tbuckley/cabot-search huggingface dataset:
Fully reversible pulmonary arterial hypertension associated with dasatinib treatment for chronic myeloid leukaemia
Authors: D. Dumitrescu, C. Seck, Henrik. ten Freyhaus, F. Gerhardt, E. Erdmann, S. Rosenkranz
Journal: European Respiratory Journal (2011)

To the Editors:

Pulmonary arterial hypertension (PAH) is a devastating disease that is characterised by a progressive increase in pulmonary vascular resistance (PVR), chronic right heart failure and premature death. Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure ( P pa) ≥25 mmHg at rest, and the haemodynamic definition discerns pre- and post-capillary PH [1]. Furthermore, PAH is distinguished from other forms of PH that may occur secondary to various underlying causes, including left heart disease, chronic lung disorders and thromboembolic disease [1]. Although the development of targeted PAH therapies, such as endothelin receptor antagonists, phosphodiesterase type-5 inhibitors (PDE5i) and prostanoids, has markedly improved the clinical situation and outcome of affected patients, the current medical treatment of PAH is not satisfactory.

Recently, tyrosine kinase inhibitors (TKIs), particularly imatinib, have been proposed as a potential novel treatment option in PAH [2–7]. Imatinib was the first TKI that achieved regulatory approval for the treatment of chronic myeloid leukaemia (CML) and has become the standard of care for patients with this disease, as it inhibits the hybrid BCR–ABL oncogene that is pathogenic in the development of CML. Imatinib inhibits several tyrosine kinases, including BCR–ABL, the platelet-derived growth factor receptor (PDGFR) and c-Kit. More recently, additional TKIs, including dasatinib and nilotinib, have been introduced for the treatment of CML in patients who are intolerant or unresponsive to imatinib.

The potential efficacy of imatinib in PAH is attributable to its inhibitory effect on the PDGFR. Platelet-derived growth factor (PDGF) is thought to play a pivotal role in the pathobiology of PAH by initiating and maintaining the underlying pulmonary vascular remodelling [7, 8]. Consistent with this, inhibition of PDGFR signalling by imatinib was recently shown to reverse PAH in animal models, and to …
Quantum probability, intuition, and human rationality
Authors: Mike Oaksford
Journal: Behavioral and Brain Sciences (2013)

Abstract This comment suggests that Pothos &amp; Busmeyer (P&amp;B) do not provide an intuitive rational foundation for quantum probability (QP) theory to parallel standard logic and classical probability (CP) theory. In particular, the intuitive foundation for standard logic, which underpins CP, is the elimination of contradictions – that is, believing p and not- p is bad. Quantum logic, which underpins QP, explicitly denies non-contradiction, which seems deeply counterintuitive for the macroscopic world about which people must reason. I propose a possible resolution in situation theory.
Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center
Authors: Troy Z. Horvat, Nelly G. Adel, Thu-Oanh Dang, Parisa Momtaz, Michael A. Postow, Margaret K. Callahan, Richard D. Carvajal, Mark A. Dickson, Sandra P. D'Angelo, Kaitlin M. Woo, Katherine S. Panageas, Jedd D. Wolchok, Paul B. Chapman
Journal: Journal of Clinical Oncology (2015)

Purpose Ipilimumab is a standard treatment for metastatic melanoma, but immune-related adverse events (irAEs) are common and can be severe. We reviewed our large, contemporary experience with ipilimumab treatment outside of clinical trials to determine the frequency of use of systemic corticosteroid or anti-tumor necrosis factor α (anti-TNFα) therapy and the effect of these therapies on overall survival (OS) and time to treatment failure (TTF). Patients and Methods We reviewed retrospectively the medical records of patients with melanoma who had received treatment between April 2011 and July 2013 with ipilimumab at the standard dose of 3 mg/kg. We collected data on patient demographics, previous and subsequent treatments, number of ipilimumab doses, irAEs and how they were treated, and overall survival. Results Of the 298 patients, 254 (85%) experienced an irAE of any grade. Fifty-six patients (19%) discontinued therapy because of an irAE, most commonly diarrhea. Overall, 103 patients (35%) required systemic corticosteroid treatment for an irAE; 29 (10%) also required anti-TNFα therapy. Defining TTF as either starting a new treatment or death, estimated median TTF was 5.7 months. Twelve percent of patients experienced long-term disease control without receiving additional antimelanoma therapy. OS and TTF were not affected by the occurrence of irAEs or the need for systemic corticosteroids. Conclusion IrAEs are common in patients treated with ipilimumab. In our experience, approximately one-third of ipilimumab-treated patients required systemic corticosteroids, and almost one-third of those required further immune suppression with anti-TNFα therapy. Practitioners and patients should be prepared to treat irAEs and should understand that such treatment does not affect OS or TTF.
Promoter Variation in the DC-SIGN–Encoding Gene CD209 Is Associated with Tuberculosis
Authors: Luis B Barreiro, Olivier Neyrolles, Chantal L Babb, Ludovic Tailleux, Hélène Quach, Ken McElreavey, Paul D. van Helden, Eileen G Hoal, Brigitte Gicquel, Lluis Quintana-Murci
Journal: PLoS Medicine (2005)

Background Tuberculosis, which is caused by Mycobacterium tuberculosis, remains one of the leading causes of mortality worldwide. The C-type lectin DC-SIGN is known to be the major M. tuberculosis receptor on human dendritic cells. We reasoned that if DC-SIGN interacts with M. tuberculosis, as well as with other pathogens, variation in this gene might have a broad range of influence in the pathogenesis of a number of infectious diseases, including tuberculosis. Methods and Findings We tested whether polymorphisms in CD209, the gene encoding DC-SIGN, are associated with susceptibility to tuberculosis through sequencing and genotyping analyses in a South African cohort. After exclusion of significant population stratification in our cohort, we observed an association between two CD209 promoter variants (−871G and −336A) and decreased risk of developing tuberculosis. By looking at the geographical distribution of these variants, we observed that their allelic combination is mainly confined to Eurasian populations. Conclusions Our observations suggest that the two −871G and −336A variants confer protection against tuberculosis. In addition, the geographic distribution of these two alleles, together with their phylogenetic status, suggest that they may have increased in frequency in non-African populations as a result of host genetic adaptation to a longer history of exposure to tuberculosis. Further characterization of the biological consequences of DC-SIGN variation in tuberculosis will be crucial to better appreciate the role of this lectin in interactions between the host immune system and the tubercle bacillus as well as other pathogens.
New IBD genetics: common pathways with other diseases
Authors: C. W. Lees, J. C. Barrett, M. Parkes, J. Satsangi
Journal: Gut (2011)

Complex disease genetics has been revolutionised in recent years by the advent of genome-wide association (GWA) studies. The chronic inflammatory bowel diseases (IBDs), Crohn9s disease and ulcerative colitis have seen notable successes culminating in the discovery of 99 published susceptibility loci/genes (71 Crohn9s disease; 47 ulcerative colitis) to date. Approximately one-third of loci described confer susceptibility to both Crohn9s disease and ulcerative colitis. Amongst these are multiple genes involved in IL23/Th17 signalling (<i>IL23R</i>, <i>IL12B</i>, <i>JAK2</i>, <i>TYK2</i> and <i>STAT3</i>), <i>IL10</i>, <i>IL1R2</i>, <i>REL</i>, <i>CARD9</i>, <i>NKX2.3</i>, <i>ICOSLG</i>, <i>PRDM1</i>, <i>SMAD3</i> and <i>ORMDL3</i>. The evolving genetic architecture of IBD has furthered our understanding of disease pathogenesis. For Crohn9s disease, defective processing of intracellular bacteria has become a central theme, following gene discoveries in autophagy and innate immunity (associations with <i>NOD2</i>, <i>IRGM</i>, <i>ATG16L1</i> are specific to Crohn9s disease). Genetic evidence has also demonstrated the importance of barrier function to the development of ulcerative colitis (<i>HNF4A</i>, <i>LAMB1</i>, <i>CDH1</i> and <i>GNA12</i>). However, when the data are analysed in more detail, deeper themes emerge including the shared susceptibility seen with other diseases. Many immune-mediated diseases overlap in this respect, paralleling the reported epidemiological evidence. However, in several cases the reported shared susceptibility appears at odds with the clinical picture. Examples include both type 1 and type 2 diabetes mellitus. In this review we will detail the presently available data on the genetic overlap between IBD and other diseases. The discussion will be informed by the epidemiological data in the published literature and the implications for pathogenesis and therapy will be outlined. This arena will move forwards very quickly in the next few years. Ultimately, we anticipate that these genetic insights will transform the landscape of common complex diseases such as IBD.
The Continuous Recording of Central Venous Pressure Changes from an Arm Vein
Authors: OTTO H. GAUER, HERBERT O. SIEKER
Journal: Circulation Research (1956)

With the subject in the right lateral decubitus position, changes of central venous pressure can be recorded accurately and conveniently from a vein in the antecubital fossa of the dependent arm. Theoretically the hydrostatic, pressure transforms the venous bed between the heart and the site of puncture into uninterrupted wide channels with relatively low distensibility. Simultaneous recordings of pressure by the method described and by catheterization of the central veins showed that induced changes of central venous pressure were identically recorded from both sites. The mean pressure gradient between the peripheral and central veins was 35 mm. of water.
Organelle Proteomics
Authors: Lukas A. Huber, Kristian Pfaller, Ilja Vietor
Journal: Circulation Research (2003)

Functional proteome analysis is not restricted to the sequence information but includes the broad spectrum of structural modifications and quantitative changes of proteins to which they are subjected in different tissues and cell organelles and during the development of an organism. Cell biology has provided the means required for the analysis of the composition and properties of purified cellular elements. Subcellular fractionation is an approach universal across all cell types and tissues, including cardiac and vascular system. Subcellular fractionation and proteomics form an ideal partnership when it comes to enrichment and analysis of intracellular organelles and low abundant multiprotein complexes. Subcellular fractionation is a flexible and adjustable approach resulting in reduced sample complexity and is most efficiently combined with high-resolution 2D gel/mass spectrometry analysis as well as with gel-independent techniques. In this study we introduce state of the art subcellular fractionation techniques and discuss their suitability, advantages, and limitations for proteomics research.
F<scp>ATTY</scp> A<scp>CID</scp> T<scp>RANSPORT</scp> A<scp>CROSS</scp> M<scp>EMBRANES</scp>: Relevance to Nutrition and Metabolic Pathology
Authors: Tahar Hajri, Nada A. Abumrad
Journal: Annual Review of Nutrition (2002)

Long-chain fatty acids are an important constituent of the diet and they contribute to a multitude of cellular pathways and functions. Uptake of long-chain fatty acids across plasma membranes is the first step in fatty acid utilization, and recent evidence supports an important regulatory role for this process. Although uptake of fatty acids involves two components, passive diffusion through the lipid bilayer and protein-facilitated transfer, the latter component appears to play the major role in mediating uptake by key tissues. Identification of several proteins as fatty acid transporters, and emerging evidence from genetically altered animal models for some of these proteins, has contributed significant insight towards understanding the limiting role of transport in the regulation of fatty acid utilization. We are also beginning to better appreciate how disturbances in fatty acid utilization influence general metabolism and contribute to metabolic pathology.
Distribution of arterial lesions in Takayasu's arteritis and giant cell arteritis
Authors: Peter C Grayson, Kathleen Maksimowicz-McKinnon, Tiffany M Clark, Gunnar Tomasson, David Cuthbertson, Simon Carette, Nader A Khalidi, Carol A Langford, Paul A Monach, Philip Seo, Kenneth J Warrington, Steven R Ytterberg, Gary S Hoffman, Peter A Merkel
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> To compare patterns of arteriographic lesions of the aorta and primary branches in patients with Takayasu9s arteritis (TAK) and giant cell arteritis (GCA). <h3>Methods</h3> Patients were selected from two North American cohorts of TAK and GCA. The frequency of arteriographic lesions was calculated for 15 large arteries. Cluster analysis was used to derive patterns of arterial disease in TAK versus GCA and in patients categorised by age at disease onset. Using latent class analysis, computer derived classification models based upon patterns of arterial disease were compared with traditional classification. <h3>Results</h3> Arteriographic lesions were identified in 145 patients with TAK and 62 patients with GCA. Cluster analysis demonstrated that arterial involvement was contiguous in the aorta and usually symmetric in paired branch vessels for TAK and GCA. There was significantly more left carotid (p=0.03) and mesenteric (p=0.02) artery disease in TAK and more left and right axillary (p&lt;0.01) artery disease in GCA. Subclavian disease clustered asymmetrically in TAK and in patients ≤55 years at disease onset and clustered symmetrically in GCA and patients &gt;55 years at disease onset. Computer derived classification models distinguished TAK from GCA in two subgroups, defining 26% and 18% of the study sample; however, 56% of patients were classified into a subgroup that did not strongly differentiate between TAK and GCA. <h3>Conclusions</h3> Strong similarities and subtle differences in the distribution of arterial disease were observed between TAK and GCA. These findings suggest that TAK and GCA may exist on a spectrum within the same disease.
Insulin and gall stones: a population case control study in southern Italy
Authors: G Misciagna, V Guerra, A Di Leo, M Correale, M Trevisan
Journal: Gut (2000)

Hyperinsulinaemia has been associated with many common diseases in developed countries, such as ischaemic heart disease and colon cancer. Gall stones are also very prevalent in these countries but little is known about the association between insulin and gall stones.To study the relationships between insulin and the incidence of gall stones in a sample of the general population.Between May 1985 and June 1986, systematic sampling from the electoral register of Castellana, a small town in southern Italy, yielded 2472 subjects who had their gall bladder checked for gall stones by ultrasonography. Between May 1992 and June 1993, 1962 of the 2235 subjects without gall stones at the first examination agreed to a further ultrasound examination. A total of 101 subjects with newly diagnosed gall stones and 303 randomly chosen controls entered the study. Serum insulin was determined by radioimmunoassay, and concentrations of cholesterol, cholesterol high density lipoprotein (HDL), glucose, and triglycerides by standard enzymatic colorimetric methods. Unconditional multiple logistic regression was used to study the association between insulin and gall stones, controlling for the most common confounding factors.In individuals with no clinical diagnosis of diabetes and serum glucose <7 mmol/l, insulin was associated with gall stones. This association persisted even after controlling for sex, age, body mass index, and serum glucose. The risk of gall stones in the highest quintile of serum insulin was 2.66 (95% confidence interval 1.04-6.72; chi(2) test for trend, p=0.03). The association of insulin with gall stones persisted when total and HDL cholesterol were entered in the logistic regression models, and only slightly decreased when serum triglycerides were included in the model.The results of the study indicate that hyperinsulinaemia may play an important role in the aetiology of gall stones even in individuals without diabetes and with normal serum glucose levels.
Interleukin (IL)-6 induction of osteoclast differentiation depends on IL-6 receptors expressed on osteoblastic cells but not on osteoclast progenitors.
Authors: N Udagawa, N Takahashi, T Katagiri, T Tamura, S Wada, D M Findlay, T J Martin, H Hirota, T Taga, T Kishimoto, T Suda
Journal: The Journal of Experimental Medicine (1995)

We reported that interleukin (IL) 6 alone cannot induce osteoclast formation in cocultures of mouse bone marrow and osteoblastic cells, but soluble IL-6 receptor (IL-6R) strikingly triggered osteoclast formation induced by IL-6. In this study, we examined the mechanism of osteoclast formation by IL-6 and related cytokines through the interaction between osteoblastic cells and osteoclast progenitors. When dexamethasone was added to the cocultures, IL-6 could stimulate osteoclast formation without the help of soluble IL-6R. Osteoblastic cells expressed a very low level of IL-6R mRNA, whereas fresh mouse spleen and bone marrow cells, both of which are considered to be osteoclast progenitors, constitutively expressed relatively high levels of IL-6R mRNA. Treatment of osteoblastic cells with dexamethasone induced a marked increase in the expression of IL-6R mRNA. By immunoblotting with antiphosphotyrosine antibody, IL-6 did not tyrosine-phosphorylate a protein with a molecular mass of 130 kD in osteoblastic cells but did so in dexamethasone-pretreated osteoblastic cells. Osteoblastic cells from transgenic mice constitutively expressing human IL-6R could support osteoclast development in the presence of human IL-6 alone in cocultures with normal spleen cells. In contrast, osteoclast progenitors in spleen cells from transgenic mice overexpressing human IL-6R were not able to differentiate into osteoclasts in response to IL-6 in cocultures with normal osteoblastic cells. These results clearly indicate that the ability of IL-6 to induce osteoclast differentiation depends on signal transduction mediated by IL-6R expressed on osteoblastic cells but not on osteoclast progenitors.
Is mammalian chromosomal evolution driven by regions of genome fragility?
Authors: Aurora Ruiz-Herrera, Jose Castresana, Terence J Robinson
Journal: Genome biology (2006)

Abstract Background A fundamental question in comparative genomics concerns the identification of mechanisms that underpin chromosomal change. In an attempt to shed light on the dynamics of mammalian genome evolution, we analyzed the distribution of syntenic blocks, evolutionary breakpoint regions, and evolutionary breakpoints taken from public databases available for seven eutherian species (mouse, rat, cattle, dog, pig, cat, and horse) and the chicken, and examined these for correspondence with human fragile sites and tandem repeats. Results Our results confirm previous investigations that showed the presence of chromosomal regions in the human genome that have been repeatedly used as illustrated by a high breakpoint accumulation in certain chromosomes and chromosomal bands. We show, however, that there is a striking correspondence between fragile site location, the positions of evolutionary breakpoints, and the distribution of tandem repeats throughout the human genome, which similarly reflect a non-uniform pattern of occurrence. Conclusion These observations provide further evidence that certain chromosomal regions in the human genome have been repeatedly used in the evolutionary process. As a consequence, the genome is a composite of fragile regions prone to reorganization that have been conserved in different lineages, and genomic tracts that do not exhibit the same levels of evolutionary plasticity.
Molecular Mechanisms of Platelet Aggregation
Authors: L Leung, R Nachman
Journal: Annual Review of Medicine (1986)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Meta-Analysis Suggests Association of L-<b> <i>myc Eco</i> </b>RI Polymorphism with Cancer Prognosis
Authors: Monica Spinola, Paola Pedotti, Tommaso A. Dragani, Emanuela Taioli
Journal: Clinical Cancer Research (2004)

The L-myc EcoRI polymorphism is a noncoding variation in the second intron of the L-myc gene, resulting in S and L alleles. Individuals carrying the S allele tend to have poor prognosis and increased risk of several tumor types, although controversial results have been reported. A meta-analysis of 36 studies on L-myc EcoRI genotyping, including 3563 patients with different types of cancer and 2953 controls, was performed. In lung cancer patients the S/S genotype was significantly associated with lymph node metastasis [odds ratio (OR), 2.8; 95% confidence interval (CI), 1.8-4.3], distant metastasis (OR, 4.7; 95% CI, 2.4-9.2), and stage (OR, 2.3; 95% CI, 1.2-4.4). No association was observed between the S/S genotype and cancer (OR, 1.1; 95% CI, 0.8-1.4). In patients with other cancers, the S/S genotype was significantly associated with tumor recurrence (OR, 2.8; 95% CI, 1.4-6.0), whereas no significant association was seen for the other prognostic parameters. When all types of cancer were examined together, the S/S genotype was associated with lymph node metastasis (OR, 2.3; 95% CI, 1.6-3.3), distant metastasis (OR, 2.9; 95% CI, 1.8-4.6), clinical stage (OR, 1.8; 95% CI, 1.2-2.9), and cancer risk (OR, 1.25; 95% CI, 1.07-1.45). The meta-analysis suggests that the L-myc EcoRI polymorphism is a marker of tumor prognosis in lung cancer and possibly in other types of cancer.
BAFF-ling autoantibodies
Authors: Stefanie Sarantopoulos, Maureen A. Su
Journal: Journal of Clinical Investigation (2013)

There is emerging evidence that autoantibodies directed against cytokines modulate the severity of autoimmune disease. Identification of cytokine-targeted autoantibodies in patients can be informative for diagnosis and predicting clinical outcome. In this issue of the JCI, Price and colleagues used a multiplex protein microarray to identify autoantibodies in serum from SLE patients. They found autoantibodies directed against the B cell-activating factor (BAFF) were associated with greater disease severity. This study highlights the contribution of cytokine-directed autoantibodies in disease and describes a valuable tool for identifying autoantibodies against serum antigens.