tbuckley/cabot-search huggingface dataset:
Tetraspanin CD151 Regulates Transforming Growth Factor β Signaling: Implication in Tumor Metastasis
Authors: Rafał Sadej, Hanna Romanska, Dean Kavanagh, Gouri Baldwin, Takashi Takahashi, Neena Kalia, Fedor Berditchevski
Journal: Cancer Research (2010)

Tetraspanin CD151 is associated with laminin-binding integrins and controls tumor cell migration and invasion. By analyzing responses of breast cancer cells to various growth factors, we showed that depletion of CD151 specifically attenuates transforming growth factor beta1 (TGFbeta1)-induced scattering and proliferation of breast cancer cells in three-dimensional Matrigel. CD151-dependent cell scattering requires its association with either alpha3beta1 or alpha6 integrins, but it is independent of the recruitment of CD151 to tetraspanin-enriched microdomains. We also found that CD151 regulates the compartmentalization of TGF-beta type I receptor (TbetaRI/ALK-5) and specifically controls the TGFbeta1-induced activation of p38. In contrast, signaling leading to activation of Smad2/3, c-Akt, and Erk1/2 proteins was comparable in CD151(+) and CD151(-) cells. Attenuation of TGFbeta1-induced responses correlated with reduced retention in the lung vascular bed, inhibition of pneumocyte-induced scattering of breast cancer cells in three-dimensional Matrigel, and decrease in experimental metastasis to the lungs. These results identify CD151 as a positive regulator of TGFbeta1-initiated signaling and highlight the important role played by this tetraspanin in TGFbeta1-induced breast cancer metastasis.
The Hypercalcemia of Cancer
Authors: G R Mundy, K J Ibbotson, S M D'Souza, E L Simpson, J W Jacobs, T J Martin
Journal: New England Journal of Medicine (1984)

HYPERCALCEMIA is one of the most common metabolic complications of cancer. It has fascinated clinicians since it was first recognized 60 years ago by Zondek et al.1 It is now being recognized more commonly, as is primary hyperparathyroidism, because of the advent of routine measurement of the serum calcium level.2,3 The estimated incidence of the hypercalcemia of cancer is 150 new cases per million persons per year.2,3 This compares with an annual incidence of approximately 250 new cases of primary hyperparathyroidism per year.2,3 However, the relative frequency of cancer as a cause of hypercalcemia is even greater in hospital populations, . . .
Prevalence of Liver Disease in a Population of Asymptomatic Persons with Hepatitis C Virus Infection
Authors: Alfredo Alberti
Journal: Annals of Internal Medicine (2002)

The prevalence of significant liver disease in persons with asymptomatic hepatitis C virus (HCV) infection is unclear.To determine the prevalence and severity of HCV infection in asymptomatic persons.Population-based cross-sectional study.Northeastern Italy.4820 apparently healthy Telecom Italy employees or their relatives who underwent screening for cardiovascular risk factors.Initial screening for anti-HCV by enzyme-linked immunosorbent assay followed by HCV RNA testing by polymerase chain reaction and monitoring of alanine aminotransferase levels in viremic persons (92% of viremic persons also had liver biopsies to assess their METAVIR scores).116 persons (2.4% [95% CI, 1.97% to 2.84%]) were positive for anti-HCV and 85 (1.76% [CI, 1.39% to 2.14%]) were also viremic. The ALT level was persistently normal in 39 (46%) of viremic patients and elevated in 46 (54%). Significant hepatic histologic abnormalities were detected in 19% (CI, 7.21% to 36.4%) of persons with persistently normal ALT levels and in 61% (CI, 45.4% to 74.9%) of viremic persons who had elevated ALT levels (P < 0.001). The prevalence of HCV infection and number of persons with chronic liver fibrosis increased with age (P = 0.003).Hepatitis C is histologically active and progressive in up to 40% of asymptomatic persons with HCV infection. The severity of liver disease correlates with abnormal ALT levels and increases with age.
1022. Efficient Dystrophin Production in Response to Local and Systemic Administration of Morpholino Antisense Oligonucleotides in the Mdx Mouse
Authors: Ian R. Graham, Francesca C. Thorogood, Helen Foster, George Dickson
Journal: Molecular Therapy (2006)

Duchenne muscular dystrophy (DMD) is an X-linked recessive inherited disease that affects 1 in 3,500 male births. It is characterised by severe muscle wasting and muscle degeneration. Affected patients are frequently wheelchair-bound prior to 12 years and usually die in their late teens or early twenties as a result of respiratory or cardiac failure. DMD arises as a result of frameshift mutations (often gross deletions) in the gene encoding dystrophin, a 427kDa protein of the muscle sarcolemma that functions as a molecular scaffold connecting the intracellular actin cytoskeleton with the extracellular matrix. Such mutations result in a complete absence of dystrophin protein and lead to the DMD phenotype, for which there is currently no cure. Gene therapy approaches have traditionally been based on gene augmentation strategies, in which a functional copy of the dystrophin cDNA, or truncations thereof, has been introduced on viral or plasmid vectors. In an alternative strategy, we and others have been developing the use of antisense oligonucleotides (AO) to induce the exclusion of specific exons during the splicing of dystrophin pre- mRNA. We have used the mdx mouse, a naturally-occurring model of DMD carrying a stop codon in exon 23 of the dystrophin gene, to demonstrate that exclusion (skipping) of exon 23 in response to AO does indeed result in de novo production of dystrophin by modulation of the splicing pathway. Recent advances in oligonucleotide chemistry and design have allowed us to compare the efficiency of delivery and bioactivity of AOs based on morpholino phosphorodiamidate backbones with those of the previous 2′-O-methyl chemistry. Again using the mdx mouse, we have performed dose-response and time-course studies of morpholino AOs targeted to exon 23, by both intramuscular and intravenous delivery. In this way, we have demonstrated widespread and efficient AO-induced dystrophin production by both delivery routes, in a manner which shows AO therapy to be a potentially viable treatment for DMD in a clinical setting.
Nancy Loudon (nee Mann)
Authors: A. E Gebbie
Journal: BMJ (2009)

Nancy Loudon (nee Mann) was born in the Black Isle in 1926 into a large farming community and was the daughter of A J Mann, a prominent Ross-shire farmer and county councillor. She was dux of Fortrose Academy and, in 1944, entered the medical school in wartime Edinburgh. She excelled academically in her studies and obtained her medical degree with honours, one of only a handful of students to do so each year. She started work in the specialty of obstetrics and gynaecology, quickly becoming the registrar on the professorial unit, working under the supervision of Professor Robert Kellar. Her professional life changed dramatically when she became engaged to be married to a fellow gynaecologist, John Loudon. Professor Kellar declared that there was no place for a married woman in obstetrics, and she was forced to resign her post. Ironically, two years later John Loudon was to accept Professor Kellar’s registrar post …
Abstract PR08: Autophagic degradation of Δ133p53 during replicative cellular senescence: An isoform-specific protein degradation mechanism for p53
Authors: Izumi Horikawa, Kaori Fujita, Lisa Miller Jenkins, Yukiharu Hiyoshi, Abdul M. Mondal, Borivoj Vojtesek, David P. Lane, Ettore Appella, Curtis C. Harris
Journal: Cancer Research (2013)

Abstract Δ133p53, a p53 isoform that dominant-negatively inhibits full-length p53, is downregulated at replicative senescence in a manner independent of mRNA regulation and proteasome-mediated degradation. We here demonstrate that, in contrast to proteasomal degradation of full-length p53, Δ133p53 is degraded by autophagy. Pharmacological inhibition of autophagy restores the reduced expression of Δ133p53 in replicatively senescent fibroblasts. The siRNA-mediated knockdown of pro-autophagic proteins (ATG5, ATG7 and Beclin-1) also results in restored expression of Δ133p53. The degradation of Δ133p53 via selective autophagy is indicated by its ubiquitination at the C-terminal lysine residues, its colocalization in the cytoplasm with a ubiquitin-binding protein p62/SQSTM1 and an autophagosome component LC3-II upon autophagy induction, and its stabilization by siRNA knockdown of p62/SQSTM1. A chaperone-associated E3 ubiquitin ligase STUB1, rather than MDM2, physically interacts with Δ133p53 and, consistent with the downregulation of endogenous STUB1 at replicative senescence, siRNA knockdown of STUB1 induces autophagic degradation of Δ133p53 and thereby senescence. Our data reveal that Δ133p53 degradation is controlled specifically by STUB1, rather than overall activity of autophagy. This study has identified for the first time a p53 isoform-specific protein turnover mechanism that orchestrates p53-mediated senescence and supports the hypothesis that Δ133p53 functions at the crossroads of senescence and autophagy. This abstract is also presented as poster B19. Citation Format: Izumi Horikawa, Kaori Fujita, Lisa Miller Jenkins, Yukiharu Hiyoshi, Abdul M. Mondal, Borivoj Vojtesek, David P. Lane, Ettore Appella, Curtis C. Harris. Autophagic degradation of Δ133p53 during replicative cellular senescence: An isoform-specific protein degradation mechanism for p53. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr PR08.
The nexus of iron and inflammation in hepcidin regulation: SMADs, STATs, and ECSIT
Authors: Elizabeth Milward, Daniel Johnstone, Debbie Trinder, Grant Ramm, John Olynyk
Journal: Hepatology (2006)

Patients with alcoholic liver disease frequently exhibit iron overload in association with increased hepatic fibrosis. Even moderate alcohol consumption elevates body iron stores; however, the underlying molecular mechanisms are unknown. Hepcidin, a circulatory peptide synthesized in the liver, is a key mediator of iron metabolism. Ethanol metabolism significantly down-regulated both in vitro and in vivo hepcidin mRNA and protein expression. 4-Methylpyrazole, a specific inhibitor of the alcohol-metabolizing enzymes, abolished the effects of ethanol on hepcidin. However, ethanol did not alter the expression of transferrin receptor1 and ferritin or the activation of iron regulatory RNa-binding proteins, IRP1 and IRP2. Mice maintained on 10-20% ethanol for 7 days displayed down-regulation of liver hepcidin expression without changes in liver triglycerides or histology. This was accompanied by elevated duodenal divalent metal transporter1 and ferroportin protein expression. Injection of hepcidin peptide negated the effect of ethanol on duodenal iron transporters. Ethanol down-regulated hepcidin promoter activity and the DNA binding activity of CCAAT/enhancer-binding protein alpha (C/EBPalpha) but not beta. Interestingly, the antioxidants vitamin E and N-acetylcysteine abolished both the alcohol-mediated down-regulation of C/EBPalpha binding activity and hepcidin expression in the liver and the up-regulation of duodenal divalent metal transporter 1. Collectively, these findings indicate that alcohol metabolism-mediated oxidative stress regulates hepcidin transcription via C/EBPalpha, which in turn leads to increased duodenal iron transport.
A177: Program Evaluation of the ACR/CARRA Inter-Institutional Mentoring Program (AMIGO) in Pediatric Rheumatology
Authors: Eyal Muscal, Lakshmi N. Moorthy, Meredith P. Riebschleger, Anne Eberhard, Anna Huttenlocher, Marisa S. Klein-Gitelman, Sampath Prahalad, Kelly Rouster Stevens, Rayfel Schneider, Peter A. Nigrovic
Journal: Arthritis & Rheumatology (2014)

Background/Purpose:

In pediatric rheumatology, the small size of many academic programs translates into limited mentoring options for early career physicians. To address this “mentorship gap,” in 2011 the American College of Rheumatology (ACR) and the Childhood Arthritis and Rheumatology Research Alliance (CARRA) joined together to develop AMIGO, the ACR/CARRA Mentoring Interest Group, that now includes greater than half of pediatric rheumatology fellows and junior faculty in the US and Canada. We report ongoing program evaluation encompassing pilot (2011) and full roll-out (2012, 2013) phases of the AMIGO project.



Methods:

Mentees and mentors participating in the AMIGO project were surveyed via online questionnaire to determine dynamics of contact and perceived benefit. The entire pediatric rheumatology community was surveyed in 2011 to determine the state of mentoring and career development, with a repeat survey planned for early 2014. We tabulated the active dyads as of January 2014.



Results:

As recently reported, detailed evaluation of the pilot phase 17 months after initial roll-out found that 19 of 20 pilot AMIGO dyads were still functioning, with substantial benefit noted by mentees in career guidance, scholarship, and job satisfaction. Benefits reported by mentors included improvement of their mentoring skills and development of their academic portfolios. Both mentees and mentors reported improved connectedness to the wider pediatric rheumatology community. 83 additional dyads were matched prior to 2012 and 2013 ACR meetings. Comparison of these 17-month pilot results to a December 2013/January 2014 survey of all active AMIGO participants is ongoing. A questionnaire administered to the whole pediatric rheumatology community in 2011 (n = 135 respondents, including an estimated 64–70% response rate among fellows and junior faculty) found that approximately 60% of fellows and junior faculty had a career development mentor. We will assess whether the AMIGO program has had a global impact upon the mentoring culture in pediatric rheumatology by collecting community-wide survey data in 2014 and then comparing to 2011 data.



Conclusion:

The 2011 AMIGO pilot program has confirmed the feasibility of a North American inter-institutional mentoring program in pediatric rheumatology. Participants identified benefits to both mentees and mentors in multiple domains, most prominently in career guidance, a core goal of the program. Ongoing program evaluation will determine how much of this benefit has been sustained after participation was opened to the whole community, and whether the program has had a measureable impact on the overall state of mentoring in pediatric rheumatology.
Cell shape changes induced by cationic anesthetics.
Authors: M Rabinovitch, M J DeStefano
Journal: The Journal of Experimental Medicine (1976)

The effects of local anesthetics on cultivated macrophages were studied in living preparations and recorded in still pictures and time-lapse cine-micrographs. Exposure to 12mM lidocaine or 1.5 mM tetracaine resulted in rounding in 10-15 min. Rounding was characterized by cell contraction, marked increase in retraction fibrils, withdrawal of cell processes, and, in late stages, pulsation-like activity and zeiosis. Cells showed appreciable membrane activity as they rounded. Respreading was complete within 15 min of perfusion in drug-free medium and entailed a marked increase in surface motility over control periods. As many as eight successive cycles of rounding and spreading were obtained with lidocaine without evidence of cell damage. The effects of anesthetics were similar to those observed with EDTA, but ethylene-glycol-bis(beta-aminoethylether)-N, N'-tetraacetic acid-Mg was ineffective. Rounding was also induced by benzocaine, an anesthetic nearly uncharged at pH 7.0. Quaternary (nondischargeable) compounds were of low activity, presumably because they are slow permeants. Lidocaine induced rounding at 10 degrees C and above but was less effective at 5 degrees C and ineffective at 0 degrees C. Rounding by the anesthetic was also obtained in media depleted or Na or enriched with 10 mM Ca or Mg. The latter finding, together with the failure of tetrodotoxin to induce rounding, suggests that the anesthetic effect is unrelated to inhibition of sodium conductance. It is possible that the drugs influence divalent ion fluxes or some component of the contractile cells' machinery, but a metabolic target of action cannot yet be excluded.
Flucloxacillin in the treatment of atopic dermatitis
Authors: None Ewing, None Ashcroft, None Gibbs, None Jones, None Connor, None David
Journal: British Journal of Dermatology (1998)

Although colonization of atopic dermatitis by Staphylococcus aureus is universal and bacterial infection is common, it is not known whether antibiotic therapy is helpful in eczematous children who do not have any signs suggestive of bacterial infection. Fifty children aged 1-16 years with atopic dermatitis took part in a randomized double-blind placebo-controlled study of 4 weeks treatment with oral flucloxacillin, with an 8-week follow-up period. The change in the mean of the log10 of the counts/cm2 of S. aureus after 4 weeks of treatment was significantly different for patients receiving treatment, compared with the change for those receiving the placebo (P = 0.008). However, the difference in the change at 14 days after stopping treatment was not significant (P = 0.32). Methicillin-resistant strains of S. aureus were cultured from five children during or after treatment. Flucloxacillin did not improve the symptoms or clinical appearance of atopic dermatitis and only temporarily changed skin colonization by S. aureus.
Infected Pancreatic Necrosis Possibly Due to Combined Percutaneous Aspiration, Cystogastric Pseudocyst Drainage and Injection of a Sclerosant
Authors: H. Kolvenbach, A. Hirner
Journal: Endoscopy (1991)

This paper reports on a patient who was treated by percutaneous aspiration, instillation of a sclerosant (polidocanol) and cystogastric drainage for a post-acute pancreatic pseudocyst. Five weeks after admission to hospital for the first episode of an acute necrotizing pancreatitis, the 60-year-old man underwent a percutaneous, ultrasound-guided puncture and aspiration of a voluminous pancreatic pseudocyst. Ten days later, recurrent fluid collection led to a second puncture, combined with the injection of polidocanol (15 ml; 1%) into the cyst cavity. Since this treatment failed, a percutaneous cystogastric drain ("double--pigtail") was inserted five days later. After developing acute abdominal pain and incipient sepsis, the patient was sent for surgical intervention twelve days after the second treatment with percutaneous aspiration and injection of polidocanol. During the operation an infected pancreatic pseudocyst with extensive contaminated necrosis of the pancreas and duodenal perforation was found. Necrectomy was performed, followed by continuous lavage of the omental bursa. Intensive care therapy was necessary for one week. Duodenal leakage persisted for nearly three weeks, the stopped spontaneously. The patient was discharged in quite a good state of health after 33 days of postoperative treatment. Although spontaneous development of infected pancreatic pseudocysts and pancreatic abscesses in necrotizing pancreatitis is known, a possible involvement of the drainage procedures, especially in combination with the injection of a sclerosant must be considered.
Patient-Reported Outcomes in Phase II Cancer Clinical Trials: Lessons Learned and Future Directions
Authors: Lynne I. Wagner, Lari Wenzel, Edward Shaw, David Cella
Journal: Journal of Clinical Oncology (2007)

With increasing limits on the resources available to conduct cancer clinical trials, the inclusion of patient-reported outcomes (PROs) in treatment and symptom management trials must be prioritized. Although it has been suggested on occasion that phase III trials should take precedence over phase II trials, we argue that there is a clear and important role for PRO assessment in phase II trials going forward. To illustrate the value realized from including PROs in phase II trials, we provide case examples from cancer treatment and supportive care. The benefits of including PROs in symptom management intervention research are exemplified using phase II trials targeting cognitive impairment. The inclusion of PROs in phase II cancer clinical trials adds important information about the impact of treatment in health-related quality of life, and advances the science of PRO measurement. These contributions significantly enhance the design of phase III trials, ultimately leading to the efficient utilization of clinical trial resources.
Quam Artem Exerceas?
Authors: James J. Andonian
Journal: JAMA (1997)

Before I begin the actual review of this software, some explanation:<i>Hypertext</i>(see above) refers to any text which contains words or phrases that can be selected by the reader thereby causing another document to be displayed. The author, who teaches occupational medicine in two Italian universities, has been developing hypertexts in this field as learning tools since 1988. The phrase "Quam artem excerceas?"—What do you do for a living?"—is attributed to Bernardino Ramazzini (1633-1714), considered the father of occupational medicine. The software program is described by the editor as "an examination of the life and work of [Bernardino Ramazzini] that situates his accomplishments within the historical context of 17th and 18th century Europe. The author emphasizes the economic, industrial, and cultural changes during this period and their impact on Ramazzini's discoveries in the field of occupational medicine." Actually, it is a creative tool for the person who relies heavily
Expression of a pemphigoid gestationis-related antigen by human placenta
Authors: SUSAN E. KELLY, B.S. BHOGAL, FENELLA WOJNAROWSKA, M.M. BLACK
Journal: British Journal of Dermatology (1988)

We studied the antigen binding of sera from 25 patients with pemphigoid gestationis (PG) using skin and amnion as substrates in an indirect immunofluorescence technique. In addition, skin was studied after prior incubation with I M NaCl which allows BMZ cleavage through the lamina lucida. Linear BMZ staining was obtained with sera from patients with PG using human amnion as substrate. This was seen with both full-term and second trimester placentae, but not with first trimester placentae. In NaCl incubated skin all sera bound to the epidermal aspect of the separated tissue. The pattern of staining in skin, chemically split skin and amnion was identical to that previously seen with the sera of patients with bullous pemphigoid suggesting that the antigen against which circulating anti-BMZ antigens are directed may be the same in the two conditions.
Animal mitochondrial DNA as a genetic marker in population and evolutionary biology
Authors: Richard G. Harrison
Journal: Trends in Ecology & Evolution (1989)

Animal mitochondrial DNA (mtDNA) is playing an increasingly important role as a genetic marker in population and evolutionary biology. The popularity of this molecule derives, in part, from the relative ease with which clearly homologous sequences can be isolated and compared. Simple sequence organization, maternal inheritance and absence of recombination make mtDNA an ideal marker for tracing maternal genealogies. Rapid rate of sequence divergence (at least in vertebrates) allows discrimination of recently diverged lineages. Studies of mtDNAs from a diversity of animal groups have revealed significant variation among taxa in mtDNA sequence dynamics, gene order and genome size. They have also provided important insights into population structure, geographic variation, zoogeography and phylogeny.