tbuckley/cabot-search huggingface dataset:
Understanding controlled trials: Randomising groups of patients
Authors: C. Roberts, B. Sibbald
Journal: BMJ (1998)

This is the sixth of an occasional series on the methods of randomised controlled trials

In a simple randomised trial each patient is assigned independently to a treatment group. Sometimes, however, randomising individual patients is either technically impossible or may compromise the evaluation.

Some interventions can be delivered only to groups. Public health initiatives, for example, may be delivered to communities rather than to individuals. When an intervention entails changing the organisation of health care in a unit all patients attending that unit will be affected. Similarly, when interventions are targeted at changing the behaviour of health professionals — for example, a training package — the care given to all subsequent patients may be modified once staff have been exposed to the intervention. In both situations it would be difficult or impossible for staff to revert …
Aptamers: An Emerging Class of Therapeutics
Authors: Shahid M. Nimjee, Christopher P. Rusconi, Bruce A. Sullenger
Journal: Annual Review of Medicine (2005)

Numerous nucleic acid ligands, also termed decoys or aptamers, have been developed during the past 15 years that can inhibit the activity of many pathogenic proteins. Two of them, Macugen and E2F decoy, are in phase III clinical trials. Several properties of aptamers make them an attractive class of therapeutic compounds. Their affinity and specificity for a given protein make it possible to isolate a ligand to virtually any target, and adjusting their bioavailability expands their clinical utility. The ability to develop aptamers that retain activity in multiple organisms facilitates preclinical development. Antidote control of aptamer activity enables safe, tightly controlled therapeutics. Aptamers may prove useful in the treatment of a wide variety of human maladies, including infectious diseases, cancer, and cardiovascular disease. We review the observations that facilitated the development of this emerging class of therapeutics, summarize progress to date, and speculate on the eventual utility of such agents in the clinic.
Prognostic Value of the Insertion/Deletion Polymorphism of the <i>ACE</i> Gene in Type 2 Diabetic Subjects
Authors: Samy Hadjadj, Frédéric Fumeron, Ronan Roussel, Pierre-Jean Saulnier, Yves Gallois, Amos Ankotche, Florence Travert, Charbel Abi Khalil, Aurélie Miot, François Alhenc-Gelas, Michel Lievre, Michel Marre
Journal: Diabetes Care (2008)

We tested whether determination of the ACE insertion/deletion polymorphism is useful for renal and cardiovascular prognoses of type 2 diabetic subjects.The French participants (3,126 of 4,912) in the Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) trial were studied for their prognosis over 4 years according to their ACE insertion/deletion polymorphism. We used two cohorts of French type 2 diabetic patients for replication: a 3-year follow-up study (n = 917; Survie, Diabete de type 2 et Genetique [SURDIAGENE] study) and a case-control study on diabetic nephropathy (n = 1,277; Diabete de type 2, Nephropathie et Genetique [DIAB2NEPHROGENE] study). We investigated the effect of the insertion/deletion polymorphism on the primary outcome in the DIABHYCAR trial (defined as the first of the following events to occur: cardiovascular death, nonfatal myocardial infarction, stroke, heart failure leading to hospital admission, or end-stage renal failure) and its components.In DIABHYCAR, the primary outcome and most of its components were not affected by the ACE insertion/deletion genotype. Only renal outcome was favored by the I allele (P = 0.03). The risk of myocardial infarction was not affected by ACE genotype, but the probability of fatal outcome increased with the number of D alleles (P < 0.03). In SURDIAGENE, the association between the ACE I allele and renal outcome was not replicated. In DIAB2NEPHROGENE, no association was found with nephropathy.We were not able to demonstrate the manifest usefulness of the ACE insertion/deletion polymorphism for the prognosis of type 2 diabetic subjects.
Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus
Authors: Carlo Colombo, Ottavia Porzio, Ming Liu, Ornella Massa, Mario Vasta, Silvana Salardi, Luciano Beccaria, Carla Monciotti, Sonia Toni, Oluf Pedersen, Torben Hansen, Luca Federici, Roberta Pesavento, Francesco Cadario, Giorgio Federici, Paolo Ghirri, Peter Arvan, Dario Iafusco, Fabrizio Barbetti
Journal: Journal of Clinical Investigation (2008)

Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth. Although several genes have been linked to this disorder, in almost half the cases documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic β cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM.
The Role of Adiponectin in Cancer: A Review of Current Evidence
Authors: Maria Dalamaga, Kalliope N. Diakopoulos, Christos S. Mantzoros
Journal: Endocrine Reviews (2012)

Excess body weight is associated not only with an increased risk of type 2 diabetes and cardiovascular disease (CVD) but also with various types of malignancies. Adiponectin, the most abundant protein secreted by adipose tissue, exhibits insulin-sensitizing, antiinflammatory, antiatherogenic, proapoptotic, and antiproliferative properties. Circulating adiponectin levels, which are determined predominantly by genetic factors, diet, physical activity, and abdominal adiposity, are decreased in patients with diabetes, CVD, and several obesity-associated cancers. Also, adiponectin levels are inversely associated with the risk of developing diabetes, CVD, and several malignancies later in life. Many cancer cell lines express adiponectin receptors, and adiponectin in vitro limits cell proliferation and induces apoptosis. Recent in vitro studies demonstrate the antiangiogenic and tumor growth-limiting properties of adiponectin. Studies in both animals and humans have investigated adiponectin and adiponectin receptor regulation and expression in several cancers. Current evidence supports a role of adiponectin as a novel risk factor and potential diagnostic and prognostic biomarker in cancer. In addition, either adiponectin per se or medications that increase adiponectin levels or up-regulate signaling pathways downstream of adiponectin may prove to be useful anticancer agents. This review presents the role of adiponectin in carcinogenesis and cancer progression and examines the pathophysiological mechanisms that underlie the association between adiponectin and malignancy in the context of a dysfunctional adipose tissue in obesity. Understanding of these mechanisms may be important for the development of preventive and therapeutic strategies against obesity-associated malignancies.
An exploratory study of adherence to topical benzoyl peroxide in patients with acne vulgaris
Authors: Brad A. Yentzer, Ali Alikhan, Hoa Teuschler, Lisa L. Williams, Mark Tusa, Alan B. Fleischer, Mandeep Kaur, Rajesh Balkrishnan, Steven R. Feldman
Journal: Journal of the American Academy of Dermatology (2009)
International Multicenter Tool to Predict the Risk of Nonsentinel Node Metastases in Breast Cancer
Authors: Tuomo J. Meretoja, Marjut H. K. Leidenius, Päivi S. Heikkilä, Gabor Boross, István Sejben, Peter Regitnig, Gero Luschin-Ebengreuth, Janez Žgajnar, Andraz Perhavec, Barbara Gazic, György Lázár, Tibor Takács, Andras Vörös, Zuhair A. Saidan, Rana M. Nadeem, Isabella Castellano, Anna Sapino, Simonetta Bianchi, Vania Vezzosi, Emmanuel Barranger, Ruben Lousquy, Riccardo Arisio, Maria Pia Foschini, Shigeru Imoto, Hiroshi Kamma, Tove F. Tvedskov, Niels Kroman, Maj-Brit Jensen, Riccardo A. Audisio, Gabor Cserni
Journal: JNCI Journal of the National Cancer Institute (2012)

BackgroundAxillary treatment of breast cancer patients is undergoing a paradigm shift, as completion axillary lymph node dissections (ALNDs) are being questioned in the treatment of patients with tumor-positive sentinel nodes. This study aims to develop a novel multi-institutional predictive tool to calculate patient-specific risk of residual axillary disease after tumor-positive sentinel node biopsy.
Confluent monolayers of bile duct epithelial cells with tight junctions
Authors: Hiromasa Okamoto, Motoyasu Ishii, Yutaka Mano, Takehiko Igarashi, Yoshiyuki Ueno, Koju Kobayashi, Takayoshi Toyota
Journal: Hepatology (1995)

The culture of fully differentiated intrahepatic bile duct epithelial cells (IBDECs) to use as a model for the in vivo intrahepatic biliary tract has not been established. IBDECs from normal rat livers were grown on a collagen-coated permeable filter and formed a confluent monolayer 7 days after being plated. Positive reactions for cytokeratin-19 and retained gamma-glutamyl transpeptidase (GGTP) activity were shown. The transepithelial electrical resistance between the apical and the basolateral compartment culture chambers increased with the culture age and plateaued after the 7th day. The resulting cultured cells displayed a number of characteristics. (1) The cells formed a thin, continuous monolayer and displayed microvilli on the apical surface and junctional complexes between the cells, consistent with in vivo IBDECs. (2) Cells cultured for more than 7 days prevented the passage of horseradish peroxidase (HRP) and ruthenium red through paracellular pathways. (3) Seven-day-old cultures displayed a mean transepithelial electrical resistance of 137.3 omega-cm2, which decreased by 27.1% from its initial level after cell treatment with ethylenediamineteraacetic acid (EDTA). These results indicate that confluent IBDEC monolayers are well differentiated and polarized with tight junctions (TJs) between the cells. These cell monolayers can provide a useful and relevant model for the in vitro study of various in vivo bile duct phenomena.
Hip pads reduce the overall risk of injuries in recreational snowboarders
Authors: Daichi Ishimaru, Hiroyasu Ogawa, Kazuhiko Wakahara, Hiroshi Sumi, Yasuhiko Sumi, Katsuji Shimizu
Journal: British Journal of Sports Medicine (2012)

Objective The purpose is to determine common injuries in recreational snowboarding as targets of preventive strategy and protective gear that reduces the overall risk of these injuries. Methods The subjects comprised 5561 injured recreational snowboarders. On the basis of patients’ self-reporting form, ‘the common snowboarding injuries’ (cut-off point &gt;2.0% in prevalence) were decided, and all injured snowboarders were categorised into two groups: common injuries and the other injuries (control). Several factors such as age, gender, self-reported skill level, experienced seasons, experienced days, previous snowboarding school attendance and the use of protective gears (helmet, elbow pads, wrist guards, backbone guard, hip pads and knee pads) were recorded. Multiple logistic regression analysis was conducted to investigate which type of protective gear reduced the overall risk of the common injuries. Results The common snowboarding injuries consisted of eight types, in which distal radial fracture was the most common (17.7%), followed by head injury (9.4%) and clavicle fracture (6.5%). In univariate regression analysis, skill level, experienced seasons, experienced days and the use of hip pads and knee pads were manifested potential risk factors on the common injuries. In subsequent multivariate regression analysis, the use of hip pads was related with a lower overall risk of these common injuries (OR, 0.84; 95% CI, 0.75 to 0.95), specifically that of distal radial fracture and glenohumeral dislocation. Conclusions The use of hip pads is recommended for snowboarders as it reduces the overall risk of common snowboarding injuries.
A dose finding study with 0.1%, 0.2%, and 0.4% glyceryl trinitrate ointment in patients with chronic anal fissures
Authors: J H Scholefield
Journal: Gut (2003)

<b>Background:</b> Anal fissure is a common painful condition affecting the anal canal. The majority of acute fissures heal spontaneously. However, some of these acute fissures do not resolve but become chronic. Chronic anal fissures were traditionally treated by anal dilation or by lateral sphincterotomy. However, both of these surgical treatments may cause a degree of incontinence in up to 30% of patients. Several recent trials have shown that nitric oxide donors such as glyceryl trinitrate (GTN) can reduce sphincter pressure and heal up to 70% of chronic fissures. <b>Aim:</b> This study addressed the dose-response to three different concentrations of GTN ointment compared with placebo in a double blind randomised controlled trial. <b>Method:</b> A double blind, multicentre, randomised controlled trial was set up to compare placebo ointment against three active treatment arms (0.1%, 0.2%, and 0.4% GTN ointment applied at a dose of 220 mg twice daily) in chronic anal fissures. The primary end point was complete healing of the fissure. <b>Results:</b> Two hundred patients were recruited over an eight month period from 18 centres. After eight weeks of treatment the healing rate in the placebo group was 37.5% compared with 46.9% for 0.1%, 40.4% for 0.2%, and 54.1% for 0.4% GTN. None was significantly better than the placebo response. A secondary analysis excluded fissures without secondary criteria for chronicity. Healing rates were then found to be 24% in the placebo group compared with 50% in the 0.1% GTN group, 36% in the 0.2% group, and 57% in the 0.4% GTN group. These values were statistically significantly different for the placebo group compared with 0.1% GTN, 0.4% GTN, and for the GTN treated group as a whole. <b>Conclusions:</b> The results of this study have demonstrated the significant benefit of topical GTN when applied to patients suffering from chronic anal fissures but acute fissures showed a tendency to resolve spontaneously. The high proportion of fissures which healed in the placebo group suggests that the definition of “chronicity” needs to be reassessed. Further studies are required to confirm the optimal therapeutic strategy.
Determinants of loaded shortening velocity in single cardiac myocytes permeabilized with alpha-hemolysin.
Authors: N K Sweitzer, R L Moss
Journal: Circulation Research (1993)

Force-velocity relations were obtained from single cardiac myocytes isolated by enzymatic digestion of rat myocardium and permeabilized with the pore-forming staphylococcal toxin alpha-hemolysin. Single cardiac myocytes were attached to a force transducer and piezoelectric translator and viewed with an inverted microscope to allow periodic monitoring of sarcomere length during experiments. Permeabilized cells were activated by immersion in a bath of known [Ca2+]. We report that the Ca2+ sensitivity of cells obtained by enzymatic digestion and permeabilized using alpha-hemolysin is similar to that reported previously for mechanically disrupted ventricular myocardium; however, the tension-pCa relation is less steep in the new preparation. During isotonic measurements, force was clamped to various loads using a rapid-response servo system. All recordings of shortening under load were distinctly curvilinear, and analysis of data involved fitting each shortening recording with a single exponential curve and calculating the value of the slope at the initial time of the load clamp. In addition, the presence of significant resting force at initial sarcomere lengths in these cells required that the possibility of alteration of velocity due to the presence of resting force be addressed. The maximum shortening velocity in fully Ca(2+)-activated single ventricular myocytes studied by this method was 2.83 muscle lengths per second on average. The basis for curvilinear shortening is postulated to be multifactorial in cardiac muscle, involving a combination of shortening inactivation and one or more passive elasticities that resist stretch or compression depending on sarcomere length. Shortening velocity shows a dependence on myosin isoform content when cells from a single heart are compared; however, this relation does not hold when cells from different hearts are compared. The behavior of single alpha-hemolysin-permeabilized myocyte shortening under loaded conditions at lower levels of Ca2+ is also described. During submaximal Ca2+ activation, initial shortening velocities are faster than those observed in maximally activated cells. This may be due to contributions of high passive force to increase shortening velocity under conditions of low active force generation, when passive force in the cell is a greater proportion of the total force and there are fewer bound crossbridges.
Adjuvants of Immunity
Authors: Albert Bendelac, Ruslan Medzhitov
Journal: The Journal of Experimental Medicine (2002)

Since Jules Freund reported that crude mycobacterial extracts greatly promoted immune responses to antigens ([1][1]), the use of adjuvants has become a widespread, but poorly understood practice to promote T and B cell responses ([2][2]). Recent studies have begun to identify the chemical nature of
Renal Cyst Development in Mice with Conditional Inactivation of the von Hippel-Lindau Tumor Suppressor
Authors: Erinn B. Rankin, John E. Tomaszewski, Volker H. Haase
Journal: Cancer Research (2006)

Abstract Inactivation of the von Hippel-Lindau tumor suppressor, pVHL, is associated with both hereditary and sporadic renal cysts and renal cell carcinoma, which are commonly thought to arise from the renal proximal tubule. pVHL regulates the protein stability of hypoxia-inducible factor (HIF)-α subunits and loss of pVHL function leads to HIF stabilization. The role of HIF in the development of VHL-associated renal lesions remains to be determined. To investigate the functional consequences of pVHL inactivation and the role of HIF signaling in renal epithelial cells, we used the phosphoenolpyruvate carboxykinase (PEPCK) promoter to generate transgenic mice in which Cre-recombinase is expressed in the renal proximal tubule and in hepatocytes. We found that conditional inactivation of VHL in PEPCK-Cre mutants resulted in renal cyst development that was associated with increased erythropoietin levels and polycythemia. Increased expression of the HIF target gene erythropoietin was limited to the liver, whereas expression of carbonic anhydrase 9 and multidrug resistance gene 1 was up-regulated in the renal cortex of mutant mice. Inactivation of the HIF-α binding partner, arylhydrocarbon receptor nuclear translocator (Arnt), but not Hif-1α, suppressed the development of renal cysts. Here, we present the first mouse model of VHL-associated renal disease that will provide a basis for further genetic studies to define the molecular events that are required for the progression of VHL-associated renal cysts to clear cell renal cell carcinoma. (Cancer Res 2006; 66(5): 2576-83)
Place for Biochemical Markers in Early-Stage Lung Cancer Detection?
Authors: Mark W. Duncan
Journal: Journal of Clinical Oncology (2009)

A recent publication by Yee and colleagues 1 provides an opportunity to reflect on how we discover blood-borne biomarkers, validate them, and establish criteria for their use in routine clinical practice.As of yet, no blood test has made a significant impact on lung cancer diagnosis, but that will change.In the meantime, Yee et al would likely argue that we demand too much of our candidate markers, and while no marker has transformed diagnosis, one or more offering suboptimal specificity or sensitivity could be part of our existing armamentarium.It is an intriguing idea.The work by Yee et al 1 is notable for several reasons.First, the group adopted an unconventional discovery strategy.Typically, cancer-specific differences are measured in the systemic circulation and the analytic challenge is to define quantitative differences that distinguish cases from controls in the presence of a "complex and variable" chemical background.It is a demanding task that often requires impractically large sample sets to account for patient heterogeneity and the mediocre precision of our discovery tools.Alternatively, Yee et al used each subject as their own control, and determined elevated proteins in the pulmonary venous effluent draining the tumor vascular bed relative to matched systemic arterial blood.Because the chemical background is essentially constant, the task is reduced to determining differences between two samples drawn from the same individual pre-and postpassage through the affected organ.Initially they paired pulmonary venous-radial arterial blood samples from 16 lung cancer patients and identified two candidate biomarkers by surface-enhanced laser desorption ionization mass spectrometry-connective tissue-activating peptide III/neutrophil activating protein-2 (CTAP III/NAP-2) and haptoglobin.Both were higher in venous versus arterial blood.Given that extraordinarily encouraging findings can arise through chance or bias alone, verification is a critical next step in the biomarker development pipeline.They verified their initial findings in 64-paired venous-arterial blood samples by immunoassay-a more practical, precise, and cost-effective analytic approach.In subsequent validation studies, elevated levels of CTAP III/NAP-2 and haptoglobin were confirmed in 28 pre-and postsurgical resection peripheral blood samples, two blinded sets of plasma from 149 participants in a lung cancer screening study (49 lung cancers and 100 controls), and in 266 participants from the National Heart, Lung, and Blood Institute Lung Health Study (45 lung cancers and 221 matched controls).CTAP III/NAP-2 levels were elevated in lung cancer and in the plasma of smokers who subsequently developed lung cancer, and in