tbuckley/cabot-search huggingface dataset:
Sidekick-1 Is Upregulated in Glomeruli in HIV-Associated Nephropathy
Authors: Lewis Kaufman, Kayo Hayashi, Michael J. Ross, Michael D. Ross, Paul E. Klotman
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Infection of podocytes by HIV-1 induces unique changes in phenotype, which contribute to the pathogenesis of glomerular disease in HIV-associated nephropathy (HIVAN). The host genetic pathways altered by HIV-1 infection that are responsible for these phenotypic changes are largely unknown. For identifying such pathways, representational difference analysis was performed comparing cDNA from HIV-1 transgenic podocytes with nontransgenic controls. In this way, a gene named sidekick-1 (sdk-1) was cloned, a transmembrane protein of the Ig superfamily that is highly upregulated in HIV-1 transgenic podocytes. Sdk-1 and its ortholog, sidekick-2 (sdk-2), were recently shown to guide axonal terminals to specific synapses in developing neurons. Their presence and role in other organs, including the kidney, has not been described. The current study demonstrates developmental expression of both sdk-1 and sdk-2 and a tight spatial and temporal regulation of these genes in kidney. During nephrogenesis, sidekick expression was observed first in ureteric bud and ureteric bud–derived tissues in a pattern similar to other genes known to play important roles in branching morphogenesis. In adult murine renal tissue, sidekick proteins were seen in glomeruli at low levels, and expression of sdk-1 was greatly upregulated in diseased HIV-1 transgenic mouse kidneys. In a human HIVAN kidney biopsy, sidekick expression was increased in glomeruli in a pattern consistent with the mouse model. It is proposed that the dysregulation of sdk-1 protein may play an important role in HIVAN pathogenesis.
Clinical Utility of Circulating Tumor Cells in Metastatic Breast Cancer
Authors: Francois-Clement Bidard, Jean-Yves Pierga
Journal: Journal of Clinical Oncology (2015)

TO THEEDITOR: A few months ago, we reported in a large pooled analysis the clinical validity of circulating tumor cells (CTC) as a dynamic prognostic biomarker in 1,944 patients with metastatic breast cancer; moreover, this study demonstrated the superiority of CTC count over the serum markers carcinoembryonic antigen and CA15-3. 1 In light these results, recently published survival outcomes in the SWOG S0500 randomized trial may appear disappointing. 2 These negative results were however foreseen—not because of the CTC detection technique itself, but for reasons related to the way the test was developed. The issue of chemoresistance to first line being often associated with a broad resistance to subsequent lines of therapy is discussed in the article and is probably the best explanation for the trial’s results. Janni et al 3 also noticed that early switch to second-line chemotherapy has never demonstrated a clinical utility in metastatic breast cancer, whatever the tool used (positron emission tomography scanner, serum markers . . .). We propose some other issues should be also taken into account to fully understand the published results: First, the CTC response test is basically meant to detect early resistance to treatment. Whatever its intrinsic characteristics (sensitivity, specificity), the CTC test would have probably exhibited better performances (number of false positive and false negative) in a population with a high prevalence of chemoresistance (ie, after the first line[s] of therapy). Second, in an ideal scenario, the CTC test would have 100% sensitivity and specificity to detect early tumor progression: patients with early chemoresistance would have been switched off ineffective first-line chemotherapy after 1 month of treatment in the CTC arm and after 3 months of treatment in the standard arm (radiological evaluation). In that most favorable scenario, second-line therapy would have been initiated 2 months earlier in the CTC arm than in the standard arm. Notwithstanding the real performances of the CTC test, this 2-month difference at the initial beginning of the metastatic disease was unlikely to translate into a significant increase of overall survival (main study end point) for the 60 patients randomly assigned in the CTC arm. Third, threshold defined for clinical validity may differ from those relevant for clinical utility. The 5 CTC/7.5 mL threshold was initially optimized as a baseline prognostic biomarker. 4 This threshold allowed distinguishing two populations of patients with metastatic breast cancer with good versus bad survival with a high hazard ratio and a significant P value. However, we do not know whether 5 CTC/7.5 mL during treatment is the best threshold as an early resistance screening test. In future trials, we would recommend to check that thresholds used for clinical utility translate into high sensitivity
The pyramid of sports medicine and child health
Authors: Steven D Stovitz
Journal: British Journal of Sports Medicine (2009)

As seen within this thematic issue on children’s and youth sports, sports medicine has a complex relationship with child health. On the one hand, much of the world is experiencing an epidemic of childhood obesity. The physical activity inherent in sports is viewed as a means of combating this epidemic. However, sports also lead to injuries which can cause short- and long-term disabilities. With homage to legendary UCLA basketball coach John Wooden, the role of sports medicine in promoting the health of children fits within the construct of a pyramid. Coach Wooden used a pyramid to describe the qualities necessary for success.1 A pyramid depends upon symmetrical strength, a firm foundation, and a solid heart at its centre. Its peak is the goal, which in this case is child health. The pyramid of sports medicine and child health is shown in fig 1 and described below.



Figure 1 
Pyramid of sports medicine and child health.



### Lower-left cornerstone: physical activity promotion

Lack of physical activity is becoming a worldwide problem,1 and sports are a wonderful means of increasing physical activity. Observational studies show sports participation in youth is associated with higher overall levels of physical activity.2 3 A study of youth wearing accelerometers found that approximately one-quarter of daily moderate–vigorous physical activity was due to sports.4 Furthermore, participation in youth sports is positively associated with physical activity in adulthood.5

### Lower-right cornerstone: injury prevention

Approximately 30–40% of adolescents seek medical attention annually for a sport-related injury.6 Sports have inherent acute risks, and injury-prevention programmes can decrease the rates of certain injuries. The future approach must be threefold.

1. Accurate assessment of injury rates. The future must not be dominated by anecdotal reports. Is there an epidemic of injury among girls who play sports? In this issue, Knowles et al present evidence that girls, in fact, have lower …
Cost-effectiveness of improved treatment services for sexually transmitted diseases in preventing HIV-1 infection in Mwanza Region, Tanzania
Authors: Lucy Gilson, Rashid Mkanje, Heiner Grosskurth, Frank Mosha, John Picard, Awena Gavyole, James Todd, Philippe Mayaud, Roland Swai, Lieve Fransen, David Mabey, Anne Mills, Richard Hayes
Journal: The Lancet (1997)
PROPERTIES OF PLASMINOGEN ACTIVATORS FORMED BY NEOPLASTIC HUMAN CELL CULTURES
Authors: Daniel B. Rifkin, John N. Loeb, George Moore, E. Reich
Journal: The Journal of Experimental Medicine (1974)

A series of human cell lines has been examined for fibrinolysis in culture. The sera that are activating for fibrinolysis by human cells are mouse, monkey, human, horse, and bovine. Individual human sera show considerable variation in the ability to activate fibrinolysis. In common with other neoplastic or transformed mammalian and avian cell cultures, human cell lines of neoplastic origin produce substantial amounts of plasminogen activator. Several cultures of nonmalignant origin also produce plasminogen activator, whereas cultures obtained from trypsinized human embryos, or from human embryonic skin do not. The human melanoma plasminogen activators are of two kinds: a major component with a mol wt of 50,000, and a minor species with a mol wt of approximately 60,000. Both are DFP sensitive, serine proteases.
Selective intestinal decontamination increases serum and ascitic fluid C3 levels in cirrhosis
Authors: Jose Such, Carlos Guarner, German Soriano, Montserrat Teixidó, José Barrios, Francisco Tena, Carmen Méndez, Jaime Enríquez, José Luis Rodríguez, Francisco Vilardell
Journal: Hepatology (1990)

Selective intestinal decontamination for 7 days with norfloxacin was performed in 14 cirrhotic patients with ascites and low ascitic fluid total protein. Variations in serum and ascitic fluid of C3 and C4 and ascitic fluid total protein after therapy were compared with those of a control group of 14 untreated patients with similar characteristics. After oral norfloxacin administration, we saw a significant increase of C3 in serum (p less than 0.05) and ascitic fluid (p = 0.01). A significant increase was also observed in ascitic fluid total protein (p less than 0.05) but not in serum and ascitic fluid C4. There were no changes in serum C3, ascitic fluid C3, ascitic fluid C4 or in ascitic fluid total protein in group 2. These data demonstrate that selective intestinal decontamination increases serum and ascitic fluid C3 levels and, therefore, might be useful in preventing spontaneous infections in cirrhotic patients at high risk of infection.
Expression of Bcl-2 and Bcl-2-Ig fusion transcripts in normal and neoplastic cells.
Authors: W B Graninger, M Seto, B Boutain, P Goldman, S J Korsmeyer
Journal: Journal of Clinical Investigation (1987)

We examined the expression of the Bcl-2 gene at chromosome segment 18q21, that is translocated into the Ig heavy chain gene locus in t(14;18) bearing lymphomas. Bcl-2, while B cell associated, is expressed in a variety of hematopoietic lineages including T cells. Bcl-2 mRNA levels are high during pre-B cell development, the time at which the t(14;18) translocation occurs, but are down regulated with maturation. Like certain other oncogenes, Bcl-2 is quiescent in resting B cells but up-regulated with B cell activation. Mature B cell lymphomas with a t(14;18) have log-folds more mRNA than matched counterparts without the translocation. A sensitive S1 protection assay revealed that all transcripts in t(14;18) B cells were Bcl-2-Ig fusion mRNAs and originated from the translocated allele. Thus, there is a marked deregulation of Bcl-2 when it is introduced into the Ig locus in t(14;18) lymphomas.
Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer
Authors: R. Paridaens, L. Dirix, C. Lohrisch, L. Beex, M. Nooij, D. Cameron, L. Biganzoli, T. Cufer, L. Duchateau, A. Hamilton, J.P. Lobelle, M. Piccart
Journal: Annals of Oncology (2003)
The NFkappaB luciferase mouse: a new tool for real time measurement of NFkappaB activation in the whole animal
Authors: D A Mann
Journal: Gut (2002)

Development of transgenic mice that express luciferase under the control of nuclear factor κB (NFκB) enables real time in vivo imaging of NFκB activity in intact animals

Of the many different transcription factors found in mammalian cells by far the best known among scientists and clinicians alike is nuclear factor κB (NFκB). In addition to its pivotal role as a regulator of innate and adaptive immune responses, NFκB has also been linked as a contributory factor in many human disorders.1 NFκB stimulates transcription of over 150 different genes encoding cytokines, adhesion molecules, immunoreceptors, acute phase proteins, enzymes, and regulators of the cell cycle and apoptosis.2 Transcription of these genes is stimulated in response to binding of NFκB to a specific 10 base pair DNA sequence (GGGRNNYYCC, where R corresponds to a purine, Y represents a pyrimidine, and N can be any base) located in either the enhancer or upstream promoter regions of a gene. Binding of NFκB to these sequences is tightly regulated by the inhibitory function of the IκB-α protein which forms a complex with NFκB that masks functional domains of the transcription factor required for its nuclear localisation and DNA binding activities. The mechanism by which IκB-α bound NFκB is activated is now well understood (fig 1).3 Following stimulation of the cell by an extracellular signal, such as the interaction of tumour necrosis factor α with its receptor, the recently discovered IκB kinase (IKK) complex is activated. The IKK complex then catalyses phosphorylation of IκB-α at two N terminal serine residues (ser 32 and 36) which then renders IκB-α a substrate for ubiquitination and finally …
Colonic responses to enteral tube feeding
Authors: T E BOWLING, D B A SILK
Journal: Gut (1998)

Enteral feeding has become an invaluable treatment in both the hospital and home setting. However, it is not without complications, the commonest of which is diarrhoea. This occurs in up to 25% of patients on general wards1-3 and 63% of patients on intensive care units.4  5 Diarrhoea not only limits the efficacy of enteral feeding, but also adds to potential complications, distresses both patients and staff, and increases costs.6Until recently, its pathogenesis has remained unknown, although a number of factors have been implicated, including infected diets,7 lactose intolerance,8 concomitant antibiotic therapy,9  10 osmotically active medications,11  12 and co-existing hypoalbuminaemia.13  14 However, despite attention to these factors, diarrhoea still occurs in up to 15% of patients.15 This would imply, therefore, that some other mechanism or mechanisms are involved.

In an attempt to unravel the pathophysiological mechanisms underlying enteral feeding related diarrhoea, a series of in vivo experiments in humans was undertaken examining the response of the small and large intestine to enteral feeding.16-20 In these studies two different strengths of a polymeric diet were infused either intragastrically or intraduodenally: a low load diet infused at 1.4 ml/min (1.4 kcal/min; 8.75 mgN/min) and a high load diet infused at 2.8 ml/min (4.2 kcal/min; 26.1 mgN/min). The low load diet corresponded clinically to the administration of 2 litres (2000 kcal) over 24 hours (equivalent to 2 litres/day), which is what most patients will receive on the wards. Catabolic patients or those being fed cyclically over 12–14 hours per day, a common situation especially in the home setting, require higher dietary loads—the high load diet in our studies corresponded to this type of feeding.

In the small intestinal studies intraduodenal feeding of the low load diet caused a normal …
Do gastroenterologists want to be trained in ultrasound? A national survey of trainees in gastroenterology
Authors: C P Jamieson, E R E Denton, W R Burnham
Journal: Gut (1999)

Aims (1) To establish whether gastroenterologists wish to train in abdominal ultrasound according to the Royal College of Radiologists’ document, Guidance for the training in ultrasound of medical non-radiologists . (2) To determine whether the ultrasound workload generated by gastroenterologists differs from that by other clinicians. Methods A postal questionnaire was sent to all 278 gastroenterology trainees. The indications and findings of 100 consecutive gastroenterologist requested scans were compared with 100 scans requested sequentially by other clinicians through a teaching hospital radiology department. Results 82% of the survey forms were returned. 77% of trainees wished to train in abdominal ultrasound and 68% were prepared to train in the manner outlined in the guideline document. However, 86% felt that they would ideally prefer not to assess renal or pelvic pathology, restricting to hepatobiliary diagnosis only. 73% of trainees did not anticipate that a further scan by a radiologist would be required. Comparison of gastroenterology scans with those requested by other clinicians revealed a relative excess of hepatobiliary indications and findings, and a notable paucity of renal and pelvic pathology in gastroenterology practice. Conclusions There is general interest in abdominal ultrasound training among gastroenterology trainees and broad acceptance of the guideline document. However, most trainees perceive a focus of training restricted to hepatobiliary disease to be most appropriate. The case mix study provides support for this viewpoint. It is suggested that a more focused ultrasound training for gastroenterologists be considered.
Acute Alcohol Consumption Improves Insulin Action Without Affecting Insulin Secretion in Type 2 Diabetic Subjects
Authors: Angelo Avogaro, Richard M. Watanabe, Alessandra Dall’Arche, Saula Vigili De Kreutzenberg, Antonio Tiengo, Giovanni Pacini
Journal: Diabetes Care (2004)

Long-term exposure to alcohol is associated with an improvement in insulin sensitivity. At this time, however, there is no definitive proof that alcohol per se has an effect on the insulin sensitivity index (S(i)) in type 2 diabetes patients. The aim of the present study was to assess the role of acute moderate alcohol intake on insulin sensitivity and insulin secretion in comparable subjects with and without type 2 diabetes.Frequently sampled intravenous glucose tolerance tests (FSIGTs) were performed twice on eight healthy and eight type 2 diabetic volunteers. Forty grams of alcohol (vodka 40% wt/vol) or tap water were sipped from time -60 min to the end of the FSIGT.Lactate area under the curve (AUC) was higher in both groups during the alcohol study than in the control study. Free fatty acid (FFA) AUC was higher in type 2 diabetic subjects than in control subjects; alcohol slightly reduced FFA by 17% in control subjects (34 +/- 4 mmol. min(-1). l(-1); P = 0.1) but significantly decreased FFA by 23% in type 2 diabetic subjects (54 +/- 10; P = 0.007). Beta-cell response was markedly reduced in type 2 diabetic subjects regardless of the type of study. Alcohol significantly increased S(i) in both groups.Acute alcohol consumption improves insulin action without affecting beta-cell secretion. This effect may be partly due to the inhibitory effect of alcohol on lipolysis. Alcohol intake increases insulin sensitivity and may partly explain both the J-shaped relationship between the prevalence of diabetes and the amount of alcohol consumption and the decreased mortality for myocardial infarction.
Exosomes From Human CD34 <sup>+</sup> Stem Cells Mediate Their Proangiogenic Paracrine Activity
Authors: Susmita Sahoo, Ekaterina Klychko, Tina Thorne, Sol Misener, Kathryn M. Schultz, Meredith Millay, Aiko Ito, Ting Liu, Christine Kamide, Hemant Agrawal, Harris Perlman, Gangjian Qin, Raj Kishore, Douglas W. Losordo
Journal: Circulation Research (2011)

Transplantation of human CD34(+) stem cells to ischemic tissues has been associated with reduced angina, improved exercise time, and reduced amputation rates in phase 2 clinical trials and has been shown to induce neovascularization in preclinical models. Previous studies have suggested that paracrine factors secreted by these proangiogenic cells are responsible, at least in part, for the angiogenic effects induced by CD34(+) cell transplantation.Our objective was to investigate the mechanism of CD34(+) stem cell-induced proangiogenic paracrine effects and to examine if exosomes, a component of paracrine secretion, are involved.Exosomes collected from the conditioned media of mobilized human CD34(+) cells had the characteristic size (40 to 90 nm; determined by dynamic light scattering), cup-shaped morphology (electron microscopy), expressed exosome-marker proteins CD63, phosphatidylserine (flow cytometry) and TSG101 (immunoblotting), besides expressing CD34(+) cell lineage marker protein, CD34. In vitro, CD34(+) exosomes replicated the angiogenic activity of CD34(+) cells by increasing endothelial cell viability, proliferation, and tube formation on Matrigel. In vivo, the CD34(+) exosomes stimulated angiogenesis in Matrigel plug and corneal assays. Interestingly, exosomes from CD34(+) cells but not from CD34(+) cell-depleted mononuclear cells had angiogenic activity.Our data demonstrate that human CD34(+) cells secrete exosomes that have independent angiogenic activity both in vitro and in vivo. CD34(+) exosomes may represent a significant component of the paracrine effect of progenitor cell transplantation for therapeutic angiogenesis.
Docetaxel Conjugate Nanoparticles That Target α-Smooth Muscle Actin–Expressing Stromal Cells Suppress Breast Cancer Metastasis
Authors: Mami Murakami, Mark J. Ernsting, Elijus Undzys, Nathan Holwell, Warren D. Foltz, Shyh-Dar Li
Journal: Cancer Research (2013)

Abstract Docetaxel-conjugate nanoparticles, known as Cellax, were synthesized by covalently conjugating docetaxel and polyethylene glycol to acetylated carboxymethylcellulose via ester linkages, yielding a polymeric conjugate that self-assembled into 120 nm particles suitable for intravenous administration. In 4T1 and MDA-MB-231 orthotopic breast tumor models, Cellax therapy reduced α-smooth muscle actin (α-SMA) content by 82% and 70%, respectively, whereas native docetaxel and nab-paclitaxel (albumin-paclitaxel nanoparticle, Abraxane) exerted no significant antistromal activity. In Cellax-treated mice, tumor perfusion was increased by approximately 70-fold (FITC-lectin binding), tumor vascular permeability was enhanced by more than 30% (dynamic contrast-enhanced magnetic resonance imaging), tumor matrix was decreased by 2.5-fold (immunohistochemistry), and tumor interstitial fluid pressure was suppressed by approximately 3-fold after Cellax therapy compared with the control, native docetaxel, and nab-paclitaxel groups. The antistromal effect of Cellax treatment corresponded to a significantly enhanced antimetastatic effect: lung nodules were reduced by 7- to 24-fold by Cellax treatment, whereas native docetaxel and nab-paclitaxel treatments were ineffective. Studies of the 4T1 tumor showed that more than 85% of the Cellax nanoparticles were delivered to the α-SMA+ stroma. Significant tumor stromal depletion occurred within 16 hours (∼50% depletion) postinjection, and the α-SMA+ stroma population was almost undetectable (∼3%) by 1 week. The 4T1 tumor epithelial cell population was not significantly reduced in the week after Cellax injection. These data suggest that Cellax targets tumor stroma and performs more efficaciously than docetaxel and nab-paclitaxel. Cancer Res; 73(15); 4862–71. ©2013 AACR.