In cats, 7/30 (23%) of carcinomas were PTEN-positive and 24/30 (80%) AKT-positive. Both in canine and feline tumors, AKT was inversely correlated with PTEN expression (P<0.05)In dogs, PTEN statistically correlated with complex type carcinoma, absence of lymphatics invasion and better survival period, AKT with simple type carcinoma, presence og lymphatics invasion and a poorer overall survival. In cats, PTEN expression was correlated with tubulopapillary simple type carcinoma, absence of lymphatics invasion, lower mitotic index and better overall survival while AKT with a shorter survival period.
Our data suggest PTEN/AKT pathway involvement in canine and feline mammary tumors, confirming PTEN tumor suppressive role and AKT involvement in tumor malignancy. Furthermore, the negative statistic correlation between these two molecules confirms the inhibitory role of PTEN within this pathway.
PTEN/AKT pathway è altamente coinvolta nello sviluppo e nella crescita dei tumori. PTEN è una proteina di soppressione dei tumori che regola negativamente lo sviluppo di questa catena metabolica e la proliferazione delle cellule neoplasich,inibendo la produzione di AKT. Il ruolo svolto da queste due molecole è stato di solito studiato nei tumori mammari umani. Lo scopo di questo studio è la valutazione, attraverso la immunoistochimica, del ruolo della PTEN e della AKT nello sviluppo dei tumori mammari canini e felini e le loro interazioni.
39 tumori mammari canini (7 adenomi e 32 carcinomi), e 30 carcinomi mammari felini sono stati sottoposti a immunoistochimica al fine di studiare la manifestazione delle PTEN e AKT. Soggetti affetti da carcinoma mammario sono stati inoltre sottoposti ad uno studio continuativo della durata di due anni allo scopo di confrontare i tassi generali di sopravvivenza con l’insorgenza delle PTEN e delle AKT.
Tutti gli adenomi mammari canini sono risultati positivi alla PTEN e negativi alla AKT, mentre 22 carcinomi canini su 32 (pari al 69%) hanno mostrato l’insorgenza della PTEN e 10 su 32 l’insorgenza della AKT. Una correlazione costante è stata osservata tra i carcinomi mammari canini e la positività alla AKT (P < 0.05). Nei gatti, 7 carcinomi su 30 (pari al 23%) sono risultati positivi alla PTEN, mentre 24 su 30 erano positivi alla AKT. Nei tumori canini come in quelli felini, la AKT risultava essere inversamente proporzionale al tasso di insorgenza della PTEN (P < 0.05). Nei cani, la PTEN era statisticamente legata al carcinoma di tipo complesso, all’assenza di invasione linfatica e ad un maggiore periodo di sopravvivenza; la AKT era statisticamente legata al carcinoma di tipo semplice, alla presenza di invasione linfatica e ad un ridotto periodo di sopravvivenza. Nei gatti, l’insorgenza della PTEN era correlata al tipo semplice di carcinoma tubulopapillare, all’assenza di invasione linfatica, ad un minore indice mitotico e ad un periodo di sopravvivenza più elevato, mentre la AKT era correlata ad un periodo di sopravvivenza più breve.
I dati raccolti suggeriscono il coinvolgimento della catena metabolica PTEN/AKT nello sviluppo dei tumori mammari canini e felini, confermando il ruolo soppressivo della PTEN e il coinvolgimento della AKT nell’insorgenza della caratteristica maligna nei tumori. Inoltre, la correlazione statistica negativa tra queste due molecole conferma il ruolo inibitore della PTEN all’interno di questa catena metabolica
The impact of hypoxia on B cells in COVID-19
No full textBackground: Prominent early features of COVID-19 include severe, often clinically silent, hypoxia and a pronounced reduction in B cells, the latter important in defence against SARS-CoV-2. This presentation resembles the phenotype of mice with VHL-deficient B cells, in which Hypoxia-Inducible Factors are constitutively active, suggesting hypoxia might drive B cell abnormalities in COVID-19. Methods: Detailed B cell phenotyping was undertaken by flow-cytometry on longitudinal samples from patients with COVID-19 across a range of severities (NIHR Cambridge BioResource). The impact of hypoxia on the transcriptome was assessed by single-cell and whole blood RNA sequencing analysis. The direct effect of hypoxia on B cells was determined through immunisation studies in genetically modified and hypoxia-exposed mice. Findings: We demonstrate the breadth of early and persistent defects in B cell subsets in moderate/severe COVID-19, including reduced marginal zone-like, memory and transitional B cells, changes also observed in B cell VHL-deficient mice. These findings were associated with hypoxia-related transcriptional changes in COVID-19 patient B cells, and similar B cell abnormalities were seen in mice kept in hypoxic conditions. Interpretation: Hypoxia may contribute to the pronounced and persistent B cell pathology observed in acute COVID-19 pneumonia. Assessment of the impact of early oxygen therapy on these immune defects should be considered, as their correction could contribute to improved outcomes. Funding: Evelyn Trust, Addenbrooke's Charitable Trust, UKRI/NIHR, Wellcome Trus
Acute haemodynamic responses to inhaled nitric oxide and intravenous sildenafil in distal chronic thromboembolic pulmonary hypertension (CTEPH)
No full textIntroduction: Although surgery is the treatment of choice for CTEPH, it is not appropriate for patients with surgically inaccessible distal disease. These patients are traditionally managed supportively, but may benefit from newer, more specific vasoactive therapies. This study examines the acute haemodynamic responses to inhaled nitric oxide (iNO) and intravenous sildenafil in this patient population.Methods: Nine patients with de novo distal CTEPH and nine with persistent pulmonary hypertension post-pulmonary endarterectomy (PEA) were enrolled. At right heart catheterisation, following baseline haemodynamic measurements, iNO was administered at 20 ppm for 10 min. Following repeat measurements, iNO was discontinued with a subsequent washout period of 10 min. Sildenafil was then administered intravenously at two doses, to achieve plasma levels equivalent to 25 mg and 50 mg orally, with further measurements obtained at the end of each infusion.Results: Significant reductions in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) were demonstrated following both iNO (-4.3 mm Hg or -10.3% p=0.001 and -101 dyn/s/cm(5) or - 15.6% p < 0.001) and sildenafil (-7.4 mm Hg or -16.9% p < 0.001 and -188.8 dyn/s/cm(5) or -25.1% p < 0.001). Individual mPAP and cardiac output (CO) responses to iNO and sildenafil correlated well, but haemodynamic changes following sildenafil were consistently more marked. There was, however, no difference in effect between the two doses of sildenafil. Although sildenafil caused significant reductions in systemic vascular resistance, the net haemodynamic effect of sildenafil remained pulmonary selective. Subgroup analysis suggested that post-PEA patients were more responsive to both iNO and sildenafil than de novo patients.Discussion: Although all but one patient failed to fulfil the formal haemodynamic response criteria typically used in idiopathic pulmonary arterial hypertension (IPAH), subjects displayed significant acute responses to both iNO and sildenafil suggesting that increased vascular tone forrns an important component of distal CTEPH. It is possible that these acute haemodynamic responses may translate to improved clinical outcomes, and thus further long term trials of sildenafil in distal CTEPH are warranted. (c) 2007 Published by Elsevier Inc.</p
Whole-lake Herbicide Treatments for Eurasian Watermilfoil in Four Wisconsin Lakes: Effects on Vegetation and Water Clarity
No full textDecreased time constant of the pulmonary circulation in chronic thromboembolic pulmonary hypertension
No full textThis study analysed the relationship between pulmonary vascular resistance (PVR) and compliance (Ca) in patients with idiopathic pulmonary arterial hypertension (IPAH) and proximal chronic thromboembolic pulmonary hypertension (CTEPH). It has recently been shown that the time constant of the pulmonary circulation (RC-time), or PVR x Ca, remains unaltered in various forms and severities of PH, with the exception of left heart failure. We reasoned that increased wave reflection in proximal CTEPH would be another cause of decreased RC-time. We conducted a retrospective analysis of invasive pulmonary hemodynamic measurements in IPAH (n=78), proximal CTEPH (n=91) before and after pulmonary endarterectomy (PEA) and distal CTEPH (n=53). Proximal CTEPH was defined by a postoperative mean pulmonary artery pressure (mPAP) ≤ 25 mmHg. Outcome measures were the RC-time, PVR, Ca and the relationship between systolic and mean pulmonary artery pressures. The RC time for Pre-PEA CTEPH was 0.49 ± 0.11s compared with Post PEA-CTEPH 0.37 ± 0.11s (p<0.0001), IPAH 0.63 ± 0.14s (p<0.001) and Distal CTEPH 0.55 ± 0.12s (p<0.05). A shorter RC-time was associated with a disproportionate decrease in systolic PAP with respect to mPAP. We concluded that the pulmonary RC-time is decreased in proximal CTEPH compared to IPAH, before and after PEA, which may be explained by increased wave reflection but also importantly by persistent structural changes after removal of proximal obstructions. A reduced RC-time in CTEPH is in accord with a wider pulse pressure and hence greater RV work for a given mean PA pressure.JOURNAL ARTICLESCOPUS: ar.jinfo:eu-repo/semantics/publishe
Occlusion pressure analysis role in partitioning of pulmonary vascular resistance in CTEPH.
No full textFlow-directed pulmonary artery occlusion is posited to enable partitioning of vascular resistance into small and large vessels. As such it may have a role in assessment for pulmonary endarterectomy.To test if the occlusion technique distinguished small from large vessel disease we studied 59 subjects with CTEPH, idiopathic PAH, and connective tissue disease (CTD) PAH. At right heart catheterisation, occlusion pressures were recorded. With fitting of the pressure decay curve, PVR was partitioned into downstream (small vessels) and upstream (large vessels, Rup).47 patients completed the study; 14 operable CTEPH, 15 non-operable CTEPH, 13 idiopathic or CTD-PAH, 5 post-operative CTEPH. There was a significant difference in mean Rup in the proximal operable CTEPH group 87.3(95%CI 84.1;90.5); non-operable CTEPH mean 75.8(95%CI 66.76;84.73) p=0.048; and IPAH/CTD, mean 77.1(95%CI 71.86;82.33) p=0.003. ROC curves to distinguish operable from non-operable CTEPH demonstrated an AUC of 0.75, p=0.0001. A cut off of 79.3 gave sensitivity 100%(CI 73.5-100%) but specificity 57.1%(CI 28.9-82.3%). In a subgroup analysis of multiple lobar sampling there was demonstrable heterogeneity.Rup is significantly increased in operable proximal CTEPH compared with non-operable distal CTEPH and IPAH/CTD. Rup variability in patients with CTEPH and PAH is suggestive of pathophysiological heterogeneity.JOURNAL ARTICLESCOPUS: ar.jinfo:eu-repo/semantics/publishe
Acute haemodynamic responses to inhaled nitric oxide and intravenous sildenafil in distal chronic thromboembolic pulmonary hypertension
No full textAuthor Correction: Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood (Nature Communications, (2021), 12, 1, (7104), 10.1038/s41467-021-27326-0)
No full text\ua9 2022, The Author(s).The original version of this Article omitted Richard C Trembath from the UK National PAH Cohort Study consortium from Health and Life Sciences, King’s College London. This has been corrected in both the PDF and HTML versions of the Article
Myeloid angiogenic cells exhibit impaired migration, reduced expression of endothelial markers and increased apoptosis in idiopathic pulmonary arterial hypertension
No full textIdiopathic pulmonary arterial hypertension (IPAH) is a rare and devastating condition. There is no known cure for IPAH, and current treatment options are not always effective. Autologous myeloid angiogenic cells (MACs) have been explored as a novel therapy for IPAH but preliminary data from clinical trials show limited beneficial effects. A complete understanding of IPAH MAC function remains elusive. This study was designed to comprehensively compare cell function between IPAH MACs and healthy control MACs. MACs were procured through the culture of peripheral blood mononuclear cells in endothelial selective medium for 7 days. Compared with healthy MACs, IPAH MACs exhibited 1) significantly lower levels of endothelial markers as shown by fluorescence microscopy; 2) a markedly higher rate of apoptosis under both normal culture condition and serum starvation as shown by the TUNEL assay; 3) significantly decreased migration towards VEGF as shown by a modified Boyden chamber migration assay; and 4) similar VEGF and eNOS mRNA levels as shown by RT-qPCR. In conclusion, various aspects of IPAH MAC function are impaired. In order to achieve greater therapeutic benefits, pharmacologic and/or genetic manipulations to improve IPAH MAC function, particularly to promote cell survival and migration, are warranted.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author
- …
