tbuckley/cabot-search huggingface dataset:
Characteristics of a rapid, point‐of‐care lateral flow immunoassay for the diagnosis of sickle cell disease
Authors: Patrick T. McGann, Beverly A. Schaefer, Mary Paniagua, Thad A. Howard, Russell E. Ware
Journal: American Journal of Hematology (2015)

Sickle cell disease (SCD) is a common and life‐threatening hematological disorder, affecting approximately 400,000 newborns annually worldwide. Most SCD births occur in low‐resource countries, particularly in sub‐Saharan Africa, where limited access to accurate diagnostics results in early mortality. We evaluated a prototype immunoassay as a novel, rapid, and low‐cost point‐of‐care (POC) diagnostic device (Sickle SCAN™) designed to identify HbA, HbS, and HbC. A total of 139 blood samples were scored by three masked observers and compared to results using capillary zone electrophoresis. The sensitivity (98.3–100%) and specificity (92.5–100%) to detect the presence of HbA, HbS, and HbS were excellent. The test demonstrated 98.4% sensitivity and 98.6% specificity for the diagnosis of HbSS disease and 100% sensitivity and specificity for the diagnosis of HbSC disease. Most variant hemoglobins, including samples with high concentrations of HbF, did not interfere with the ability to detect HbS or HbC. Additionally, HbS and HbC were accurately detected at concentrations as low as 1–2%. Dried blood spot samples yielded clear positive bands, without loss of sensitivity or specificity, and devices stored at 37°C gave reliable results. These analyses indicate that the Sickle SCAN POC device is simple, rapid, and robust with high sensitivity and specificity for the detection of HbA, HbS, and HbC. The ability to obtain rapid and accurate results with both liquid blood and dried blood spots, including those with newborn high‐HbF phenotypes, suggests that this POC device is suitable for large‐scale screening and potentially for accurate diagnosis of SCD in limited resource settings. Am. J. Hematol. 91:205–210, 2016. © 2015 Wiley Periodicals, Inc.
US experts urge more neonatal screening for genetic disorders
Authors: Janice Hopkins Tanne
Journal: BMJ (2004)

All newborn babies in the United States should be screened at birth for 30 detectable and treatable disorders, says a report of the American College of Medical Genetics. Babies should also be screened for 25 other disorders that are not now treatable but that may be in the future, making it important for their parents and doctors to know about.

Tandem mass spectrometry from a blood spot from the baby's heel makes it …
FAS Engagement Induces the Maturation of Dendritic Cells (Dcs), the Release of Interleukin (Il)-1β, and the Production of Interferon γ in the Absence of IL-12 during Dc–T Cell Cognate Interaction
Authors: Maria Rescigno, Vincent Piguet, Barbara Valzasina, Suzanne Lens, Rudolf Zubler, Lars French, Vincent Kindler, Jurg Tschopp, Paola Ricciardi-Castagnoli
Journal: The Journal of Experimental Medicine (2000)

Ligation of the Fas (CD95) receptor leads to an apoptotic death signal in T cells, B cells, and macrophages. However, human CD34+–derived dendritic cells (DCs) and mouse DCs, regardless of their maturation state, are not susceptible to Fas-induced cell death. This resistance correlates with the constitutive expression of the Fas-associated death domain–like IL-1β–converting enzyme (FLICE)-inhibitory protein (FLIP) ligand. We demonstrate a new role of Fas in DC physiology. Engagement of Fas on immature DCs by Fas ligand (FasL) or by anti-Fas antibodies induces the phenotypical and functional maturation of primary DCs. Fas-activated DCs upregulate the expression of the major histocompatibility complex class II, B7, and DC–lysosome-associated membrane protein (DC-LAMP) molecules and secrete proinflammatory cytokines, in particular interleukin (IL)-1β and tumor necrosis factor α. Mature DCs, if exposed to FasL, produce even higher amounts of IL-1β. Importantly, it is possible to reduce the production of IL-1β and interferon (IFN)-γ during DC–T cell interaction by blocking the coupling of Fas–FasL with a Fas competitor. Finally, during cognate DC–T cell recognition, IL-12 (p70) could not be detected at early or late time points, indicating that Fas-induced, IFN-γ secretion is independent of IL-12.
Molecular Targeting of Neural Cancer Stem Cells: TTAGGG, You're It!
Authors: Anita B. Hjelmeland, Jeremy N. Rich
Journal: Clinical Cancer Research (2011)

Abstract Telomerase is an important mechanism by which cancers escape replicative senescence. In neural tumors, cancer stem cells express telomerase, suggesting that this may explain their preferential tumorigenesis. Oligonucleotide telomerase targeting selectively disrupts cancer stem cell growth through the induction of differentiation, adding to the armamentarium of anticancer stem cell therapies. Clin Cancer Res; 17(1); 3–5. ©2011 AACR.
S109 Five-Repetition Sit-To-Stand Test: Reliability, Validity and Response to Pulmonary Rehabilitation in COPD
Authors: SE Jones, SSC Kon, JL Canavan, AL Clark, MS Patel, D Dilaver, M Peasey, MGS Ng, MI Polkey, WD-C Man
Journal: Thorax (2012)

<h3>Background</h3> Validated field exercise tests, such as the six minute walk test and incremental/endurance shuttle walks, require space and may be time-consuming as repeat walks are needed due to learning effect. Hence they are rarely used outside the research or pulmonary rehabilitation (PR) setting. The five-repetition Sit to Stand test (STS) is a simple test that is feasible in most settings. It measures the quickest time taken to stand and sit five times from a chair, with arms folded. We hypothesized that the STS would be reliable, correlate with the incremental shuttle walk (ISW), and be responsive to PR. <h3>Methods</h3> The STS was measured in 80 COPD patients on two occasions 24–48 hours apart. Test-retest reliability was calculated using ICCs. STS and ISW were measured in a convenience sample of 396 COPD patients (Mean (SD) age 69 (10); FEV1%predicted 47 (20); ISW 202 (141)) recruited from hospital outpatient clinics. Spearman rank correlation was used to evaluate the relationship between STS and ISW. The STS was measured before and after an 8-week outpatient PR programme in 168 COPD patients. Paired t-tests were used to compare pre- and post-PR outcomes. <h3>Results</h3> The STS demonstrated excellent test-retest reliability with an ICC value of 0.99 with no learning effect. A significant correlation was seen between STS and ISW (rho = –0.68; p&lt;0.001). The STS improved significantly following PR (Pre: 20.91 (16.23) versus Post: 17.87 (14.93) seconds; 95% confidence interval –1.5 to –4.6 seconds; p&lt;0.001). <h3>Conclusions</h3> The STS is reliable, correlates with the incremental shuttle walk, and is responsive to PR in patients with COPD. The STS is a practical functional outcome measure suitable for use in most healthcare settings.
Erratum to: A coherent approach for analysis of the Illumina HumanMethylation450 BeadChip improves data quality and performance in epigenome-wide association studies
Authors: Benjamin Lehne, Alexander W. Drong, Marie Loh, Weihua Zhang, William R. Scott, Sian-Tsung Tan, Uzma Afzal, Reiner Schulz, James Scott, Marjo-Ritta Jarvelin, Paul Elliott, Mark I. McCarthy, Jaspal S. Kooner, John C. Chambers
Journal: Genome biology (2016)

DNA methylation plays a fundamental role in the regulation of the genome, but the optimal strategy for analysis of genome-wide DNA methylation data remains to be determined. We developed a comprehensive analysis pipeline for epigenome-wide association studies (EWAS) using the Illumina Infinium HumanMethylation450 BeadChip, based on 2,687 individuals, with 36 samples measured in duplicate. We propose new approaches to quality control, data normalisation and batch correction through control-probe adjustment and establish a null hypothesis for EWAS using permutation testing. Our analysis pipeline outperforms existing approaches, enabling accurate identification of methylation quantitative trait loci for hypothesis driven follow-up experiments.
PI3K/mTOR Dual Inhibitor VS-5584 Preferentially Targets Cancer Stem Cells
Authors: Vihren N. Kolev, Quentin G. Wright, Christian M. Vidal, Jennifer E. Ring, Irina M. Shapiro, Jill Ricono, David T. Weaver, Mahesh V. Padval, Jonathan A. Pachter, Qunli Xu
Journal: Cancer Research (2014)

Cancer stem cells (CSC) have been implicated in disease recurrence, metastasis, and therapeutic resistance, but effective targeting strategies for these cells are still wanting. VS-5584 is a potent and selective dual inhibitor of mTORC1/2 and class I PI 3-kinases. Here, we report that VS-5584 is up to 30-fold more potent in inhibiting the proliferation and survival of CSC compared with non-CSC in solid tumor cell populations. VS-5584 preferentially diminished CSC levels in multiple mouse xenograft models of human cancer, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Likewise, VS-5584 treatment ex vivo preferentially reduced CSC in surgically resected breast and ovarian patient tumors. In contrast, chemotherapeutics such as paclitaxel and cisplatin were less effective in targeting CSC than bulk tumor cells. Mechanistic investigations revealed that preferential targeting of CSC required inhibition of multiple components of the PI3K-mTOR pathway: coordinate RNAi-mediated silencing of PI3Kα, PI3Kβ, and mTOR phenocopied the effect of VS-5584, exhibiting the strongest preferential targeting of CSC, while silencing of individual PI3K isoforms or mTOR failed to replicate the effect of VS-5584. Consistent with CSC ablation, VS-5584 delayed tumor regrowth following chemotherapy in xenograft models of small-cell lung cancer. Taken together, the preferential targeting of CSC prompts a new paradigm for clinical testing of VS-5584: clinical trials designed with CSC-directed endpoints may facilitate demonstration of the therapeutic benefit of VS-5584. We suggest that combining VS-5584 with classic chemotherapy that debulks tumors may engender a more effective strategy to achieve durable remissions in patients with cancer.
Molecular physiology of oxygen-sensitive potassium channels
Authors: A.J. Patel, E. Honoré
Journal: European Respiratory Journal (2001)

Physiological adaptation to acute hypoxia involves oxygen-sensing by a variety of specialized cells including carotid body type I cells, pulmonary neuroepithelial body cells, pulmonary artery myocytes and foetal adrenomedullary chromaffin cells. Hypoxia induces depolarization by closing a specific set of potassium channels and triggers cellular responses. Molecular biology strategies have recently allowed the identification of the K + channel subunits expressed in these specialized cells. Several voltage-gated K + channel subunits comprising six transmembrane segments and a single pore domain (Kv1.2, Kv1.5, Kv2.1, Kv3.1, Kv3.3, Kv4.2 and Kv9.3) are reversibly blocked by hypoxia when expressed in heterologous expression systems. Additionally, the background K + channel subunit TASK-1, which comprises four transmembrane segments and two pore domains, is also involved in both oxygen- and acid-sensing in peripheral chemoreceptors. Progress is currently being made to identify the oxygen sensors. Regulatory β subunits may play an important role in the modulation of Kv channel subunits by oxygen.
Hypoxaemia, sport and polycythaemia: a case from Imperial College London
Authors: Wakana Yasuda, James E Jackson, D Mark Layton, Claire L Shovlin
Journal: Thorax (2015)

WY : An 18-year-old footballer with no previous significant medical history sustained a tendon injury during a football match. This was repaired successfully under general anaesthetic, but the SaO2 (% saturation of haemoglobin) was found to be 78.5% on air. Following recovery from the injury, he returned to playing football six times per week while he was investigated further. Chest X-ray and CT scan demonstrated three pulmonary arteriovenous malformations (PAVMs) that were thought to be due to underlying hereditary haemorrhagic telangiectasia (HHT).

CLS : That would be the most likely cause of the clinical picture. PAVMs1 affect approximately 1 in 2600 people,2 have usually completed growth by puberty and frequently result in hypoxaemia.3 The PAVM vessels provide an anatomic right-to-left shunt that allows a fraction of pulmonary arterial blood to bypass the pulmonary capillary bed and hence gas exchange. Greater shunt flow (as a proportion of cardiac output) results in lower PaO2/SaO2, but this is frequently asymptomatic. The majority of patients have underlying HHT, especially if they have multiple PAVMs.

WY : How was it possible for him to be so sporty?

CLS : The relevant term for oxygen transport to the tissues is not the SaO2 or PaO2 (in kPa or mm Hg), but the arterial oxygen content (CaO2 (mL of oxygen per unit blood volume)). CaO2 depends on the concentration of haemoglobin in addition to the commonly measured oxygen parameters. I would predict that the patient had secondary polycythaemia at presentation.

WY : Yes, the haemoglobin was 20.9 g/dL and haematocrit 0.61%.

CLS : So this will have maintained his CaO2, which we can calculate as SaO2×haemoglobin×1.34/100. His CaO2 was 22 mL/dL, which is higher than normal, as seen in 23 athletes with PAVMs, …
The enhanced pressor response in type 2 diabetes is not based upon a generalized increase in vascular responsiveness
Authors: F Huvers
Journal: Cardiovascular Research (1998)

The present study was performed to discriminate between central and peripheral effects of noradrenaline (NA) in normotensive, non-obese, type 2 diabetic patients.Study I: In 10 patients and 10 healthy volunteer (HV) cumulative doses of NA were infused intravenously until mean arterial pressure (MAP) rose with 20 mmHg, and subsequently the effects on the forearm blood flow (FBF) was measured. Also, the FBF response to intra-arterial NA (0.025, 0.1, 0.4 micrograms min-1) was measured. Study II: In 13 patients and 14 HV the venous constrictor response to a cumulative local infusion of NA in a dorsal hand vein was determined.In study I the circulating plasma NA concentrations inducing a rise in MAP of 20 mmHg, were lower in the type 2 patients relative to the HV (p < 0.01). The relationship between changes in pressure and changes in heart rate were similar in both groups. Moreover, FBF responsiveness to intra-arterial NA was not different between the two groups. The slopes of the delta MAP/NA regression lines were correlated with basal insulin levels and relative insulin resistance in the healthy volunteers (R = 0.77, p < 0.01, and R = 0.83, p < 0.01), but not in the type 2 diabetic patients. In study II no differences were observed in the dose generating half maximum (ED50) and the maximum (Emax) response to NA between the type 2 patients and the HV.Non-obese normotensive type 2 patients have an increased pressor response to NA, which is not based upon a defect in skeletal muscle resistance arterioles, peripheral veins, or a defect in the baroreceptor system. Therefore, in type 2 diabetes the noradrenergic responsiveness of other vascular beds, such as the splanchnic or renal, must be enhanced.
Vascular hypothesis of Alzheimer’s disease: role of apoE and apoE receptors
Authors: Guojun Bu, Chia-Chen Liu, Takahisa Kanekiyo
Journal: Molecular Neurodegeneration (2013)

Background Alzheimer’s disease (AD) is a progressive neurodegenerative disease that has emerged as the most prevalent form of late-life dementia in humans [1]. Production of amyloid-b (Ab) from the amyloid precursor protein (APP) and its subsequent accumulation, aggregation and deposition in the brain are central events in the pathogenesis of AD [1]. Cerebral amyloid angiopathy (CAA) is a major pathological feature of AD where amyloid spreads and deposits throughout the blood vessel walls in the central nervous system. These pathogenic events induce a specific clinical presentation profile including cerebral hemorrhage, stroke, ischemic infarctions, subarachnoid hemorrhage, seizures, cognitive impairment and dementia [2]. While Ab is a key molecule in AD, epidemiological studies have shown that several well-established risk factors for AD, including diabetes mellitus, atherosclerosis, stroke, hypertension, transient ischemic attacks, microvessel pathology and smoking, have a vascular component that reduces cerebral perfusion [3]. In fact, detection of regional cerebral hypoperfusion through neuroimaging techniques can preclinically identify individuals at risk for AD. Further, cerebral hypoperfusion precedes hypometabolism, cognitive decline, and neurodegeneration in AD [3]. Therefore, disturbance of cerebrovascular system is likely a major contributor to AD pathogenesis. Among the three human apolipoprotein E (apoE) isoforms (E2, E3 and E4), APOE4 is the strongest genetic risk factor for late-onset AD. The most consistent finding that differentiates apoE4 from apoE3 is their respective roles in brain Ab clearance, where apoE4 is less efficient than apoE3 in promoting Ab clearance [4]. In addition, APOE4 also increases the risk for CAA and vascular dementia [4]. Because apoE4 is known to damage blood-brain barrier (BBB) integrity and reduces small cerebral vessels [5], apoE is likely involved in the maintenance of cognitive function through regulating the function of cerebrovascular systems.
TWO CASES ILLUSTRATING THE COMBINATION OF AFFECTIVE AND SCHIZOPHRENIC SYMPTOMS
Authors: C. Macfie Campbell
Journal: American Journal of Psychiatry (1926)

The review of two patients presenting the combination or alter-nation of manic-depressive and schizophrenic modes of reaction. The constitution of the patients may have determined to a certain extent the type of their reaction, but early environment and experiences had probably influenced their stability and left their stamp on the later psychoses. A fatalistic emphasis on the congenital endowment is less useful than attention to the moulding environmental factors, the study of which encourages effort in the direction both of prophylaxis and treatment.
Sequence Variants in Cell Cycle Control Pathway, X-ray Exposure, and Lung Cancer Risk: A Multicenter Case-Control Study in Central Europe
Authors: Rayjean J. Hung, Paolo Boffetta, Federico Canzian, Norman Moullan, Neonila Szeszenia-Dabrowska, David Zaridze, Jolanta Lissowska, Peter Rudnai, Eleonora Fabianova, Dana Mates, Lenka Foretova, Vladimir Janout, Vladimir Bencko, Amelie Chabrier, Stefano Landi, Federica Gemignani, Janet Hall, Paul Brennan
Journal: Cancer Research (2006)

Abstract Exposure to ionizing radiation (IR) results in various types of DNA damage and is a suspected cause of lung cancer. An essential cellular machinery against DNA damage is cell cycle control, which is regulated by several genes, including TP53, CCND1, and CDKN2A. Therefore, we hypothesized that the genetic variants in these three genes influence the predisposition of lung cancer (i.e., CCND1 G870A, CDKN2A Ala148Thr, TP53 Arg72Pro, and 16-bp repeat in intron 3) and that the effect of X-ray on lung cancer risk can be modified by the presence of these genetic variations. The study was conducted in 15 centers in 6 countries of Central Europe between 1998 and 2002. A total of 2,238 cases and 2,289 controls were recruited and provided DNA samples. Cases with positive family history were analyzed separately. The joint effect of X-ray and previous risk genotypes was assessed, and modification by sequence variants on X-ray dose-response relationship with lung cancer risk was evaluated. We found an overall effect of TP53 intron 3 16-bp repeats [odds ratio (OR), 1.99; 95% confidence interval (95% CI), 1.27-3.13], which was stronger among cases with family history of lung cancer (OR, 2.98; 95% CI, 1.29-6.87). In addition, our results suggested an interaction that was greater than multiplicativity between TP53 intron 3 16-bp repeats and multiple X-ray exposures (interaction OR, 5.69; 95% CI, 1.33-24.3). We did not observe a main effect of CCND1 G870A polymorphism; however, the dose-response relationship between lung cancer risk and X-ray exposures was modified by CCND1 genotype with no risk from X-ray exposures among subjects who carried G/G genotype, intermediate risk [trend OR for X-ray, 1.16; 95% CI, 1.05-1.27) among subjects with G/A genotype, and highest risk [trend OR for X-ray, 1.29; 95% CI, 1.12-1.49) among subjects with A/A genotype. Sequence variants in cell cycle control pathway may increase the risk of lung cancer and modify the risk conferred by multiple X-ray exposures. However, a definite conclusion can only be drawn on replication by different studies among individuals who are highly exposed to IR. (Cancer Res 2006; 66(16): 8280-6)
Quantitative Analysis of Mitral Valve Morphology in Mitral Valve Prolapse With Real-Time 3-Dimensional Echocardiography
Authors: Alex Pui-Wai Lee, Ming C. Hsiung, Ivan S. Salgo, Fang Fang, Jun-Min Xie, Yan-Chao Zhang, Qing-Shan Lin, Jen-Li Looi, Song Wan, Randolph H.L. Wong, Malcolm J. Underwood, Jing-Ping Sun, Wei-Hsian Yin, Jeng Wei, Shen-Kou Tsai, Cheuk-Man Yu
Journal: Circulation (2012)

Background— Few data exist on the relation of the 3-dimensional morphology of mitral valve and degree of mitral regurgitation (MR) in mitral valve prolapse. Methods and Results— Real-time 3-dimensional transesophageal echocardiography of the mitral valve was acquired in 112 subjects, including 36 patients with mitral valve prolapse and significant MR (≥3+; MR+ group), 32 patients with mitral valve prolapse but no or mild MR (≤2+; MR− group), 12 patients with significant MR resulting from nonprolapse pathologies (nonprolapse group), and 32 control subjects. The 3-dimensional geometry of mitral valve apparatus was measured with dedicated quantification software. Compared with the normal and MR− groups, the MR+ group had more dilated mitral annulus ( P &lt;0.0001), a reduced annular height to commissural width ratio (AHCWR) ( P &lt;0.0001) indicating flattening of annular saddle shape, redundant leaflet surfaces ( P &lt;0.0001), greater leaflet billow volume ( P &lt;0.0001) and billow height ( P &lt;0.0001), longer lengths from papillary muscles to coaptation ( P &lt;0.0001), and more frequent chordal rupture ( P &lt;0.0001). Prevalence of chordal rupture increased progressively with annulus flattening (7% versus 24% versus 42% for AHCWR &gt;20%, 15%–20%, and &lt;15%, respectively; P =0.004). Leaflet billow volume increased exponentially with decreasing AHCWR in patients without chordal rupture ( r 2 =0.66, P &lt;0.0001). MR severity correlated strongly with leaflet billow volume ( r 2 =0.74, P &lt;0.0001) and inversely with AHCWR ( r 2 =0.44, P &lt;0.0001). In contrast, annulus dilatation but not flattening occurred in nonprolapse MR patients. An AHCWR &lt;15% (odds ratio=7.1; P =0.0004) was strongly associated with significant MR in mitral valve prolapse. Conclusion— Flattening of the annular saddle shape is associated with progressive leaflet billowing and increased frequencies of chordal rupture and may be important in the pathogenesis of MR in mitral valve prolapse.