tbuckley/cabot-search huggingface dataset:
Intravital imaging of podocyte calcium in glomerular injury and disease
Authors: James L. Burford, Karie Villanueva, Lisa Lam, Anne Riquier-Brison, Matthias J. Hackl, Jeffrey Pippin, Stuart J. Shankland, János Peti-Peterdi
Journal: Journal of Clinical Investigation (2014)

Intracellular calcium ([Ca²⁺]i) signaling mediates physiological and pathological processes in multiple organs, including the renal podocyte; however, in vivo podocyte [Ca²⁺]i dynamics are not fully understood. Here we developed an imaging approach that uses multiphoton microscopy (MPM) to directly visualize podocyte [Ca²⁺]i dynamics within the intact kidneys of live mice expressing a fluorescent calcium indicator only in these cells. [Ca²⁺]i was at a low steady-state level in control podocytes, while Ang II infusion caused a minor elevation. Experimental focal podocyte injury triggered a robust and sustained elevation of podocyte [Ca²⁺]i around the injury site and promoted cell-to-cell propagating podocyte [Ca²⁺]i waves along capillary loops. [Ca²⁺]i wave propagation was ameliorated by inhibitors of purinergic [Ca²⁺]i signaling as well as in animals lacking the P2Y2 purinergic receptor. Increased podocyte [Ca²⁺]i resulted in contraction of the glomerular tuft and increased capillary albumin permeability. In preclinical models of renal fibrosis and glomerulosclerosis, high podocyte [Ca²⁺]i correlated with increased cell motility. Our findings provide a visual demonstration of the in vivo importance of podocyte [Ca²⁺]i in glomerular pathology and suggest that purinergic [Ca²⁺]i signaling is a robust and key pathogenic mechanism in podocyte injury. This in vivo imaging approach will allow future detailed investigation of the molecular and cellular mechanisms of glomerular disease in the intact living kidney.
LSC 2011 Abstract: The effect of endothelin-1 on human basophil function in vitro
Authors: Katharina Cima, Silvia Blunder, Susanna Desole, Julia Günther, Judith Löffler-Ragg, Christian M. Kähler
Journal: European Respiratory Journal (2011)

Endothelin-1 (ET-1) has proinflammatory properties and contributes to allergic late-phase responses. As basophils play a key role in allergic rhinitis or asthma, we investigated the effect of ET-1 on basophils.  Cells were isolated from venous blood of healthy donors via magnetic cell sorting. To show ETA or ETB receptor expression RT-PCR was performed. The chemotactic effect of ET-1 [10 -6 -10 -16 M] was analysed in modified Boyden chambers (positive control MCP-1 [10 -8 M]). To explore ET-1 signalling, cells were preincubated with BQ-123 [10 -6 -10 -16 M] or BQ-788 [10 -6 -10 -16 M]. Migration depth was quantified microscopically. Histamine release upon ET-1 [10 -6 -10 -12 M] and upon additional stimulation with the secretagogue fMLP [10 -5 M] was determined by ELISA.  The RT-PCR revealed basophils to express both, ETAR and ETBR. ET-1 [10 -6 -10 -8 M] further proved to be a strong chemoattractant for human basophils (p -6 -10 -12 M] significantly blocked migration towards ET-1 [10 -8 M]. Furthermore, the histamine release was increased by 2.46 to 2.6 fold after ET-1 stimulation [10 -6 -10 -12 M]. Interestingly, only the evoking of histamine release by additional stimulation with fMLP [10 -5 M] resulted in a dose dependent effect of ET-1, showing ET-1 [10 -8 M] to be most effective.  Our observations reveal for the first time that basophils express ETAR and ETBR and ET-1 induces histamine release and basophil migration, which seems ETAR dependent. Considering the fact that ET-1 is involved in the mechanisms of airway inflammation, targeting ET-1 by receptor antagonists may be a new option in the treatment of allergic airway disease.
Flow limitation and dyspnoea in healthy supine subjects during methacholine challenge
Authors: J Sulc, CA Volta, Y Ploysongsang, L Eltayara, R Olivenstein, J Milic-Emili
Journal: European Respiratory Journal (1999)

The purpose of this study was to assess whether during standard methacholine (Mch) challenge (concentration up to 128 mg x mL(-1)) healthy supine subjects a) develop tidal expiratory flow limitation (FL) and hyperinflation, and b) whether the onset of tidal FL is associated with dyspnoea. Eight healthy subjects were studied. Dyspnoea was assessed using the Borg scale, FL by the negative expiratory pressure (NEP) method and hyperinflation in terms of decrease in inspiratory capacity (IC). Seven patients became flow limited at Mch doses ranging 4-64 mg x mL(-1), with FL encompassing 34-84% of the control tidal volume. In six of them the onset of tidal FL was associated with little or no dyspnoea and a modest degree of hyperinflation (deltaIC <-0.4 L). In one subject, however, onset of FL was associated with a substantial reduction in IC (0.58 L) and moderately severe dyspnoea. In all of these seven subjects FL was transiently reversed after an IC manoeuvre. In conclusion, the results show that a) most healthy subjects may develop flow limitation and hyperinflation during methacholine challenge in supine position, and b) at onset of flow limitation there is little or no dyspnoea, suggesting that onset of dynamic airway compression per se does not elicit significant dyspnoea. Significant dyspnoea probably only occurs with marked dynamic hyperinflation.
Ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) is a potential tumour suppressor in prostate cancer and is frequently silenced by promoter methylation
Authors: Ramesh Ummanni, Edgar Jost, Melanie Braig, Frithjof Lohmann, Frederike Mundt, Christine Barett, Thorsten Schlomm, Guido Sauter, Tina Senff, Carsten Bokemeyer, Holger Sültmann, Catherine Meyer-Schwesinger, Tim H Brümmendorf, Stefan Balabanov
Journal: Molecular Cancer (2011)

Abstract Background We have previously reported significant downregulation of ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) in prostate cancer (PCa) compared to the surrounding benign tissue. UCHL1 plays an important role in ubiquitin system and different cellular processes such as cell proliferation and differentiation. We now show that the underlying mechanism of UCHL1 downregulation in PCa is linked to its promoter hypermethylation. Furthermore, we present evidences that UCHL1 expression can affect the behavior of prostate cancer cells in different ways. Results Methylation specific PCR analysis results showed a highly methylated promoter region for UCHL1 in 90% (18/20) of tumor tissue compared to 15% (3/20) of normal tissues from PCa patients. Pyrosequencing results confirmed a mean methylation of 41.4% in PCa whereas only 8.6% in normal tissues. To conduct functional analysis of UCHL1 in PCa, UCHL1 is overexpressed in LNCaP cells whose UCHL1 expression is normally suppressed by promoter methylation and found that UCHL1 has the ability to decrease the rate of cell proliferation and suppresses anchorage-independent growth of these cells. In further analysis, we found evidence that exogenous expression of UCHL1 suppress LNCaP cells growth probably via p53-mediated inhibition of Akt/PKB phosphorylation and also via accumulation of p27kip1 a cyclin dependant kinase inhibitor of cell cycle regulating proteins. Notably, we also observed that exogenous expression of UCHL1 induced a senescent phenotype that was detected by using the SA-ß-gal assay and might be due to increased p14ARF, p53, p27kip1 and decreased MDM2. Conclusion From these results, we propose that UCHL1 downregulation via promoter hypermethylation plays an important role in various molecular aspects of PCa biology, such as morphological diversification and regulation of proliferation.
161 COLLAGEN PROPORTIONATE AREA: BEST INDEX TO PREDICT DECOMPENSATION IN PATIENTS WITH LIVER CIRRHOSIS OF DIFFERENT ETIOLOGIES
Authors: G. Isgro, L. Andreana, M. Garcovich, T.V. Luong, A. Hall, P. Manousou, N. Goossens, J. O'Beirne, D. Patch, A.P. Dhillon, A.K. Burroughs
Journal: Journal of Hepatology (2011)
Factors That Determine Risk for Surgery in Pediatric Patients With Crohn's Disease
Authors: Marc E. Schaefer, Jason T. Machan, David Kawatu, Christine R. Langton, James Markowitz, Wallace Crandall, David R. Mack, Jonathan S. Evans, Marian D. Pfefferkorn, Anne M. Griffiths, Anthony R. Otley, Athos Bousvaros, Subra Kugathasan, Joel R. Rosh, David J. Keljo, Ryan S. Carvalho, Gitit Tomer, Petar Mamula, Marsha H. Kay, Benny Kerzner, Maria Oliva–Hemker, Michael D. Kappelman, Shehzad A. Saeed, Jeffrey S. Hyams, Neal S. LeLeiko
Journal: Clinical Gastroenterology and Hepatology (2010)
What Does It Mean to Be a Cancer Gene Carrier? Problems in Establishing Causality From the Molecular Genetics of Cancer
Authors: A. Schatzkin, A. Goldstein, L. S. Freedman
Journal: JNCI Journal of the National Cancer Institute (1995)

Journal Article What Does It Mean to Be a Cancer Gene Carrier? Problems in Establishing Causality From the Molecular Genetics of Cancer Get access Arthur Schatzkin, Arthur Schatzkin Cancer Prevention Studies Branch, National Cancer InstituteBethesda, MD. Correspondence to : Arthur Schatzkin, M.D., Dr.P.H., Cancer Prevention Studies Branch, Division of Cancer Prevention and Control. National Cancer Institute, EPN, Rm. 211, 6130 Executive Blvd., Rockville, MD 20852. Search for other works by this author on: Oxford Academic PubMed Google Scholar Alisa Goldstein, Alisa Goldstein Genetic Epidemiology Branch, Division of Cancer Etiology, National Cancer InstituteBethesda, MD. Search for other works by this author on: Oxford Academic PubMed Google Scholar Laurence S. Freedman Laurence S. Freedman Cancer Prevention Studies Branch, National Cancer InstituteBethesda, MD. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 87, Issue 15, 2 August 1995, Pages 1126–1130, https://doi.org/10.1093/jnci/87.15.1126 Published: 02 August 1995 Article history Received: 28 October 1994 Revision received: 17 March 1995 Accepted: 23 May 1995 Published: 02 August 1995
Epidemiological Study of Sudden and Unexpected Deaths due to Arteriosclerotic Heart Disease
Authors: LEWIS KULLER, ABRAHAM LILIENFELD, RUSSELL FISHER
Journal: Circulation (1966)

A study of sudden unexpected nontraumatic deaths was begun on June 1, 1964. A sample of all nontraumatic deaths in Baltimore residents between the ages of 20 and 64 from June 15, 1964, to June 14, 1965, was obtained. The deaths were then studied by reviewing all available medical information in order to determine: (1) whether the death was possibly sudden or not and (2) the accuracy of the diagnosis reported on the death certificate. The next of kin or other relative or friend of each deceased person who died suddenly was then interviewed. For comparison, information was obtained on (1) a probability sample of the Baltimore population, and (2) deaths due to arteriosclerotic heart disease (ASHD deaths) that were found to be "not-sudden." There were 1,857 deaths in the original sample, of which 589 were sudden according to the definition of sudden death. After adjustment for sampling, it was estimated that 1,178 (32%) of the total 3,648 deaths in Baltimore were sudden. Arteriosclerotic heart disease (ASHD) accounted for 58% and the cardiovascular group together for 69% of the sudden deaths. Sixty per cent of all ASHD deaths were sudden. Of the 1,030 ASHD deaths in Baltimore City between the ages of 40 and 64, 20.6% occurred outside of a hospital and 46.2% represented deaths on arrival at a hospital. Only 18.9% of all ASHD deaths occurred after the first 24 hours of hospitalization. By use of data provided in several crosssectional and prospective studies, it was estimated that 22% of new coronary events were sudden deaths and that the case-fatality rate was 31%. In approximately half of the ASHD sudden deaths the deceased had a history of heart disease prior to death and in 24% the deceased had seen a physician within the week prior to death. Unfortunately we were not able to determine the reasons for these visits. In considering the implications of these findings with regard to the prevention of ASHD deaths, it would appear that prevention of only a comparatively small percentage (8.2%) of ASHD deaths is completely dependent on primary prevention. For the remaining ASHD deaths a combination of both primary and secondary prevention may be effective. Because of the rapidity of death and the high frequency of these deaths either occurring outside of a hospital or being called deaths on arrival, hospital treatment may well have little effect on reducing the ASHD mortality, while, on the other hand, the combination of better and earlier diagnosis and intensive treatment in a hospital could conceivably re- duce the mortality.
So many precious stories: a reflective narrative of patient based medicine in general practice, Christmas 1996
Authors: G. J. Elwyn
Journal: BMJ (1997)

In the treatment of patients with metastatic cancer, the current paradigm states that metastasis-directed therapy does not prolong life. This paradigm forms the basis of clinical trial null hypotheses, where trials are built to test the null hypothesis: patients garner no overall survival benefit from targeting metastatic lesions. However, with advancing imaging technology and increasingly precise techniques for targeting lesions, a much larger proportion of metastatic disease can be treated. As a result, the life-extending benefit of targeting metastatic disease is becoming increasingly clear. In this work, we suggest shifting this qualitative null hypothesis, and describe a mathematical model which can be used to frame a new, quantitative null. We begin with a very simple formulation of tumor growth, an exponential function, and illustrate how the same intervention (removing a given number of cells from the tumor) at different times effects survival. Additionally, we postulate where recent clinical trials fit into this parameter space and discuss the implications of clinical trial design in changing these quantitative parameters. Our model shows that while any amount of cell kill will extend survival, in many cases the extent is so small as to be unnoticeable in a clinical context or out-weighed by factors related to toxicity and treatment time. Recasting the null in these quantitative terms will allow trialists to design trials specifically to increase understanding of what circumstances (patient selection, disease burden, tumor growth kinetics) can lead to improved OS when targeting metastatic lesions, rather than whether or not targeting metastases extends survival for patients with (oligo-)metastatic disease.
Endometriosis: New Genetic Approaches and Therapy
Authors: David H. Barlow, Stephen Kennedy
Journal: Annual Review of Medicine (2005)

Endometriosis is a relatively common condition in women of reproductive age and is associated with considerable morbidity. Despite an extensive literature describing its multiple clinical manifestations, their management, and many aspects of the biology of endometriotic lesions, the pathophysiological mechanisms involved remain poorly understood. A genetic component in endometriosis is now recognized, and several groups have taken up the challenge of using genetic techniques to identify the aberrant molecular and cellular mechanisms in endometriosis with the intention of providing much-needed insights that might, in turn, lead to new therapies. The techniques that have been applied include expression profiling, tumor genetic studies, functional candidate gene studies, and linkage studies that can adopt a hypothesis-free approach. This review describes the current status of these studies and explores the prospects for new therapies.
Transcatheter versus Surgical Aortic-Valve Replacement in High-Risk Patients
Authors: Craig R. Smith, Martin B. Leon, Michael J. Mack, D. Craig Miller, Jeffrey W. Moses, Lars G. Svensson, E. Murat Tuzcu, John G. Webb, Gregory P. Fontana, Raj R. Makkar, Mathew Williams, Todd Dewey, Samir Kapadia, Vasilis Babaliaros, Vinod H. Thourani, Paul Corso, Augusto D. Pichard, Joseph E. Bavaria, Howard C. Herrmann, Jodi J. Akin, William N. Anderson, Duolao Wang, Stuart J. Pocock
Journal: New England Journal of Medicine (2011)

The use of transcatheter aortic-valve replacement has been shown to reduce mortality among high-risk patients with aortic stenosis who are not candidates for surgical replacement. However, the two procedures have not been compared in a randomized trial involving high-risk patients who are still candidates for surgical replacement.
Taking Your Child's Breath Away — The Extension of Asthma's Global Reach
Authors: Eva C. Mantzouranis
Journal: New England Journal of Medicine (2008)

On a clear summer day, as Michael runs through the fields playing with his friends, the view from his farm is spectacular. You can look past the hills where his family grows olives and raises sheep to the Mediterranean Sea. Last winter, however, the picture was far less tranquil for the 4-year-old and his family. In their small cottage that is heated by burning olive pits left over from the olive-oil press, with his mother cooking over an open fire and his father smoking two to three packs of cigarettes a day, Michael developed frequent colds, a chronic cough that . . .
HISTOCHEMICAL APPLICATIONS OF SKIN SURFACE BIOPSY*
Authors: R. MARKS
Journal: British Journal of Dermatology (1972)

Journal Article HISTOCHEMICAL APPLICATIONS OF SKIN SURFACE BIOPSY Get access R. MARKS R. MARKS Institute of Dermatology, St JOhn's Hospital for Diseases of the Skin, Leicester Square, London, W.C.2 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 86, Issue 1, 1 January 1972, Pages 20–26, https://doi.org/10.1111/j.1365-2133.1972.tb01887.x Published: 01 January 1972 Article history Accepted: 14 September 1971 Published: 01 January 1972
p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells
Authors: Alexandre Iannello, Thornton W. Thompson, Michele Ardolino, Scott W. Lowe, David H. Raulet
Journal: The Journal of Experimental Medicine (2013)

The induction of cellular senescence is an important mechanism by which p53 suppresses tumorigenesis. Using a mouse model of liver carcinoma, where cellular senescence is triggered in vivo by inducible p53 expression, we demonstrated that NK cells participate in the elimination of senescent tumors. The elimination of senescent tumor cells is dependent on NKG2D. Interestingly, p53 restoration neither increases ligand expression nor increases the sensitivity to lysis by NK cells. Instead, p53 restoration caused tumor cells to secrete various chemokines with the potential to recruit NK cells. Antibody-mediated neutralization of CCL2, but not CCL3, CCL4 or CCL5, prevented NK cell recruitment to the senescent tumors and reduced their elimination. Our findings suggest that elimination of senescent tumors by NK cells occurs as a result of the cooperation of signals associated with p53 expression or senescence, which regulate NK cell recruitment, and other signals that induce NKG2D ligand expression on tumor cells.
Brachytherapy for Accelerated Partial-Breast Irradiation: A Rapidly Emerging Technology in Breast Cancer Care
Authors: Grace L. Smith, Ying Xu, Thomas A. Buchholz, Benjamin D. Smith, Sharon H. Giordano, Bruce G. Haffty, Frank A. Vicini, Julia R. White, Douglas W. Arthur, Jay R. Harris, Ya-Chen T. Shih
Journal: Journal of Clinical Oncology (2010)

Brachytherapy is a method for delivering partial-breast irradiation after breast-conserving surgery (BCS). It is currently used in the community setting, although its efficacy has yet to be validated in prospective comparative trials. Frequency and factors influencing use have not been previously identified.In a nationwide database of 6,882 Medicare beneficiaries (age ≥ 65 years) with private supplemental insurance (MarketScan Medicare Supplemental), claims codes identified patients treated with brachytherapy versus external-beam radiation after BCS for incident breast cancer (diagnosed from 2001 to 2006). Logistic regression modeled predictors of brachytherapy use.Frequency of brachytherapy use as an alternative to external-beam radiation after BCS increased over time (< 1% in 2001, 2% in 2002, 3% in 2003, 5% in 2004, 8% in 2005, 10% in 2006; P < .001). Increased use correlated temporally with US Food and Drug Administration approval and Medicare reimbursement of brachytherapy technology. Brachytherapy use was more likely in women with lymph node-negative disease (odds ratio [OR], 2.19; 95% CI, 1.17 to 4.11) or axillary surgery (OR, 1.74; 95% CI, 1.23 to 2.44). Brachytherapy use was also more likely in women with non-health maintenance organization insurance (OR, 1.81; 95% CI, 1.24 to 2.64) and in areas with higher median income (OR, 1.58; 95% CI, 1.05 to 2.38), lower density of radiation oncologists (OR, 1.78; 95% CI, 1.11 to 2.86), or higher density of surgeons (OR, 1.57; 95% CI, 1.07 to 2.31).Despite ongoing questions regarding efficacy, breast brachytherapy was rapidly incorporated into the care of older, insured patients. In our era of frequently emerging novel technologies yet growing demands to optimize costs and outcomes, results provide insight into how clinical, policy, and socioeconomic factors influence new technology diffusion into conventional care.
Histone deacetylase inhibitors suppress IL-6 production by rheumatoid arthritis firoblast-like synoviocytes and macrophages via modulation of mRNA stability rather than blockade of NF- B signalling
Authors: A. M. Grabiec, P. P. Tak, K. A. Reedquist
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background and objectives</h3> Interleukin 6 (IL-6) is a key inflammatory cytokine in the pathobiology of rheumatoid arthritis (RA) and biological therapies targeting the IL-6 receptor have shown clinical benefit. The production of inflammatory cytokines is tightly regulated by reversible acetylation and deacetylation of histones and transcription factors. Histone deacetylase (HDAC) inhibitors (HDACi) are effective therapeutics in animal models of arthritis and have anti-inflammatory effects in RA synovial macrophages and tissue. Here, we examined the effects of HDACi on IL-6 production by RA FLS, and the molecular mechanisms underlying regulation of IL-6 expression by HDACi. <h3>Materials and methods</h3> RA FLS and macrophages were treated with IL-1β, TNFα, LPS or poly (I:C) in the absence or presence of the HDACi trichostatin A (TSA). IL-6 production was measured by ELISA. The expression and stability of IL-6 mRNA was analysed by quantitative PCR. Activation of NF-κB and MAP kinase signalling pathways was assessed by immunoblotting. The nuclear translocation and DNA binding activity of NF-κB and AP-1 components was assessed by immunoblotting and ELISA-based DNA-binding assays. <h3>Results</h3> TSA potently suppressed RA FLS IL-6 production induced by IL-1β, TNF and TLR ligands LPS and poly (I-C) (p &lt; 0.05). Treatment with TSA did not modulate early signalling events occurring after IL-1β receptor triggering: phosphorylation of IκBα, as well as p38, ERK and JNK MAP kinases remained unaffected by HDACi. Furthermore, changes in activity of AP-1 components c-Jun, JunB and JunD in response to IL-1β were not modulated by TSA. While TSA also failed to affect NF-κB activity at early time points following stimulation, it induced a significant reduction in nuclear retention of NF-κB subunits p65 and p50 in FLS 24 h after IL-1β stimulation. However, TSA-mediated inactivation of NF-κB did not coincide with reduction of IL-6 mRNA accumulation, detectable 4 h following stimulation with IL-1β. IL-6 mRNA demonstrated accelerated degradation in the presence of TSA. Similar effects of TSA were observed in macrophages, indicating regulation of IL-6 mRNA stability as a common mechanism responsible for suppression of IL-6 production by HDACi. <h3>Conclusions</h3> Inhibition of HDAC activity in RA FLS efficiently blocks the production of IL-6, and modulation of IL-6 mRNA stability is a potential mechanism underlying this regulation both in RA FLS and macrophages. Enhanced nuclear export of NF-κB mediated by HDACi might lead to suppressed transcription of other inflammatory mediators. Our findings suggest that therapies targeting HDAC activity may be useful in suppressing inflammation in RA.