tbuckley/cabot-search huggingface dataset:
Statistical ritual in clinical journals: is there a cure?--I.
Authors: D Mainland
Journal: BMJ (1984)

The shambles mentioned at the beginning of Part I referred to the confusion in the use of standard deviations and standard errors of means,1 with the latter apparently more popular, perhaps because they are so much smaller than their parent standard deviations and thus suggest higher precision. The author denned the standard deviation as representing the variation among the individual measurements,2 but this does not help us unless we know what multiple of standard deviation would enclose a certain percentage of the observations. The formula commonly used is mean ?1-96 SD (or 2 SD), on the assumption that we have individual measurements that, if increased in number, would form approximately a Gaussian distribution?an assumption for which most medical data provide scanty evidence. Bell shaped is not synonymous with Gaussian; and a trick such as the logarithmic transformation cannot be guaranteed to make the approximation safe. We should remember that the Gaussian curve started as the  curve of error, a mathematical invention that was believed to represent the scatter of the variable (chance) errors in physical measurements, but thorough investigation3 failed to substantiate the belief. Perhaps, however, some authors producing a standard deviation do not visualise any distribution. If they did, I would expect to see comments when mean minus 2 SD (or even minus 1 SD) leads to a ridiculous negative value in data such as: sodium concentration in saliva before and after a certain drug treatment; days off work after minor surgery for haemorrhoids ; activity of an enzyme in ascitic fluid in hepatic cirrhosis; serum concentration of amyloid in rheumatoid arthritis; duration of labour; number of vaginal examinations during labour. The widespread use of the Gaussian distribution to express inter subject variation has been apparently due, firstly, to the illegitimate application of the mathematical term normal (Gaussian) as if synonymous with healthy,4 5 and, secondly, to the use of standard deviation to produce standard error of the mean in the Gaussian based t test.
Calcium in milk and fermentation by yoghurt bacteria increase the resistance of rats to Salmonella infection.
Authors: I Bovee-Oudenhoven, D Termont, R Dekker, R Van der Meer
Journal: Gut (1996)

Calcium in milk products stimulates gastric acid secretion and inhibits the cytolytic activity of intestinal contents. Based on these effects, it was hypothesised that calcium might lessen the severity of food borne intestinal infections. The possible differential effects of a low calcium milk and normal milk products (milk, acidified milk, and pasteurised yoghurt) on the resistance of rats to a salmonella infection was therefore studied. Rats were infected orally with Salmonella enteritidis just after food consumption. The first day after infection, faecal salmonella counts of the yoghurt fed rats were significantly lower than those of the other groups. Thereafter, faecal salmonella excretion declined rapidly in all high calcium groups, whereas rats fed the low calcium milk continued to excrete high numbers of salmonella. The reduced colonisation resistance to salmonella of rats fed low calcium milk might be caused by the high cytolytic activity of faecal water or a high iron concentration in faecal water, already present before infection, or both. The reduced resistance of these rats corresponded with a large infection induced increase in the cytolytic activity of faecal water, an appreciable reduction in apparent iron absorption, and a large increase in faecal mucin and alkaline phosphatase excretion. In yoghurt fed rats, only minor infection induced changes in luminal parameters were noticed. The rats fed milk and acidified milk always showed intermediate reactions. In conclusion, in addition to fermentation by yoghurt bacteria, calcium in milk products strongly enhanced the resistance to salmonella infection by lowering luminal cytolytic activity or diminishing the availability of iron for pathogen growth, or both.
SCHIZOPHRENIC REACTION TIME RESPONSES TO VARIABLE PREPARATORY INTERVALS
Authors: CHARLES A. KNEHR
Journal: American Journal of Psychiatry (1954)

1. No difference was observed in speed of reaction when a group of patients with schizophrenic illnesses was compared to a control group. 2. Previously reported differential responsiveness of patients and controls to variation in length of preparatory interval and regularity of stimulus presentation was not observed. The usefulness of such a technique for differentiating schizophrenics from normals is questioned. 3. Variability of speed of reaction tends to be significantly greater in the patient group. This result is consistent with previous findings. It is suggested that this represents an increase in the amplitude of fluctuations in readiness which are oscillatory in character.
Fibronectin and α5β1 integrin mediate binding of Pseudomonas aeruginosa to repairing airway epithelium
Authors: P. Roger, E. Puchelle, O Bajolet-Laudinat, J-M Tournier, C Debordeaux, M-C Plotkowski, J.H.m Cohen, D Sheppard, S de Bentzmann
Journal: European Respiratory Journal (1999)

Initial infection of the airway by Pseudomonas aeruginosa may occur through a variety of bacterial strategies including binding to epithelial receptors present at the surface of the respiratory epithelium. In order to characterize the adherence sites for P. aeruginosa in damaged and repairing bronchial tissue, an ex vivo model of airway epithelial injury and repair was developed using primary cell cultures of nasal cells from 14 subjects with polyposis. P. aeruginosa strongly adhered to flattened dedifferentiated (FD) bronchial and nasal cytokeratin 13-positive epithelial cells in the process of migration for repair. In in vitro experiments, competitive binding inhibition assays demonstrated that alpha5beta1 integrins and cellular fibronectin, in particular the RGD sequence, are receptors involved in P. aeruginosa adherence to FD nasal epithelial cells. Fluorescent cell sorting analysis and immunofluorescence techniques revealed that the alpha5beta1 integrins are overexpressed and apically exposed in FD nasal epithelial cells. One 50 kDa outer membrane protein was identified in piliated and nonpiliated strains of P. aeruginosa that was involved in binding to cellular fibronectin and alpha5beta1 epithelial integrins. These results demonstrate that Pseudomonas aeruginosa adherence is related to the dedifferentiation of airway epithelium during the repair process which unmasks and upregulates the alpha5beta1 integrin expression and induces active synthesis of cellular fibronectin. These epithelial receptors are then used by a Pseudomonas aeruginosa 50 kDa outer membrane protein as sites of bacterial adherence.
Big data in the new media environment
Authors: Matthew Brook O'Donnell, Emily B. Falk, Sara Konrath
Journal: Behavioral and Brain Sciences (2014)

Abstract Bentley et al. argue for the social scientific contextualization of “big data” by proposing a four-quadrant model. We suggest extensions of the east–west (i.e., socially motivated versus independently motivated) decision-making dimension in light of findings from social psychology and neuroscience. We outline a method that leverages linguistic tools to connect insights across fields that address the individuals underlying big-data media streams.
Antibodies to TWEAK Receptor Inhibit Human Tumor Growth through Dual Mechanisms
Authors: Patricia A. Culp, Donghee Choi, Yongke Zhang, Johnny Yin, Pui Seto, Suzanne E. Ybarra, Mian Su, Mien Sho, Roxanne Steinle, Melanie H.L. Wong, Ferdinand Evangelista, Jennifer Grove, Marie Cardenas, Marjorie James, Eric D. Hsi, Debra T. Chao, David B. Powers, Vanitha Ramakrishnan, Robert Dubridge
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Targeted therapeutics have significantly changed the outcome for patients diagnosed with cancer. Still, effective therapeutic intervention does not exist for many cancers and much remains to be done. The objective of this study was to identify novel genes that potentially regulate tumor growth, to target these gene products with monoclonal antibodies, and to examine the therapeutic potential of these antibodies. Experimental Design: Using cDNA microarray analysis, we identified genes overexpressed in several solid malignancies. We generated a mouse monoclonal antibody, 19.2.1, and its humanized counterpart, PDL192, to one such target, TweakR (TWEAK receptor, Fn14, TNFRSF12A, CD266), and characterized the antitumor activities in vitro and in mouse xenograft models. Results: Both 19.2.1 (mouse IgG2a) and PDL192 (human IgG1), like TWEAK, the natural ligand of TweakR, inhibited the growth of several TweakR-expressing cancer cell lines in anchorage-dependent and anchorage-independent assays in vitro. Both antibodies showed significant antitumor activity in multiple mouse xenograft models. PDL192 and 19.2.1 also induced antibody-dependent cellular cytotoxicity (ADCC) of cancer cell lines in vitro. A chimeric version of 19.2.1 containing the mouse IgG1 Fc region (19.2.1×G1) exhibited significantly less ADCC than 19.2.1. However, 19.2.1×G1 showed differential activity in vivo, with activity equivalent to 19.2.1 in one model, but significantly less efficacy than 19.2.1 in a second model. These results indicate that PDL192 and 19.2.1 mediate their antitumor effects by signaling through TweakR, resulting in reduced tumor cell proliferation, and by ADCC. Clin Cancer Res; 16(2); 497–508
Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial
Authors: Thomas Sandmann, Richard Bourgon, Josep Garcia, Congfen Li, Timothy Cloughesy, Olivier L. Chinot, Wolfgang Wick, Ryo Nishikawa, Warren Mason, Roger Henriksson, Frank Saran, Albert Lai, Nicola Moore, Samir Kharbanda, Franklin Peale, Priti Hegde, Lauren E. Abrey, Heidi S. Phillips, Carlos Bais
Journal: Journal of Clinical Oncology (2015)

The AVAglio (Avastin in Glioblastoma) and RTOG-0825 randomized, placebo-controlled phase III trials in newly diagnosed glioblastoma reported prolonged progression-free survival (PFS), but not overall survival (OS), with the addition of bevacizumab to radiotherapy plus temozolomide. To establish whether certain patient subgroups derived an OS benefit from the addition of bevacizumab to first-line standard-of-care therapy, AVAglio patients were retrospectively evaluated for molecular subtype, and bevacizumab efficacy was assessed for each patient subgroup.A total of 349 pretreatment specimens (bevacizumab arm, n = 171; placebo arm, n = 178) from AVAglio patients (total, N = 921) were available for biomarker analysis. Samples were profiled for gene expression and isocitrate dehydrogenase 1 (IDH1) mutation status and classified into previously identified molecular subtypes. PFS and OS were assessed within each subtype.A multivariable analysis accounting for prognostic covariates revealed that bevacizumab conferred a significant OS advantage versus placebo for patients with proneural IDH1 wild-type tumors (17.1 v 12.8 months, respectively; hazard ratio, 0.43; 95% CI, 0.26 to 0.73; P = .002). This analysis also revealed an interaction between the proneural subtype biomarker and treatment arm (P = .023). The group of patients with mesenchymal and proneural tumors derived a PFS benefit from bevacizumab compared with placebo; however, this translated to an OS benefit in the proneural subset only.Retrospective analysis of AVAglio data suggests that patients with IDH1 wild-type proneural glioblastoma may derive an OS benefit from first-line bevacizumab treatment. The predictive value of the proneural subtype observed in AVAglio should be validated in an independent data set.
Who and what should we rely on in early diagnosis of idiopathic pulmonary fibrosis?
Authors: Vincent Cottin, Jean-François Cordier
Journal: European Respiratory Journal (2012)

From the authors:

C. Xiaoqian and colleagues comment on our recent editorial [1], in which we emphasised the potential role of “Velcro” crackles at auscultation for earlier diagnosis of idiopathic pulmonary fibrosis (IPF). They are right to underline that “velcro” crackles were formerly one of the minor criteria for the diagnosis of IPF in the absence of a lung biopsy, and to discuss the role of high-resolution computed tomography (HRCT) of the chest.

Although “velcro” crackles alone are undoubtedly not specific of IPF, their …
Impact of the New Lung Cancer Staging System for a Predominantly Advanced-Disease Patient Population
Authors: Chun-Ru Chien, Su-Tso Yang, Chih-Yi Chen, Hsin-Yuan Fang, Chih-Yen Tu, Guan-Chin Tseng, Yang-Ho Yu, Hung-Jen Chen, Chih-Te Ho, Ching-Yun Hsieh, Hsiang-Ni Chen, Pin-Ru Chen, Juhn-Cherng Liu, Yao-Ching Wang, Hui-Hua Wu, Te-Chun Hsia
Journal: Journal of Thoracic Oncology (2010)
Smooth Muscle—Specific Expression of CYP4A1 Induces Endothelial Sprouting in Renal Arterial Microvessels
Authors: Miao Jiang, Alexandre Mezentsev, Rowena Kemp, Kihwan Byun, John R. Falck, Joseph M. Miano, Alberto Nasjletti, Nader G. Abraham, Michal Laniado-Schwartzman
Journal: Circulation Research (2003)

Cytochrome P450 (CYP) 4A1 has been characterized as the most efficient arachidonic acid omega-hydroxylase catalyzing the formation of 20-hydroxyeicosatetraenoic acid (20-HETE), a potent constrictor of the renal and cerebral microcirculation and a mitogen for smooth muscle cells. We constructed adenoviruses expressing the CYP4A1 cDNA or LacZ under the control of the smooth muscle cell-specific promoter SM22alpha (Ad-SM22-4A1 and Ad-SM22-nLacZ, respectively). Beta-galactosidase expression was detected in Ad-SM22-nLacZ-transduced vascular smooth muscle A7r5 and PAC1 cells, but not in Ad-SM22-nLacZ-transduced 3T3 fibroblasts or vascular endothelial cells. Likewise, CYP4A1 mRNA and protein were detected in Ad-SM22-4A1-transduced A7r5 and PAC1 cells. Ad-SM22-4A1-transduced A7r5 cells metabolized lauric acid to 12-hydroxy-lauric acid at a rate 5 times greater than that of cells transduced with Ad-SM22-nLacZ (4.79+/-1.77 versus 0.97+/-0.57 nmol 12-hydroxy lauric acid/10(6) cells per h). Smooth muscle-specific LacZ expression was also detected in microdissected renal interlobar arteries transduced with Ad-SM22-nLacZ. Arteries transduced with Ad-SM22-4A1 produced higher levels of 20-HETE (4.04+/-0.29 and 13.43+/-2.84 ng/mg protein in Ad-SM22-nLacZ-transduced and Ad-SM22-4A1-transduced arteries, respectively) and demonstrated a marked angiogenic activity measured as the total length of sprouting neovessels (12.63+/-3.66 mm in Ad-SM22-4A1-transduced vessels versus 1.79+/-0.89 mm in Ad-SM22-nLacZ-transduced vessels). This angiogenic activity represented endothelial cell sprouting and was fully blocked by treatment with HET0016, a selective inhibitor of CYP4A-catalyzed reactions. The inhibitory effect of HET0016 was reversed by addition of a 20-HETE agonist. We conclude that Ad-SM22-4A1 drives a smooth muscle-specific functional expression of CYP4A1 and demonstrates increased angiogenesis, presumably via increased production of 20-HETE.
Exhaled Nitric Oxide Does Not Provide a Marker of Vascular Endothelial Function in Healthy Humans
Authors: CLAUDIO SARTORI, MATTIA LEPORI, THILO BUSCH, HERVÉ DUPLAIN, WULF HILDEBRANDT, PETER BÄRTSCH, PASCAL NICOD, KONRAD J. FALKE, URS SCHERRER
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

In the lung, nitric oxide synthase (NOS) has been found in both alveolar epithelial and vascular endothelial cells. Nitric oxide (NO) in the exhaled air stemming from the lower respiratory tract has been claimed to represent a marker of the vascular endothelial NO production. Experimental evidence for this concept, however, is lacking. We compared, in eight healthy volunteers, effects on exhaled NO of epithelial NOS inhibition by N G-monomethyl-l-arginine (l-NMMA) inhalation (6 mg/kg over 15 min) with those of endothelial NOS inhibition by l-NMMA infusion (25 μ g/kg/min for 30 min). We also measured blood pressure, heart rate, and l-NMMA plasma concentration. The major new findings were that l-NMMA inhalation which did not have any detectable effect on hemodynamics and l-NMMA plasma concentration, decreased the pulmonary exhaled NO by almost 40%. In contrast, l-NMMA infusion that inhibited endothelial NOS, as evidenced by an increase in blood pressure and a decrease in heart rate, had only a barely detectable effect on exhaled NO ( − 11 ± 4% from baseline). Pulmonary exhaled NO is mostly of epithelial rather than endothelial origin, and does not provide a marker for vascular endothelial NO production and/or endothelial function in healthy humans.
PGP9.5 Promoter Methylation Is an Independent Prognostic Factor for Esophageal Squamous Cell Carcinoma
Authors: Diana L. Mandelker, Keishi Yamashita, Yutaka Tokumaru, Koshi Mimori, David L. Howard, Yoichi Tanaka, Andre Lopes Carvalho, Wei-Wen Jiang, Hannah Lui Park, Myoung Sook Kim, Motonobu Osada, Masaki Mori, David Sidransky
Journal: Cancer Research (2005)

Abstract PGP9.5/UCHL1 is a member of the carboxyl-terminal ubiquitin hydrolase family with a potential role in carcinogenesis. We previously identified PGP9.5 as a putative tumor-suppressor gene and methylation of the promoter as a cancer-specific event in primary cancer tissues. In this current study, we analyzed PGP9.5 methylation in 50 esophageal squamous cell carcinoma (ESCC) primary tumors with well characterized clinicopathologic variables including patient outcome. Two independent modalities for methylation analysis (TaqMan methylation-specific PCR and combined bisulfite restriction analysis) were used to analyze these samples. The two data sets were consistent with each other, as the 21 patients (42%) with highest methylation levels by TaqMan analysis all showed visible combined bisulfite restriction analysis bands on acrylamide gels. Using an optimized cutoff value by TaqMan quantitation, we found that patients with higher PGP9.5 methylation ratios in the primary tumor showed poorer 5-year survival rates than those without PGP9.5 methylation (P = 0.01). A significant correlation was also seen between PGP9.5 promoter methylation and the presence of regional lymph node metastases (P = 0.03). Multivariate analysis subsequently revealed that PGP9.5 methylation was an independent prognostic factor for ESCC survival (P = 0.03). These results suggest that PGP9.5 promoter methylation could be a clinically applicable marker for ESCC progression.
Temporal induction of clusterin in cisplatin nephrotoxicity.
Authors: J R Silkensen, A Agarwal, K A Nath, J C Manivel, M E Rosenberg
Journal: Journal of the American Society of Nephrology (1997)

Clusterin is a ubiquitous glycoprotein induced in many organs, including the kidney, at times of tissue injury and/or remodeling. It is speculated in this study that clusterin preserves cell interactions that are otherwise perturbed by renal insults. The purpose of this study was to examine clusterin expression after cisplatin nephrotoxicity, a model characterized by a delayed time course of injury and a well-defined site of that injury (proximal tubule). Sprague-Dawley rats were treated with intravenous cisplatin (6 mg/kg) or vehicle. Serum creatinine concentrations were measured and kidneys harvested at 1, 2, and 5 days. Marked induction of clusterin mRNA was seen only at 5 days, a time when serum creatinine concentration was the highest. Histology of kidney tissue 5 days after cisplatin administration revealed marked tubular necrosis localized to the outer stripe of the outer medulla, a region rich in proximal tubules. Immunohistochemistry and in situ hybridization at 5 days demonstrated clusterin primarily in the inner stripe of the outer medulla. In conclusion, expression of clusterin follows renal injury with cisplatin at a time corresponding to the morphologic evidence of tubular necrosis and cell detachment; quite surprisingly, such expression occurs at a site distant from the primary injury.
ETV6-NTRK3–Mediated Breast Epithelial Cell Transformation Is Blocked by Targeting the IGF1R Signaling Pathway
Authors: Cristina E. Tognon, Aruna M. Somasiri, Valentina E. Evdokimova, Genny Trigo, Evett E. Uy, Nataliya Melnyk, Joan M. Carboni, Marco M. Gottardis, Calvin D. Roskelley, Michael Pollak, Poul H.B. Sorensen
Journal: Cancer Research (2010)

The insulin-like growth factor (IGF) 1 receptor (IGF1R) is an important therapeutic target under study in many cancers. Here, we describe a breast cancer model based on expression of the ETV6-NTRK3 (EN) chimeric tyrosine kinase that suggests novel therapeutic applications of IGF1R inhibitors in secretory breast cancers. Originally discovered in congenital fibrosarcomas with t(12;15) translocations, EN was identified subsequently in secretory breast carcinoma (SBC) which represent a variant of invasive ductal carcinoma. Because fibroblast transformation by EN requires the IGF1R axis, we hypothesized a similar dependency may exist in mammary cells and, if so, that IGF1R inhibitors might be useful to block EN-driven breast oncogenesis. In this study, we analyzed EN expressing murine and human mammary epithelial cell lines for transformation properties. Various IGF1R signaling inhibitors, including the dual specificity IGF1R/insulin receptor (INSR) inhibitor BMS-536924, were then tested for effects on three-dimensional Matrigel cell growth, migration, and tumor formation. We found that EN expression increased acinar size and luminal filling in Matrigel cultures and promoted orthotopic tumor growth in mice. Tumors were well differentiated and nonmetastatic, similar to human SBC. The known EN effector pathway, PI3K-Akt, was activated in an IGF1- or insulin-dependent manner. BMS-536924 blocked EN transformation in vitro, whereas BMS-754807, another IGIFR/INSR kinase inhibitor currently in clinical trials, significantly reduced tumor growth in vivo. Importantly, EN model systems mimic the clinical phenotype observed in human SBC. Moreover, EN has a strict requirement for IGF1R or INSR in breast cell transformation. Thus, our findings strongly encourage the evaluation of IGF1R/INSR inhibitors to treat EN-driven breast cancers.
Ability of ultrasound imaging to detect erosions in a bone phantom model
Authors: J. M. Koski, E. Alasaarela, I. Soini, K. Kemppainen, U. Hakulinen, J. O. Heikkinen, M. S. Laasanen, S. Saarakkala
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objectives</h3> The authors examined the validity, interobserver reliability and interscanner variation in detecting bone erosions with ultrasonography using a custom-made phantom. <h3>Methods</h3> 21 bovine bones were used. Artificial erosions were made into 15 bones and six bones were left as controls. In the processed bones the numbers of erosions, their depths and widths varied between 1–7, 1–4 and 1.5–5 mm, respectively. Each bone was coated with polyvinyl alcohol cryogel to mimic overlying soft tissue and to hide the erosions. Four musculoskeletal sonography experts scanned the 21 blind-coded phantoms using one of the three sets of ultrasound equipment. Finally, quality assurance measurements of the ultrasound equipment was carried out using two additional bone samples. <h3>Results</h3> The sonographers detected the erosions successfully with ultrasound. The mean correlation coefficient for a correct result in terms of the number of erosions detected was 0.88 (range 0.75–0.975). The overall Cohen9s κ coefficient for interobserver agreement was 0.683 in terms of discrimination between healthy bones and bones with erosions. The different sets of equipment showed that their overall performance was equal. <h3>Conclusions</h3> The sonographers had good correlations with the number of erosions and they were successful in separating healthy bones from bones with erosions. It seems that neither depth nor width is crucial but that in experimental conditions a 1.5 mm erosion width was the limit for the resolution with current ultrasound equipment. Ultrasound is a valid and reliable method of detecting cortical bone erosions in vitro, when the round erosion is at least 1 mm deep and 1.5 mm wide.