tbuckley/cabot-search huggingface dataset:
Trastuzumab (Herceptin) Enhances Class I-Restricted Antigen Presentation Recognized by HER-2/<b><i>neu</i></b>-Specific T Cytotoxic Lymphocytes
Authors: Koji Kono, Eiji Sato, Hirofumi Naganuma, Akihiro Takahashi, Kousaku Mimura, Hideaki Nukui, Hideki Fujii
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Numerous examples from animal models and clinical trials showed that HER-2-derived peptides are naturally processed as a CTL epitope and can be recognized by tumor-specific CTLs in several tumors with HER-2 overexpression. The humanized anti-HER-2 monoclonal antibody, Herceptin, has been designed to specifically antagonize the HER-2 function by directing against the extracellular domain of the HER-2 protein. One of the actions of Herceptin includes the internalization and degradation of HER-2, which might increase the amount of HER-2-derived peptides available for loading to MHC class I. Experimental Design: In the present study, we investigated how Herceptin treatment of HER-2-overexpressing targets affects lysis by HER-2-specific CTLs. Results: We showed that Herceptin sensitized HER-2-overexpressing tumors to lysis by HLA-A2-restricted or HLA-A24-restricted CTLs, without any effect of the expression of MHC class I, costimulatory molecules, adhesion molecules, or TAP-1 on the targets. Furthermore, the enhancement of cytolytic activity with Herceptin was inhibited by addition of a specific proteasome inhibitor, lactacystin. Conclusions: These results suggested that Herceptin treatment might enhance the class I-restricted presentation of endogenous HER-2 antigen via the proteasome step, resulting in higher susceptibility of HER-2-overexpressing tumors to lysis by the HER-2-specific CTLs.
Intrarenal Distribution of Blood Flow during Elevation of Ureteral Pressure in Dogs
Authors: EDWIN L. CARLSON, HARVEY V. SPARKS
Journal: Circulation Research (1970)

The 85 Kr method was used to determine the effect of elevated ureteral pressure on total cortical and outer medullary nutrient renal blood flow of pentobarbital-anesthetized dogs. Increased ureteral pressure during mild saline diuresis resulted in increased total nutrient blood flow from 316 to 402 ml/100 g/min. Autoradiographs demonstrated that the increased blood flow is confined to the renal cortex and that juxtamedullary cortical and outer medullary flow is unchanged. Elevated ureteral pressure decreased total renal blood flow from 473 to 381 ml/g/min during copious mannitol diuresis. This is due at least partly to decreased cortical blood flow; we were unable to measure juxtamedullary cortical plus outer medullary blood flow during mannitol diuresis. Isolated renal arteries relaxed when placed in a physiologic salt solution containing 70 mM mannitol. Renin release is increased during elevation of ureteral pressure. We concluded that the mechanism for increased renal blood flow during ureteral occlusion selectively involves the nutrient circulation of the renal cortex.
When Should Potentially False Research Findings Be Considered Acceptable?
Authors: Benjamin Djulbegovic, Iztok Hozo
Journal: PLoS Medicine (2007)

Ioannidis estimated that most published research findings are false [1], but he did not indicate when, if at all, potentially false research results may be considered as acceptable to society. We combined our two previously published models [2,3] to calculate the probability above which research findings may become acceptable. A new model indicates that the probability above which research results should be accepted depends on the expected payback from the research (the benefits) and the inadvertent consequences (the harms). This probability may dramatically change depending on our willingness to tolerate error in accepting false research findings. Our acceptance of research findings changes as a function of what we call “acceptable regret,” i.e., our tolerance of making a wrong decision in accepting the research hypothesis. We illustrate our findings by providing a new framework for early stopping rules in clinical research (i.e., when should we accept early findings from a clinical trial indicating the benefits as true?). Obtaining absolute “truth” in research is impossible, and so society has to decide when less-than-perfect results may become acceptable.
Relation between Respiratory Changes in Arterial Pulse Pressure and Fluid Responsiveness in Septic Patients with Acute Circulatory Failure
Authors: FRÉDÉRIC MICHARD, SANDRINE BOUSSAT, DENIS CHEMLA, NADIA ANGUEL, ALAIN MERCAT, YVES LECARPENTIER, CHRISTIAN RICHARD, MICHAEL R. PINSKY, JEAN-LOUIS TEBOUL
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

In mechanically ventilated patients with acute circulatory failure related to sepsis, we investigated whether the respiratory changes in arterial pressure could be related to the effects of volume expansion (VE) on cardiac index (CI). Forty patients instrumented with indwelling systemic and pulmonary artery catheters were studied before and after VE. Maximal and minimal values of pulse pressure (Pp(max) and Pp(min)) and systolic pressure (Ps(max) and Ps(min)) were determined over one respiratory cycle. The respiratory changes in pulse pressure (DeltaPp) were calculated as the difference between Pp(max) and Pp(min) divided by the mean of the two values and were expressed as a percentage. The respiratory changes in systolic pressure (DeltaPs) were calculated using a similar formula. The VE-induced increase in CI was >/= 15% in 16 patients (responders) and < 15% in 24 patients (nonresponders). Before VE, DeltaPp (24 +/- 9 versus 7 +/- 3%, p < 0.001) and DeltaPs (15 +/- 5 versus 6 +/- 3%, p < 0.001) were higher in responders than in nonresponders. Receiver operating characteristic (ROC) curves analysis showed that DeltaPp was a more accurate indicator of fluid responsiveness than DeltaPs. Before VE, a DeltaPp value of 13% allowed discrimination between responders and nonresponders with a sensitivity of 94% and a specificity of 96%. VE-induced changes in CI closely correlated with DeltaPp before volume expansion (r(2) = 0. 85, p < 0.001). VE decreased DeltaPp from 14 +/- 10 to 7 +/- 5% (p < 0.001) and VE-induced changes in DeltaPp correlated with VE-induced changes in CI (r(2) = 0.72, p < 0.001). It was concluded that in mechanically ventilated patients with acute circulatory failure related to sepsis, analysis of DeltaPp is a simple method for predicting and assessing the hemodynamic effects of VE, and that DeltaPp is a more reliable indicator of fluid responsiveness than DeltaPs.
Synergistic action of cyclic adenosine monophosphate- and calcium-mediated chloride secretion in a colonic epithelial cell line.
Authors: C A Cartwright, J A McRoberts, K G Mandel, K Dharmsathaphorn
Journal: Journal of Clinical Investigation (1985)

Vasoactive intestinal polypeptide (VIP) and the calcium ionophore A23187 caused dose-dependent changes in the potential difference and the short circuit current (Isc) across confluent T84 cell monolayers mounted in modified Ussing chambers. Both VIP and A23187 stimulated net chloride secretion without altering sodium transport. Net chloride secretion accounted for the increase in Isc. When A23187 was tested in combination with VIP, net chloride secretion was significantly greater than predicted from the calculated sum of their individual responses indicating a synergistic effect. VIP increased cellular cyclic AMP (cAMP) production in a dose-dependent manner, whereas A23187 had no effect on cellular cAMP. We then determined whether VIP and A23187 activated different transport pathways. Earlier studies suggest that VIP activates a basolaterally localized, barium-sensitive potassium channel as well as an apically localized chloride conductance pathway. In this study, stimulation of basolateral membrane potassium efflux by A23187 was documented by preloading the monolayers with 86Rb+. Stimulation of potassium efflux by A23187 was additive to the VIP-stimulated potassium efflux. By itself, 0.3 microM A23187 did not alter transepithelial chloride permeability, and its stimulation of basolateral membrane potassium efflux caused only a relatively small amount of chloride secretion. However, in the presence of an increased transepithelial chloride permeability induced by VIP, the effectiveness of A23187 on chloride secretion was greatly augmented. Our studies suggest that cAMP and calcium each activate basolateral potassium channels, but cAMP also activates an apically localized chloride channel. Synergism results from cooperative interaction of potassium channels and the chloride channel.
Formation and Phosphorylation of the PINCH-1–Integrin Linked Kinase–α-Parvin Complex Are Important for Regulation of Renal Glomerular Podocyte Adhesion, Architecture, and Survival
Authors: Yanqiang Yang, Lida Guo, Simone M. Blattner, Peter Mundel, Matthias Kretzler, Chuanyue Wu
Journal: Journal of the American Society of Nephrology (2005)

Alterations in the cellular architecture, adhesion, and/or loss of glomerular podocytes are causal factors in the development of proteinuria and the progression to end-stage renal failure. With the use of an inducible podocyte differentiation system, it was found that the cellular levels of PINCH-1, integrin linked kinase (ILK), and alpha-parvin, cytoplasmic components of cell-extracellular matrix adhesions, were significantly increased during podocyte differentiation. Concomitantly, an increased amount of the PINCH-1-ILK-alpha-parvin complex was detected in the differentiated, foot process-containing podocytes. Overexpression of the PINCH-1-binding ankyrin repeat domain of ILK but not that of a PINCH-1-binding defective mutant form of the ankyrin domain effectively inhibited the formation of the PINCH-1-ILK-alpha-parvin complex. Disruption of the PINCH-1-ILK-alpha-parvin complex significantly reduced the podocyte-matrix adhesion and foot process formation. Furthermore, a marked increase of apoptosis in the podocytes in which the assembly of the PINCH-1-ILK-alpha-parvin complex was compromised was detected. Inhibition of ILK with a small compound inhibitor also altered podocyte cytoskeleton and increased apoptosis. Finally, it is shown that alpha-parvin is phosphorylated in podocytes. Mutations at the alpha-parvin N-terminal proline-directed serine phosphorylation sites reduced its complex formation with ILK and resulted in defects in podocyte adhesion, architecture, and survival. These results provide important evidence for a crucial role of the PINCH-1-ILK-alpha-parvin complex in the control of podocyte adhesion, morphology, and survival.
CD133+ Tumor Initiating Cells in a Syngenic Murine Model of Pancreatic Cancer Respond to Minnelide
Authors: Sulagna Banerjee, Alice Nomura, Veena Sangwan, Rohit Chugh, Vikas Dudeja, Selwyn M. Vickers, Ashok Saluja
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Pancreatic adenocarcinoma is the fourth leading cause for cancer-related mortality with a survival rate of less than 5%. Late diagnosis and lack of effective chemotherapeutic regimen contribute to these grim survival statistics. Relapse of any tumor is largely attributed to the presence of tumor-initiating cells (TIC) or cancer stem cells (CSC). These cells are considered as hurdles to cancer therapy as no known chemotherapeutic compound is reported to target them. Thus, there is an urgent need to develop a TIC-targeted therapy for pancreatic cancer. Experimental Design: We isolated CD133+ cells from a spontaneous pancreatic ductal adenocarcinoma mouse model and studied both surface expression, molecular markers of pancreatic TICs. We also studied tumor initiation properties by implanting low numbers of CD133+ cells in immune competent mice. Effect of Minnelide, a drug currently under phase I clinical trial, was studied on the tumors derived from the CD133+ cells. Results: Our study showed for the first time that CD133+ population demonstrated all the molecular markers for pancreatic TIC. These cells initiated tumors in immunocompetent mouse models and showed increased expression of prosurvival and proinvasive proteins compared to the CD133− non-TIC population. Our study further showed that Minnelide was very efficient in downregulating both CD133− and CD133+ population in the tumors, resulting in a 60% decrease in tumor volume compared with the untreated ones. Conclusion: As Minnelide is currently under phase I clinical trial, its evaluation in reducing tumor burden by decreasing TIC as well as non-TIC population suggests its potential as an effective therapy. Clin Cancer Res; 20(9); 2388–99. ©2014 AACR.
The rate of curative intended therapy against recurrent lung cancer before and after introduction of a CT-based follow-up program
Authors: Niels-Chr. G. Hansen
Journal: European Respiratory Journal (2013)

A post-therapy follow-up program with visits and CT every 3 months for two years and then every 6 months for three years was gradually implemented in Denmark from 2010 to 2011. To evaluate the effects a population based quality assurance analysis has been performed. All 1587 lung cancer patients from the 10 municipalities of Funen (484,500 inhabitants) recorded in the Danish Lung Cancer Registry in the 4-year period from July 1, 2008 were included. Data concerning diagnosis and treatment of relapse were extracted from hospital records in February 2013. Curative intended primary treatment had been possible in 444 patients: 256 had a resection +/- chemo- and/or radiotherapy (16.1%), while 188 had radiotherapy +/- chemotherapy (11.8%). Recurrent lung cancer has since been found in 100 subjects from the first two years (period A), where most patients were not offered a regular follow-up with CT, while 86 recurrent cases have been found in patients from the last two years (period B). A second curative intended treatment has been given to 5 out of 49 patients (10.2%) with recurrent lung cancer after surgery in period A and to 12 patients out of 32 (37.5%) with relapse after surgery in period B (p = 0.005, Fisher9s Exact Test). The rate of curative treatment in patients with relapse after radiotherapy did not change from period A to B: 11.8% vs. 13.0%. The different development for the treatment types may be explained by the fact that patients from Funen - treated by surgery before 2011 - usually had no hospital based follow-up, while most patients treated by radiotherapy were followed by an oncology department with clinical examinations and chest X-rays.
Phenylmethimazole Decreases Toll-Like Receptor 3 and Noncanonical Wnt5a Expression in Pancreatic Cancer and Melanoma Together with Tumor Cell Growth and Migration
Authors: Anthony L. Schwartz, Ramiro Malgor, Eric Dickerson, Ashani T. Weeraratna, Andrzej Slominski, Jacobo Wortsman, Norikazu Harii, Aimee D. Kohn, Randall T. Moon, Frank L. Schwartz, Douglas J. Goetz, Leonard D. Kohn, Kelly D. McCall
Journal: Clinical Cancer Research (2009)

To evaluate whether (a) Wnt5a expression in pancreatic cancer and malignant melanoma cells might be associated with constitutive levels of Toll-like receptor 3 (TLR3) and/or TLR3 signaling; (b) phenylmethimazole (C10), a novel TLR signaling inhibitor, could decrease constitutive Wnt5a and TLR3 levels together with cell growth and migration; and (c) the efficacy of C10 as a potential inhibitor of pancreatic cancer and malignant melanoma cell growth in vivo.We used a variety of molecular biology techniques including but not limited to PCR, Western blotting, and ELISA to evaluate the presence of constitutively activated TLR3/Wnt5a expression and signaling. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-based technology and scratch assays were used to evaluate inhibition of cell growth and migration, respectively. TLR3 regulation of cell growth was confirmed using small interfering RNA technology. Nude and severe combined immunodeficient mice were implanted with human pancreatic cancer and/or melanoma cells and the effects of C10 on tumor growth were evaluated.We show that constitutive TLR3 expression is associated with constitutive Wnt5a in human pancreatic cancer and malignant melanoma cell lines, that C10 can decrease constitutive TLR3/Wnt5a expression and signaling, suggesting that they are interrelated signal systems, and that C10 inhibits growth and migration in both of these cancer cell lines. We also report that C10 is effective at inhibiting human pancreatic cancer and malignant melanoma tumor growth in vivo in nude or severe combined immunodeficient mice and associate this with inhibition of signal transducers and activators of transcription 3 activation.C10 may have potential therapeutic applicability in pancreatic cancer and malignant melanoma.
Barrett Esophagus and Risk of Esophageal Cancer
Authors: Stuart Jon Spechler
Journal: JAMA (2013)

Barrett esophagus, a complication of gastroesophageal reflux disease (GERD), predisposes patients to esophageal adenocarcinoma, a tumor that has increased in incidence more than 7-fold over the past several decades. Controversy exists regarding the issues of endoscopic screening and surveillance for Barrett esophagus, treatment for the underlying GERD, and the role of endoscopic eradication therapy.To review current concepts on the pathogenesis, diagnosis, and treatment of Barrett esophagus; to discuss the importance of dysplasia and the role of endoscopic eradication therapy for its treatment; and to review current management guidelines.MEDLINE and the Cochrane Library were searched from 1984 to April 2013. Additional citations were obtained by reviewing references from selected research and review articles.Risk factors for cancer in Barrett esophagus include chronic GERD, hiatal hernia, advanced age, male sex, white race, cigarette smoking, and obesity with an intra-abdominal body fat distribution. The annual risk of esophageal cancer is approximately 0.25% for patients without dysplasia and 6% for patients with high-grade dysplasia. High-quality studies have found no significant differences in cancer incidence for patients with Barrett esophagus whose GERD is treated medically or surgically. Endoscopic eradication therapy with radiofrequency ablation significantly reduces the frequency of progression to cancer for patients with high-grade dysplasia.Endoscopic screening is recommended for patients with multiple risk factors for cancer in Barrett esophagus. For patients with Barrett esophagus without dysplasia, endoscopic surveillance at intervals of 3 to 5 years is recommended, and GERD is treated much as it is for patients without Barrett esophagus. Endoscopic eradication therapy is the treatment of choice for high-grade dysplasia and is an option for low-grade dysplasia. Endoscopic eradication therapy is not recommended for the general population of patients with nondysplastic Barrett esophagus.
Cause-Specific Late Mortality Among 5-Year Survivors of Childhood Cancer: The Childhood Cancer Survivor Study
Authors: A. C. Mertens, Q. Liu, J. P. Neglia, K. Wasilewski, W. Leisenring, G. T. Armstrong, L. L. Robison, Y. Yasui
Journal: JNCI Journal of the National Cancer Institute (2008)

The proportion of pediatric and adolescent cancer patients surviving 5 years has increased during the past four decades. This growing population of survivors remains at risk for disease- and treatment-associated late mortality. A total of 20 483 five-year survivors of childhood and adolescent cancer diagnosed between January 1, 1970, and December 31, 1986, and enrolled in the Childhood Cancer Survivor Study (CCSS) were included in a National Death Index search for deaths occurring between January 1, 1979, and December 31, 2002. Treatment information was abstracted from primary medical records. Survival probabilities, standardized mortality ratios (SMRs), and absolute excess risks were calculated for overall and cause-specific deaths. Diagnosis- and sex-specific survival probabilities were estimated by the product-limit method. All statistical tests were two-sided. Among the CCSS cohort, 2821 (13.8%) 5-year survivors had died by the end of the follow-up period. The cause of death was obtained for 2534 individuals, with 57.5% of deaths attributed to recurrent disease. Estimated probability of survival 30 years from diagnosis was 82%. When compared with the US population, the absolute excess risk of death from any cause was 7.36 deaths per 1000 person-years. The overall SMR was 8.4 (95% confidence interval [CI] = 8.0 to 8.7). Increases in cause-specific mortality were seen for deaths due to subsequent malignancy (SMR = 15.2, 95% CI = 13.9 to 16.6) and cardiac (SMR = 7.0, 95% CI = 5.9 to 8.2), pulmonary (SMR = 8.8, 95% CI = 6.8 to 11.2), and other medical (SMR = 2.6, 95% CI = 2.3 to 3.0) causes. At 20 years of follow-up (25 years after first cancer diagnosis), the death rate due to a subsequent malignancy exceeded that due to all other causes. Our extended follow-up of 5-year survivors of pediatric and adolescent cancer indicates that excess mortality persists long after diagnosis. Continued observation is needed to further define lifetime risk and to determine the potential contribution of chronic health conditions and modifiable health behaviors.
Continuous measures of driving performance on an advanced office-based driving simulator can be used to predict simulator task failure in patients with obstructive sleep apnoea syndrome
Authors: Dipansu Ghosh, Samantha L Jamson, Paul D Baxter, Mark W Elliott
Journal: Thorax (2012)

<h3>Introduction</h3> Some patients with obstructive sleep apnoea syndrome are at higher risk of being involved in road traffic accidents. It has not been possible to identify this group from clinical and polysomnographic information or using simple simulators. We explore the possibility of identifying this group from variables generated in an advanced PC-based driving simulator. <h3>Methods</h3> All patients performed a 90 km motorway driving simulation. Two events were programmed to trigger evasive actions, one subtle and an alert driver should not crash, while for the other, even a fully alert driver might crash. Simulator parameters including standard deviation of lane position (SDLP) and reaction times at the veer event (VeerRT) were recorded. There were three possible outcomes: ‘fail’, ‘indeterminate’ and ‘pass’. An exploratory study identified the simulator parameters predicting a ‘fail’ by regression analysis and this was then validated prospectively. <h3>Results</h3> 72 patients were included in the exploratory phase and 133 patients in the validation phase. 65 (32%) patients completed the run without any incidents, 45 (22%) failed, 95 (46%) were indeterminate. Prediction models using SDLP and VeerRT could predict ‘fails’ with a sensitivity of 82% and specificity of 96%. The models were subsequently confirmed in the validation phase. <h3>Conclusions</h3> Using continuously measured variables it has been possible to identify, with a high degree of accuracy, a subset of patients with obstructive sleep apnoea syndrome who fail a simulated driving test. This has the potential to identify at-risk drivers and improve the reliability of a clinician9s decision-making.
Avoiding fetal loss
Authors: Hema Bashyam
Journal: The Journal of Experimental Medicine (2007)

![Graphic][1] 

By day 11 of a Leiden pregnancy, a fetus with paternal mutations in anticoagulant genes (left) is more decayed than its sibling (right). A pregnancy disorder that leads to an early loss of the fetus is linked to mutations that increase the mother's tendency to form blood