tbuckley/cabot-search huggingface dataset:
Rho-GDP dissociation inhibitor alpha downregulated by low shear stress promotes vascular smooth muscle cell migration and apoptosis: a proteomic analysis
Authors: Ying-Xin Qi, Ming-Juan Qu, Ding-Kun Long, Bo Liu, Qing-Ping Yao, Shu Chien, Zong-Lai Jiang
Journal: Cardiovascular Research (2008)

Low shear stress (LSS) plays a significant role in vascular remodelling during atherogenesis, which involves migration, proliferation, and apoptosis of vascular smooth muscle cells (VSMCs). The aim of the present study is to elucidate the molecular mechanisms by which LSS induces vascular remodelling. Using proteomic techniques, two-dimensional electrophoresis, and mass spectrometry, the protein profiles of Sprague–Dawley rat aorta cultured under two levels of shear stress, 5 and 15 dyn/cm2, were determined. The results showed a significantly lower expression of protein-Rho-GDP dissociation inhibitor alpha (Rho-GDIα) in the LSS vessels. Rho-GDIα signalling mechanisms and effects on VSMC migration and apoptosis were then studied to understand the role of Rho-GDIα in the LSS-induced vascular remodelling. A decrease in Rho-GDIα expression by using target small interfering RNA (siRNA) transfection caused increases in the phosphorylation of Rac1 and Akt and enhancements of VSMC migration and apoptosis. Treatment with the PI3K/Akt-specific inhibitor wortmannin significantly decreased Akt phosphorylation, but had no effect on Rho-GDIα expression and Rac1 phosphorylation. Wortmannin was able to reverse the Rho-GDIα siRNA-induced enhancement of VSMC migration, but not VSMC apoptosis. The results indicate that the LSS-induced VSMC migration and apoptosis are mediated by a downregulation of Rho-GDIα. The effect of Rho-GDIα on VSMC migration is mediated by the PI3K/Akt pathway, but its effect on VSMC apoptosis is not.
Proximal tubular function in dogs with thoracic caval constriction
Authors: R. Brewer Auld, Edward A. Alexander, Norman G. Levinsky
Journal: Journal of Clinical Investigation (1971)

The effect of saline infusion on proximal sodium reabsorption was compared in normal dogs and in dogs with acute or chronic partial thoracic vena cava obstruction. After acute vena cava obstruction, proximal fractional sodium reabsorption rose by 74%. During continued caval obstruction, saline loading strikingly reduced proximal reabsorption but sodium excretion remained minimal. In chronic caval dogs, saline loading reduced proximal fractional sodium reabsorption by 31% but sodium excretion in the micropunctured kidney was only 41 muEq/min. After saline infusion in normal dogs, proximal fractional sodium reabsorption fell 39% while unilateral sodium excretion rose to 584 muEq/min. Nephron filtration rate was also measured before and after saline loading in normal and chronic caval dogs in both repunctured and fresh tubules. There was a marked increase in nephron filtration rate in repunctured tubules and no change in freshly punctured tubules in both groups. The effect of saline loading on nephron filtration rate in normal and chronic caval dogs was similar, therefore, whether repunctured or fresh nephrons were considered.We conclude that saline infusion depresses proximal sodium reabsorption in acute and chronic TVC dogs. Since saline loading markedly increases distal delivery without a concomitant natriuresis, enhanced distal reabsorption must play a major role in the sodium retention exhibited by chronic caval dogs. Redistribution of filtrate does not appear to be a factor in this sodium retention.
The Modulation of Ocular Growth in Rabbits with Peripheral Retinal Ablation
Authors: Wayne G. Whitmore, Brian J. Curtin, Donald Fox
Journal: Ophthalmology (1993)

To study the effects of transcleral cryotherapy and laser photocoagulation of anterior retina on ocular growth.Twenty-one rabbits underwent transcleral cryotherapy or indirect ophthalmoscopic laser photocoagulation of the anterior retina on one of their eyes between 2 and 8 weeks of age.After the rabbits were killed between 3 and 6 months of age, treated rabbit eyes were found to be significantly smaller in axial length (P < 0.001), average equatorial diameter (P < 0.01), average corneal diameter (P < 0.05), and in total ocular volume (P < 0.01). The difference in eye size was not due to lowered intraocular pressure.The results demonstrate that these treatments slow growth of both the anterior and posterior segment of rabbit eyes.
The interaction of convection and diffusion in the transport of 131I-albumin within the media of the rabbit thoracic aorta.
Authors: A Tedgui, M J Lever
Journal: Circulation Research (1985)

The interaction of convection and diffusion in the transport of 131I-labeled albumin within the wall of rabbit thoracic aorta was studied in vessels excised at in vivo length. They were pressurized with a solution containing no tracer and immersed in a solution containing labeled albumin. The label then entered the wall tissue via the adventitia and had to diffuse against the convective flux which occurred from the lumen to the adventitia. Experiments were performed on intact and deendothelialized vessels pressurized to 70 and 180 mm Hg. At the end of each experiment the vessels were subjected to sequential frozen sectioning parallel to the lumenal surface. The radioactivity of the 20-micron-thick sections was determined and expressed as a tissue:labeled solution concentration ratio. Transmural profiles of these ratios were thus obtained. The steady state was found to be achieved by about 90 minutes. When the convection was enhanced by removal of the endothelium, the average ratios were lower than when the endothelium was intact, and the profile was much flatter. The results suggest that convection influenced macromolecular transport within the arterial wall, even in vessels with intact endothelium.
Investigation of the atypical<i>FBXW7</i>mutation spectrum in human tumours by conditional expression of a heterozygous propellor tip missense allele in the mouse intestines
Authors: Hayley Davis, Annabelle Lewis, Axel Behrens, Ian Tomlinson
Journal: Gut (2013)

<h3>Objective</h3> <i>FBXW7</i> encodes the substrate recognition component of a ubiquitin ligase that degrades targets such as Notch1, c-Jun, c-Myc and cyclin E. <i>FBXW7</i> mutations occur in several tumour types, including colorectal cancers. The <i>FBXW7</i> mutation spectrum in cancers is unusual. Some tumours have biallelic loss of function mutations but most have monoallelic missense mutations involving specific arginine residues at β-propellor tips involved in substrate recognition. <h3>Design</h3> FBXW7 functional studies have generally used null systems. In order to analyse the most common mutations in human tumours, we created a <i>Fbxw7<sup>fl(R482Q)</sup></i><sup>/+</sup> mouse and conditionally expressed this mutation in the intestines using <i>Vill</i>-Cre. We compared these mice with heterozygous null (<i>Fbxw7</i><sup>+/−</sup>) mutants. <h3>Results</h3> A few sizeable intestinal adenomas occurred in approximately 30% of R482Q/+ and <i>Fbxw7</i><sup>+/−</sup> mice at age &gt;300 days. Breeding the R482Q allele onto <i>Apc</i> mutant backgrounds led to accelerated morbidity and increased polyp numbers and size. Within the small bowel, polyp distribution was shifted proximally. Elevated levels of two particular Fbxw7 substrates, Klf5 and Tgif1, were found in normal intestine and adenomas of R482Q/+, R482Q/R482Q and <i>Fbxw7</i><sup>−/−</sup> mice, but not <i>Fbxw7</i><sup>+/−</sup> animals. On the <i>Apc</i> mutant background, <i>Fbxw7</i><sup>+/−</sup> mutants had a phenotype intermediate between <i>Fbxw7</i> wild-type and R482Q/+ mice. <h3>Conclusions</h3> Heterozygous <i>Fbxw7</i> propellor tip (R482Q) mutations promote intestinal tumorigenesis on an <i>Apc</i> mutant background. Klf5 and Tgif1 are strong candidates for mediating this effect. Although heterozygous null <i>Fbxw7</i> mutations also promote tumour growth, these have a weaker effect than R482Q. These findings explain the <i>FBXW7</i> mutation spectrum found in human cancers, and emphasise the need for animal models faithfully to reflect human disease.
A Dominant Mutant Allele of the <i>ING4</i> Tumor Suppressor Found in Human Cancer Cells Exacerbates <i>MYC</i>-Initiated Mouse Mammary Tumorigenesis
Authors: Suwon Kim, Alana L. Welm, J. Michael Bishop
Journal: Cancer Research (2010)

ING4 is a candidate tumor suppressor gene that is deleted in 10% to 20% of human breast cancers and is mutated in various human cancer cell lines. To evaluate whether ING4 has a tumor-suppressive role in breast tissue, we overexpressed it in mouse mammary glands using a transplant system. Ectopic expression of ING4 suppressed MYC-induced mammary hyperplasia, but not tumorigenesis. In the same model system, we show that a COOH-terminal truncation mutant of ING4 found in human cancer cells could act alone to induce abnormal gland structures resembling mammary hyperplasia, which did not progress to tumors. However, coexpression of the ING4 mutant with MYC increased the penetrance and metastasis of MYC-initiated mammary tumors, giving rise to tumors with more organized acinar structures. Similarly, in vitro expression of the ING4 mutant in MCF10A mammary epithelial cells reinforced tight junctional structures. Our results provide direct functional evidence that ING4 could suppress the early stages of breast cancer and that dominant mutant alleles of ING4 might contribute to malignant development.
Photostimulable Near-Infrared Persistent Luminescent Nanoprobes for Ultrasensitive and Longitudinal Deep-Tissue Bio-Imaging
Authors: Yen-Jun Chuang, Zipeng Zhen, Fan Zhang, Feng Liu, Jyoti P. Mishra, Wei Tang, Hongmin Chen, Xinglu Huang, Lianchun Wang, Xiaoyuan Chen, Jin Xie, Zhengwei Pan
Journal: Theranostics (2014)

In vivo fluorescence imaging suffers from suboptimal signal-to-noise ratio and shallow detection depth, which is caused by the strong tissue autofluorescence under constant external excitation and the scattering and absorption of short-wavelength light in tissues.Here we address these limitations by using a novel type of optical nanoprobes, photostimulable LiGa 5 O 8 :Cr 3+ near-infrared (NIR) persistent luminescence nanoparticles, which, with very-long-lasting NIR persistent luminescence and unique photo-stimulated persistent luminescence (PSPL) capability, allow optical imaging to be performed in an excitation-free and hence, autofluorescence-free manner.LiGa 5 O 8 :Cr 3+ nanoparticles pre-charged by ultraviolet light can be repeatedly (>20 times) stimulated in vivo, even in deep tissues, by short-illumination (~15 seconds) with a white light-emitting-diode flashlight, giving rise to multiple NIR PSPL that expands the tracking window from several hours to more than 10 days.Our studies reveal promising potential of these nanoprobes in cell tracking and tumor targeting, exhibiting exceptional sensitivity and penetration that far exceed those afforded by conventional fluorescence imaging.
Spermine Inhibits Proinflammatory Cytokine Synthesis in Human Mononuclear Cells: A Counterregulatory Mechanism that Restrains the Immune Response
Authors: Minghuang Zhang, Theresa Caragine, Haichao Wang, Pamela S. Cohen, Galina Botchkina, Kuniyasu Soda, Marina Bianchi, Peter Ulrich, Anthony Cerami, Barbara Sherry, Kevin J. Tracey
Journal: The Journal of Experimental Medicine (1997)

The local production of proinflammatory cytokines mediates the host response to inflammation, infection, and injury, whereas an overexpression of these mediators can injure or kill the host. Recently, we identified a class of multivalent guanylhydrazone compounds that are effective inhibitors of proinflammatory cytokine synthesis in monocytes/macrophages. The structure of one such cationic molecule suggested a molecular mimicry with spermine, a ubiquitous endogenous biogenic amine that increases significantly at sites of inflammation and infection. Here, we addressed the hypothesis that spermine might counterregulate the innate immune response by downregulating the synthesis of potentially injurious cytokines. When spermine was added to cultures of human peripheral blood mononuclear cells stimulated with lipopolysaccharide (LPS), it effectively inhibited the synthesis of the proinflammatory cytokines tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6, MIP-1α, and MIP-1β. The inhibition of cytokine synthesis was specific and reversible, with significant inhibition of TNF synthesis occurring even when spermine was added after LPS. The mechanism of spermine-mediated cytokine suppression was posttranscriptional and independent of polyamine oxidase activity. Local administration of spermine in vivo protected mice against the development of acute footpad inflammation induced by carrageenan. These results identify a distinct molecular counterregulatory role for spermine in downregulating the monocyte proinflammatory cytokine response.
Abstract 344: Silencing RBBP6 (retinoblastoma binding protein 6) sensitizes breast cancer cells to staurosporine and camptothecin-induced cell death
Authors: Lesetja Raymond Motadi, Pontsho Moela, Mpho S. Choene
Journal: Cancer Research (2014)

Abstract Retinoblastoma Binding Protein 6 (RBBP6) is a multi-domain protein that uses its ring finger domain to interact with p53 and pRb tumour suppressor genes. The mechanism by which RBBP6 uses to degrade p53 is still unknown; nonetheless it is well known that RBBP6 promotes cell proliferation in several cancers by negatively regulating p53 via its E3 ubiquitin ligase activity (Ntwasa, 2008). Degradation of p53 by RBBP6 may compromise p53-mediated apoptosis in breast cancer. This study is intended to investigate, the potential applications of RNA interference (RNAi) to block RBBP6 expression, as well as its subsequent effect on cell growth and apoptosis. To achieve these methodologies the following techniques were used: RT-PCR, western blotting, xCELLigence system and flow cytometry. Our studies indicate that the knockdown of RBBP6 expression by siRNA modulates p53 gene involved in cell death pathways and apoptosis, showing statistically significant gene expression differences. RBBP6 siRNA significantly reduced cell index (CI) compared to the control samples and we observed an inhibition of cellular proliferation in the interval of between 24 and 48 h, as shown in the data obtained by dynamic evaluation using the xCELLigence System. These results were further confirmed by flow cytometer which showed some apoptotic activity. About 20.7% increase in apoptosis was observed in cells co-treated with RBBP6 siRNA and camptothecin when compared to camptothecin-only whereas in siRBBP6 and Staurosporine treated there was only 8.8% increase in apoptosis. These findings suggest that silencing RBBP6 may be a novel strategy to promote staurosporine- and camptothecin-induced apoptosis in breast cancer cells. Citation Format: Lesetja Raymond Motadi, Pontsho Moela, Mpho S. Choene. Silencing RBBP6 (retinoblastoma binding protein 6) sensitizes breast cancer cells to staurosporine and camptothecin-induced cell death. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 344. doi:10.1158/1538-7445.AM2014-344
Altered CXCR3 isoform expression regulates prostate cancer cell migration and invasion
Authors: Qian Wu, Rajiv Dhir, Alan Wells
Journal: Molecular Cancer (2012)

Abstract Background Carcinoma cells must circumvent the normally suppressive signals to disseminate. While often considered 'stop' signals for adherent cells, CXCR3-binding chemokines have recently been correlated positively with cancer progression though the molecular basis remains unclear. Results Here, we examined the expression and function of two CXCR3 variants in human prostate cancer biopsies and cell lines. Globally, both CXCR3 mRNA and protein were elevated in localized and metastatic human cancer biopsies compared to normal. Additionally, CXCR3A mRNA level was upregulated while CXCR3B mRNA was downregulated in these prostate cancer specimens. In contrast to normal prostate epithelial cells (RWPE-1), CXCR3A was up to half the receptor in the invasive and metastatic DU-145 and PC-3 prostate cancer cells, but not in the localized LNCaP cells. Instead of inhibiting cell migration as in RWPE-1 cells, the CXCR3 ligands CXCL4/PF4 and CXCL10/IP10 promoted cell motility and invasiveness in both DU-145 and PC-3 cells via PLCβ3 and μ-calpain activation. CXCR3-mediated diminution of cell motility in RWPE-1 cells is likely a result of cAMP upregulation and m-calpain inhibition via CXCR3B signal transduction. Interestingly, overexpression of CXCR3B in DU-145 cells decreased cell movement and invasion. Conclusion These data suggest that the aberrant expression of CXCR3A and down-regulation of CXCR3B may switch a progression "stop" to a "go" signal to promote prostate tumor metastasis via stimulating cell migration and invasion.
Ovarian hormones induce TGF-β3 and fibronectin mRNAs but exhibit a disparate action on cardiac fibroblast proliferation
Authors: I Mercier
Journal: Cardiovascular Research (2002)

Prior to menopause, women have a lower risk of cardiovascular disease compared to age-matched men. Despite the well-documented beneficial physiological effects of ovarian hormones on vascular reactivity and growth, very little is known with regard to the direct action on cardiac cells. Objective: The following study examined the pattern of ovarian hormone receptor subtype expression in cardiac fibroblasts, the modulator role of 17β-estradiol and progesterone on growth and their respective influence on putative molecular events of extracellular matrix remodeling. Methods and results: Neonatal rat cardiac fibroblasts were isolated from 1- to 3-day-old Sprague–Dawley rats. Immunofluorescence and Western blot analysis revealed the presence of estrogen receptor-α (ER-α), and -β (ER-β) subtypes, with the ER-α subtype localized on the plasma membrane. Likewise, both progesterone receptor-A (PR-A), and -B (PR-B) subtypes were expressed in cardiac fibroblasts, and the PR-B appeared to be the predominant subtype associated with the plasma membrane. Despite the presence of both ER subtypes, the treatment of cardiac fibroblasts with 1 μM 17β-estradiol exerted a modest decrease in DNA synthesis. By contrast, progesterone treatment caused a dose-dependent decrease in [3H]thymidine uptake, without a concomitant induction of apoptosis. The progesterone-mediated decrease in DNA synthesis was associated with the upregulation of the cyclin-dependent kinase inhibitor p27Kip1, whereas p21cip and proliferating cell nuclear antigen protein levels were unchanged. Lastly, despite the modest effect on DNA synthesis, 17β-estradiol increased the steady-state mRNA levels of transforming growth factor-β3 and fibronectin. Likewise, progesterone increased the expression of both transforming growth factor-β3, and fibronectin mRNA. Conclusion: Collectively, these data are the first to highlight the presence of estrogen and progesterone receptor subtypes on the plasma membrane of neonatal rat cardiac fibroblasts, and further underscore the ability of ovarian hormones to directly suppress DNA synthesis, and influence putative molecular events associated with extracellular matrix remodeling.
Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency
Authors: I. Sadaf Farooqi, Giles S.H. Yeo, Julia M. Keogh, Shiva Aminian, Susan A. Jebb, Gary Butler, Tim Cheetham, Stephen O’Rahilly
Journal: Journal of Clinical Investigation (2000)

Over 20 severely obese subjects in 11 independent kindreds have been reported to have pathogenic heterozygous mutations in the gene encoding the melanocortin 4 receptor (MC4R), making this the most common known monogenic cause of human obesity. To date, the detailed clinical phenotype of this dominantly inherited disorder has not been defined, and no homozygous subjects have been described. We determined the nucleotide sequence of the entire coding region of the MC4R gene in 243 subjects with severe, early-onset obesity. A novel two–base pair GT insertion in codon 279 was found in two unrelated subjects, and four novel missense mutations, N62S, R165Q, V253I, C271Y, and one mutation (T112M) reported previously were found in five subjects. N62S was found in homozygous form in five children with severe obesity from a consanguineous pedigree. All four heterozygous carriers were nonobese. Several features of the phenotype, e.g. hyperphagia, tendency toward tall stature, hyperinsulinemia, and preserved reproductive function, closely resemble those reported previously in Mc4r knock-out mice. In addition, a marked increase in bone mineral density was seen in all affected subjects. In transient transfection assays, the N62S mutant receptor showed a responsiveness to αMSH that was intermediate between the wild-type receptor and mutant receptors carrying nonsense and missense mutations associated with dominantly inherited obesity. Thus MC4R mutations result in a syndrome of hyperphagic obesity in humans that can present with either dominant or recessive patterns of inheritance.
Medically unexplained symptoms: (Letter 4 of 5)
Authors: H. Goodare
Journal: Journal of the Royal Society of Medicine (2003)

The admirers of Thomas Willis are indebted to Dr O'Connor (March 2003 JRSM 1 ) for adding further evidence that Cerebri Anatome (1664) reflects the religious and political practices of mid-17th-century England.Keele previously noted that the dedication of this famous book can leave no reasonable doubt that Willis
THE ELIMINATION OF ADMINISTERED ZINC IN PANCREATIC JUICE, DUODENAL JUICE, AND BILE OF THE DOG AS MEASURED BY ITS RADIOACTIVE ISOTOPE (Zn65)
Authors: M. Laurence Montgomery, G. E. Sheline, I. L. Chaikoff
Journal: The Journal of Experimental Medicine (1943)

The excretion of intravenously injected labeled zinc into pancreatic juice, duodenal juice, and bile of the dog was investigated. The use of the radioactive isotope permitted the injection of minute amounts of zinc, amounts that were negligible when compared with the total amount of zinc already present in the animal. 1. A large proportion of the injected Zn(65) was eliminated by way of the external secretion of the pancreas. As much as 11 per cent was excreted in the pancreatic juice in 14 days. 2. Very little of the administered radiozinc appeared in the bile. The maximum excretion observed for this pathway was 0.4 per cent in 8 days. 3. Radiozinc was also found in large amounts in the juice obtained from an isolated loop of the duodenum.
Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation
Authors: Peng-Chieh Chen, Hiroko Wakimoto, David Conner, Toshiyuki Araki, Tao Yuan, Amy Roberts, Christine E. Seidman, Roderick Bronson, Benjamin G. Neel, Jonathan G. Seidman, Raju Kucherlapati
Journal: Journal of Clinical Investigation (2010)

Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, unique facial features, and congenital heart disease. About 10%-15% of individuals with NS have mutations in son of sevenless 1 (SOS1), which encodes a RAS and RAC guanine nucleotide exchange factor (GEF). To understand the role of SOS1 in the pathogenesis of NS, we generated mice with the NS-associated Sos1E846K gain-of-function mutation. Both heterozygous and homozygous mutant mice showed many NS-associated pheno-types, including growth delay, distinctive facial dysmorphia, hematologic abnormalities, and cardiac defects. We found that the Ras/MAPK pathway as well as Rac and Stat3 were activated in the mutant hearts. These data provide in vivo molecular and cellular evidence that Sos1 is a GEF for Rac under physiological conditions and suggest that Rac and Stat3 activation might contribute to NS phenotypes. Furthermore, prenatal administration of a MEK inhibitor ameliorated the embryonic lethality, cardiac defects, and NS features of the homozygous mutant mice, demonstrating that this signaling pathway might represent a promising therapeutic target for NS.