tbuckley/cabot-search huggingface dataset:
Loss of β4 Integrin Subunit Reduces the Tumorigenicity of MCF7 Mammary Cells and Causes Apoptosis upon Hormone Deprivation
Authors: Giulia Bon, Valentina Folgiero, Gianluca Bossi, Laura Felicioni, Antonio Marchetti, Ada Sacchi, Rita Falcioni
Journal: Clinical Cancer Research (2006)

The alpha6beta4 integrin, a laminin receptor, has been implicated from many studies in tumor progression and invasion. We showed that the beta4 integrin subunit associates with the ErbB-2 tyrosine kinase in human mammary carcinoma cell lines and that its overexpression in NIH3T3/ErbB-2-transformed cells causes a constitutive activation of phosphatidylinositol 3-kinase (PI3K), inducing a strong increase of their invasive capacity. In this study, we investigated the biological consequences of interference with the endogenous beta4 integrin subunit expression.In vitro and in vivo tumor growth and the biochemical consequences of beta4 integrin inactivation were studied in mammary tumor cells by using short hairpin RNA approach.Our data show that tumor growth of mammary tumor cells strictly depends on beta4 expression, confirming the relevance of beta4 protein in these cells. Moreover, interference with beta4 expression significantly reduces endogenous PI3K activity and AKT and mammalian target of rapamycin phosphorylation. Accordingly, with these results and considering that PI3K activity in mammary tumor plays a relevant role in hormone resistance, we asked whether beta4 expression might be relevant for hormone responsiveness in these cells. Data reported indicate that the interference with endogenous beta4 expression, upon hormone deprivation, induces caspase-9 and cytochrome c-mediated apoptosis, which is enhanced upon tamoxifen treatment. On the other hand, the expression of myr-AKT in MCF7 beta4-short hairpin RNA cells rescues the cells from apoptosis in the absence of hormones and upon tamoxifen treatment.Overall, these results confirm the relevance of beta4 expression in mammary tumors and indicate this integrin as a relevant target for tumor therapy.
Pooled Sequencing and Rare Variant Association Tests for Identifying the Determinants of Emerging Drug Resistance in Malaria Parasites
Authors: Ian H. Cheeseman, Marina McDew-White, Aung Pyae Phyo, Kanlaya Sriprawat, François Nosten, Timothy J.C. Anderson
Journal: Molecular Biology and Evolution (2014)

We explored the potential of pooled sequencing to swiftly and economically identify selective sweeps due to emerging artemisinin (ART) resistance in a South-East Asian malaria parasite population. ART resistance is defined by slow parasite clearance from the blood of ART-treated patients and mutations in the kelch gene (chr. 13) have been strongly implicated to play a role. We constructed triplicate pools of 70 slow-clearing (resistant) and 70 fast-clearing (sensitive) infections collected from the Thai-Myanmar border and sequenced these to high (∼ 150-fold) read depth. Allele frequency estimates from pools showed almost perfect correlation (Lin's concordance = 0.98) with allele frequencies at 93 single nucleotide polymorphisms measured directly from individual infections, giving us confidence in the accuracy of this approach. By mapping genome-wide divergence (FST) between pools of drug-resistant and drug-sensitive parasites, we identified two large (>150 kb) regions (on chrs. 13 and 14) and 17 smaller candidate genome regions. To identify individual genes within these genome regions, we resequenced an additional 38 parasite genomes (16 slow and 22 fast-clearing) and performed rare variant association tests. These confirmed kelch as a major molecular marker for ART resistance (P = 6.03 × 10(-6)). This two-tier approach is powerful because pooled sequencing rapidly narrows down genome regions of interest, while targeted rare variant association testing within these regions can pinpoint the genetic basis of resistance. We show that our approach is robust to recurrent mutation and the generation of soft selective sweeps, which are predicted to be common in pathogen populations with large effective population sizes, and may confound more traditional gene mapping approaches.
Hypermethylation in the ZBTB20 gene is associated with major depressive disorder
Authors: Matthew N Davies, Lutz Krause, Jordana T Bell, Fei Gao, Kirsten J Ward, Honglong Wu, Hanlin Lu, Yuan Liu, Pei-Chein Tsai, David A Collier, Therese Murphy, Emma Dempster, Jonathan Mill, Alexis Battle, Sara Mostafavi, Xiaowei Zhu, Anjali Henders, Enda Byrne, Naomi R Wray, Nicholas G Martin, Tim D Spector, Jun Wang
Journal: Genome biology (2014)

Although genetic variation is believed to contribute to an individual's susceptibility to major depressive disorder, genome-wide association studies have not yet identified associations that could explain the full etiology of the disease. Epigenetics is increasingly believed to play a major role in the development of common clinical phenotypes, including major depressive disorder. Genome-wide MeDIP-Sequencing was carried out on a total of 50 monozygotic twin pairs from the UK and Australia that are discordant for depression. We show that major depressive disorder is associated with significant hypermethylation within the coding region of ZBTB20, and is replicated in an independent cohort of 356 unrelated case-control individuals. The twins with major depressive disorder also show increased global variation in methylation in comparison with their unaffected co-twins. ZBTB20 plays an essential role in the specification of the Cornu Ammonis-1 field identity in the developing hippocampus, a region previously implicated in the development of major depressive disorder. Our results suggest that aberrant methylation profiles affecting the hippocampus are associated with major depressive disorder and show the potential of the epigenetic twin model in neuro-psychiatric disease.
Intrasarcoplasmic Amyloidosis Impairs Proteolytic Function of Proteasomes in Cardiomyocytes by Compromising Substrate Uptake
Authors: Quanhai Chen, Jin-Bao Liu, Kathleen M. Horak, Hanqiao Zheng, Asangi R.K. Kumarapeli, Jie Li, Faqian Li, A. Martin Gerdes, Eric F. Wawrousek, Xuejun Wang
Journal: Circulation Research (2005)

The presence of increased ubiquitinated proteins and amyloid oligomers in failing human hearts strikingly resembles the characteristic pathology in the brain of many neurodegenerative diseases. The ubiquitin–proteasome system (UPS) is responsible for degradation of most cellular proteins and plays essential roles in virtually all cellular processes. UPS impairment by aberrant protein aggregation was previously shown in cell culture but remains to be demonstrated in intact animals. Mechanisms underlying the impairment are poorly understood. We report here that UPS proteolytic function is severely impaired in the heart of a mouse model of intrasarcoplasmic amyloidosis caused by cardiac-restricted expression of a human desmin–related myopathy-linked missense mutation of αB-crystallin (CryAB R120G ). The UPS impairment was detected before cardiac hypertrophy, and failure became discernible, suggesting that defective protein turnover likely contributes to cardiac remodeling and failure in this model. Further analyses reveal that the impairment is likely attributable to insufficient delivery of substrate proteins into the 20S proteasomes, and depletion of key components of the 19S subcomplex may be responsible. The derangement is likely caused by aberrant protein aggregation rather than loss of function of the CryAB gene because UPS malfunction was not evident in CryAB-null hearts and inhibition of aberrant protein aggregation by Congo red or a heat shock protein significantly attenuated CryAB R120G -induced UPS malfunction in cultured cardiomyocytes. Because of the central role of the UPS in cell regulation and the high intrasarcoplasmic amyloidosis prevalence in failing human hearts, our data suggest a novel pathogenic process in cardiac disorders with abnormal protein aggregation.
The cognitive bases of human tool use
Authors: Krist Vaesen
Journal: Behavioral and Brain Sciences (2012)

Abstract This article has two goals. The first is to assess, in the face of accruing reports on the ingenuity of great ape tool use, whether and in what sense human tool use still evidences unique, higher cognitive ability. To that effect, I offer a systematic comparison between humans and nonhuman primates with respect to nine cognitive capacities deemed crucial to tool use: enhanced hand-eye coordination, body schema plasticity, causal reasoning, function representation, executive control, social learning, teaching, social intelligence, and language. Since striking differences between humans and great apes stand firm in eight out of nine of these domains, I conclude that human tool use still marks a major cognitive discontinuity between us and our closest relatives. As a second goal of the paper, I address the evolution of human technologies. In particular, I show how the cognitive traits reviewed help to explain why technological accumulation evolved so markedly in humans, and so modestly in apes.
Coronary pacing during percutaneous transluminal coronary angioplasty.
Authors: B Meier, W Rutishauser
Journal: Circulation (1985)

To avoid venous puncture, a new concept for standby cardiac pacing during percutaneous transluminal coronary angioplasty (PTCA) and diagnostic cardiac catheterization was developed. It uses an arterial guidewire as a unipolar pacing electrode with the second electrode attached to the skin. The system was tested in 25 coronary arteries of 22 patients undergoing PTCA and in the left ventricles of 10 patients undergoing diagnostic cardiac catheterization. Coronary pacing via the guidewire used for directing the balloon catheter was possible in all patients and in 24 of the 25 coronary arteries attempted. Maximum duration of pacing was 8 min. Threshold currents ranged from 1 to 15 mA (mean 5.7). Left ventricular pacing via the same wires or standard wires used for introduction of diagnostic or guiding catheters was possible in all patients and was maintained for up to 10 min. Threshold currents ranged from 1 to 7 mA (mean 3.9). Neither method for pacing produced adverse effects during these short applications. The setup for coronary pacing also allowed recording of an intracoronary electrocardiogram during PTCA. The presented system provides backup for the rare event of sustained bradycardia during PTCA or diagnostic cardiac catheterization. If applied cautiously, it may safely and reliably replace the standby of a conventional transvenous pacing catheter.
The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial
Authors: Scott D Solomon, Michael Zile, Burkert Pieske, Adriaan Voors, Amil Shah, Elisabeth Kraigher-Krainer, Victor Shi, Toni Bransford, Madoka Takeuchi, Jianjian Gong, Martin Lefkowitz, Milton Packer, John JV McMurray
Journal: The Lancet (2012)
Mortality Trends in Men and Women with Diabetes, 1971 to 2000
Authors: Edward W. Gregg, Qiuping Gu, Yiling J. Cheng, K. M. Venkat Narayan, Catherine C. Cowie
Journal: Annals of Internal Medicine (2007)

Whether mortality rates among diabetic adults or excess mortality associated with diabetes in the United States has declined in recent decades is not known.To examine whether all-cause and cardiovascular disease mortality rates have declined among the U.S. population with and without self-reported diabetes.Comparison of 3 consecutive, nationally representative cohorts.Population-based health surveys (National Health and Nutrition Examination Surveys I, II, and III) with mortality follow-up assessment.Survey participants age 35 to 74 years with and without diabetes.Diabetes was determined by self-report for each survey (1971-1975, 1976-1980, and 1988-1994), and mortality rates were determined through 1986, 1992, and 2000 for the 3 surveys, respectively.Among diabetic men, the all-cause mortality rate decreased by 18.2 annual deaths per 1000 persons (from 42.6 to 24.4 annual deaths per 1000 persons; P = 0.03) between 1971 to 1986 and 1988 to 2000, accompanying decreases in the nondiabetic population. Trends for cardiovascular disease mortality paralleled those of all-cause mortality, with 26.4 annual deaths per 1000 persons in 1971 to 1986 and 12.8 annual deaths per 1000 persons in 1988 to 2000 (P = 0.06). Among women with diabetes, however, neither all-cause nor cardiovascular disease mortality declined between 1971 to 1986 and 1988 to 2000, and the all-cause mortality rate difference between diabetic and nondiabetic women more than doubled (from a difference of 8.3 to 18.2 annual deaths per 1000 persons). The difference in all-cause mortality rates by sex among people with diabetes in 1971 to 1986 were essentially eliminated in 1988 to 2000.Diabetes was assessed by self-report, and statistical power to examine the factors explaining mortality trends was limited.Progress in reducing mortality rates among persons with diabetes has been limited to men. Diabetes continues to greatly increase the risk for death, particularly among women.
Interstitial Diphtheria Toxin-Epidermal Growth Factor Fusion Protein Therapy Produces Regressions of Subcutaneous Human Glioblastoma Multiforme Tumors in Athymic Nude Mice
Authors: Tie Fu Liu, Philip D. Hall, Kimberley A. Cohen, Mark C. Willingham, Jiaozhong Cai, Andrew Thorburn, Arthur E. Frankel
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The novel fusion protein, DAB389EGF, composed of the catalytic and translocation domains of diphtheria toxin (DAB389) fused with a His-Ala linker to human epidermal growth factor (EGF) was tested for antiglioma efficacy in an in vivo model of human glioma. Experimental Design: Female athymic nude mice (ages 4-6 weeks) were inoculated s.c. with 10 million U87MG human glioma cells in the right flank. When tumor volumes reached ∼100 mm3 (∼6-8 days), i.t. injections of saline, DAB389IL2, or DAB389EGF 1, 3, 5 or 10 μg in 50 μL were given every other day for three to six doses. Animals were monitored twice daily and tumor measurements were made by calipers. Results: The maximal tolerated dose (MTD) of DAB389EGF was 3 μg every other day. Above the MTD, animals experienced loss of activity, reduced oral intake, and dehydration. Blood chemistries confirmed elevated blood urea nitrogen, creatinine, aspartate transaminase, and alanine transaminase. Histopathology revealed renal tubular necrosis. At the MTD, tumor regression was seen in all animals. Relapses occurred in 4 of 16 (25%) of animals after 1 month. These tumors contained EGF receptor, were sensitive in vitro to DAB389EGF, and responded to a second course of i.t. DAB389EGF. Conclusions: DAB389EGF fusion protein shows in vivo antiglioma efficacy in a s.c. tumor model and warrants further preclinical testing in an i.c. tumor model for eventual treatment of patients with recurrent or refractory EGF receptor–positive glioblastoma multiforme.
Systematic Reviews of Categorical Versus Continuum Models in Psychosis: Evidence for Discontinuous Subpopulations Underlying a Psychometric Continuum. Implications for DSM-V, DSM-VI, and DSM-VII
Authors: Richard J. Linscott, Jim van Os
Journal: Annual Review of Clinical Psychology (2010)

Diagnostic systems, phenotype models, and theories of etiology incorporate propositions on the underlying nature of psychosis and schizophrenia phenotypes. These propositions, whether implicit or explicit, are that the distributions of the phenotypes, or the phenotype experiences themselves, are dimensional or categorical. On one hand, evidence on the epidemiology of schizophrenia phenotypes suggests symptom phenotypes may not be bound by conventional diagnostic thresholds but instead may blend imperceptibly with subclinical, statistically frequent experience, supporting continuum viewpoints. On the other hand, evidence on the population structure suggests a latent categorical structure; the population may be composed of two types of people. However, both sets of evidence are beset by methodological limitations that point unequivocally to the need to move beyond current diagnostic conceptualizations, observation, and anamnesis of psychosis, and toward responsive and scientifically refutable formulations of schizophrenia.
Exhaled nitric oxide and exercise‐induced bronchoconstriction in young male conscripts: association only in atopics
Authors: A. Rouhos, H. Ekroos, J. Karjalainen, S. Sarna, A. R. A. Sovijärvi
Journal: Allergy (2005)

This study was conducted to evaluate how bronchial responsiveness to direct and indirect stimuli relate to nitric oxide producing airway inflammation, and whether the relationship differs between atopic and nonatopic patients with various degrees of bronchial hyperresponsiveness and airway inflammation in a group of otherwise homogenous young men. We studied 181 consecutive non‐smoking steroid‐naive young male conscripts referred to military hospital because of respiratory symptoms suggesting asthma. Skin prick tests, spirometry, measurement of exhaled nitric oxide (FENO), and standardized airway challenges with histamine and exercise were performed. 128 patients were atopic. FENO was significantly higher in the atopic group, median 21.2 ppb, compared to 10.2 ppb in the nonatopic group. Still, 36% of all nonatopic patients had elevated FENO. Bronchial responsiveness to histamine (HIB) was similar in the two groups, but exercise‐induced bronchoconstriction (EIB) was stronger in atopics ( P &lt; 0.01). FENO associated significantly with atopy ( P &lt; 0.001), severity of EIB ( P &lt; 0.001) and HIB ( P = 0.006) in multiple linear regression model. In separate regression models for atopic and nonatopic patients FENO associated with severity of EIB and HIB in atopic patients only. The results were similar when patients with confirmed diagnosis of asthma were analyzed separately. Our results indicate that FENO significantly associates with EIB and HIB in atopic, but not in nonatopic steroid‐naïve patients with asthmatic symptoms. The finding suggests that in such atopic patients degree of airway hyperresponsiveness may reflect severity of airway inflammation. However, in nonatopic patients with similar symptoms other mechanisms of airway hyperresponsiveness may be more important.
Gene Delivery to the Juvenile Mouse Liver Using AAV2/8 Vectors
Authors: Sharon C Cunningham, Allison P Dane, Afroditi Spinoulas, Ian E Alexander
Journal: Molecular Therapy (2008)

Recombinant adeno-associated viral (rAAV) vectors have shown promise for use in liver-targeted gene delivery, but their effects have not been extensively investigated in the immature liver. Understanding the impact of liver growth on the efficacy of transduction is essential, because many monogenic liver diseases that are amenable to gene therapy will require treatment early in life. Here we show that rAAV2/8 transduces the neonatal mouse liver with high efficiency. With just one doubling in liver weight, however, there is a rapid reduction in vector genome numbers, irrespective of form, and the loss of episomal vector is almost complete by 2 weeks. Stable transgene expression is observed in a small percentage of hepatocytes, often in two- to eight-cell clusters, suggestive of genomic integration. Delivery at serially older ages was associated with progressively improved episome persistence and transgene expression. Vector re-administration was possible following initial neonatal administration, albeit at reduced efficacy because of an anticapsid humoral immune response. We also found that intraperitoneal (IP) delivery of rAAV2/8 was highly effective at all ages, and that promoter selection is the critical determinant of the intensity and pattern of transgene expression across the hepatic lobule. We conclude that successful use of rAAV to treat liver disease in early childhood will require optimally efficient vector constructs and probable re-administration.
Gender differences and effects of sex steroids and dehydroepiandrosterone on androgen and oestrogen α receptors in mouse sebaceous glands
Authors: L. Azzi, M. El-Alfy, F. Labrie
Journal: British Journal of Dermatology (2005)

It is generally believed that the sebaceous gland is an intracrine organ which synthesizes its own active hormones to meet its local needs.To understand further the mechanisms of sex steroid action in mouse sebaceous glands.We have used immunocytochemistry to examine the expression of oestrogen receptor alpha (ERalpha) and androgen receptor (AR) in mouse sebaceous glands.In intact males AR is exclusively localized in the nuclei of basal and mature sebocytes, while in females it is present at a lower level in both the nuclei and the cytoplasm. Three weeks following gonadectomy (GDX), a marked decrease of AR labelling is observed in male sebocytes, while no change occurs in female sebocytes. Treatment of GDX animals with dihydrotestosterone (DHT) or dehydroepiandrosterone (DHEA) increases AR expression, while 17beta-estradiol (E2) decreases the stimulatory effect of DHT and DHEA. ERalpha is detected only in basal sebocytes of intact females but not in males. Following treatment with E2, ERalpha expression becomes visible in GDX males while DHT and DHEA inhibit the effect of E2.The present data show gender differences and demonstrate that DHT, E2 and DHEA exert specific effects on the expression of AR and ERalpha in mouse sebocytes.
Is investigation of patients with haemoptysis and normal chest radiograph justified?
Authors: A. J. Conway, J. A. Bennett, A. D. Richardson, M. D. Peake
Journal: Thorax (2010)

We read with interest the article by Thirumaran et al .1 They described their experience of 270 consecutive patients referred with haemoptysis and a normal chest radiograph. In their study they found the incidence of respiratory malignancy within this group was 9.6% (26 individuals) and of these 22 were primary lung malignancies. This is slightly higher than the 3–6% incidence previously reported in the literature.2–4

We have delivered a nurse-led clinic for patients referred via the 2 week wait system with haemoptysis and a normal, or non-localising, chest x-ray. Patients were stratified into high risk or low risk groups according to age and smoking history. An algorithm was then devised to guide further investigation …