tbuckley/cabot-search huggingface dataset:
Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3)
Authors: Kevin J. Leco, Paul Waterhouse, Otto H. Sanchez, Katrina L.M. Gowing, A. Robin Poole, Andrew Wakeham, Tak W. Mak, Rama Khokha
Journal: Journal of Clinical Investigation (2001)

Tissue inhibitors of metalloproteinases regulate ECM degradation by matrix metalloproteinases (MMPs). We have developed a mouse line deficient for tissue inhibitor of metalloproteinases-3 (TIMP-3), the only TIMP known to reside within the ECM. Homozygous Timp-3–null animals develop spontaneous air space enlargement in the lung that is evident at 2 weeks after birth and progresses with age of the animal. As early as 13 months of age animals become moribund. Lung function, measured by carbon monoxide uptake, is impaired in aged null animals. Lungs from aged null animals have reduced abundance of collagen, enhanced degradation of collagen in the peribronchiolar space, and disorganization of collagen fibrils in the alveolar interstitium, but no increase in inflammatory cell infiltration or evidence of fibrosis in comparison with controls. Using in situ zymography, we show that lungs from aged null animals have heightened MMP activity over wild-type and heterozygotic animals. Finally, TIMP-3–null fibroblast cultures demonstrate enhanced destruction of ECM molecules in vitro. We propose that the deletion of TIMP-3 results in a shift of the TIMP/MMP balance in the lung to favor ECM degradation, culminating in incapacitating illness and a shorter life span.
Changes in Brain Function of Depressed Subjects During Treatment With Placebo
Authors: Andrew F. Leuchter, Ian A. Cook, Elise A. Witte, Melinda Morgan, Michelle Abrams
Journal: American Journal of Psychiatry (2002)

It has been proposed that 50%-75% of the efficacy of antidepressant medication represents the placebo effect, since many depressed patients improve when treated with either medication or placebo. This study examined brain function in depressed subjects receiving either active medication or placebo and sought to determine whether quantitative electroencephalography (QEEG) could detect differences in brain function between medication and placebo responders. Both QEEG power and cordance, a new measure that reflects cerebral perfusion and is sensitive to the effect of antidepressant medication, were examined.Fifty-one subjects with major depression were enrolled in one of two independent, 9-week double-blind, placebo-controlled studies in which either fluoxetine (N=24) or venlafaxine (N=27) was the active medication. Serial QEEG recordings were performed during the course of treatment. After 9 weeks, the blind was broken and subjects were classified as medication responders, placebo responders, medication nonresponders, or placebo nonresponders.No significant pretreatment differences in clinical or QEEG measures were found among the four outcome groups. Placebo responders, however, showed a significant increase in prefrontal cordance starting early in treatment that was not seen in medication responders (who showed decreased cordance) or in medication nonresponders or placebo nonresponders (who showed no significant change). There was no significant change in QEEG power during treatment.These findings suggest that "effective" placebo treatment induces changes in brain function that are distinct from those associated with antidepressant medication. If these results are confirmed, cordance may be useful for differentiating between medication and placebo responders.
Assessing Children’s Dietary Pesticide Exposure: Direct Measurement of Pesticide Residues in 24-Hr Duplicate Food Samples
Authors: Chensheng Lu, Frank J. Schenck, Melanie A. Pearson, Jon W. Wong
Journal: Environmental Health Perspectives (2010)

The data presented here are a response to calls for more direct measurements of pesticide residues in foods consumed by children and provide an opportunity to compare direct measures of pesticide residues in foods representing actual consumption with those reported by the U.S. Department of Agriculture Pesticide Data Program.We measured pesticide residues in 24-hr duplicate food samples collected from a group of 46 young children participating in the Children's Pesticide Exposure Study (CPES).Parents were instructed to collect 24-hr duplicate food samples of all conventional fruits, vegetables, and fruit juices equal to the quantity consumed by their children, similarly prewashed/ prepared, and from the same source or batch. Individual or composite food items were analyzed for organophosphate (OP) and pyrethroid insecticide residues.We collected a total of 239 24-hr duplicate food samples collected from the 46 CPES children. We found 14% or 5% of those food samples contained at least one OP or pyrethroid insecticide, respectively. We measured a total of 11 OP insecticides, at levels ranging from 1 to 387 ng/g, and three pyrethroid insecticides, at levels ranging from 2 to 1,133 ng/g, in children's food samples. We found that many of the food items consumed by the CPES children were also on the list of the most contaminated food commodities reported by the Environmental Working Group.The frequent consumption of food commodities with episodic presence of pesticide residues that are suspected to cause developmental and neurological effects in young children supports the need for further mitigation.
Diagnosis and management of antiretroviral-therapy failure in resource-limited settings in sub-Saharan Africa: challenges and perspectives
Authors: Anthony D Harries, Rony Zachariah, Joep J van Oosterhout, Steven D Reid, Mina C Hosseinipour, Vic Arendt, Zengani Chirwa, Andreas Jahn, Erik J Schouten, Kelita Kamoto
Journal: The Lancet Infectious Diseases (2009)
Efficacy and Tolerability of Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Patients With Breast Cancer After Moderately Emetogenic Chemotherapy
Authors: David G. Warr, Paul J. Hesketh, Richard J. Gralla, Hyman B. Muss, Jørn Herrstedt, Peter D. Eisenberg, Harry Raftopoulos, Steven M. Grunberg, Munir Gabriel, Anthony Rodgers, Norman Bohidar, George Klinger, Carolyn M. Hustad, Kevin J. Horgan, Franck Skobieranda
Journal: Journal of Clinical Oncology (2005)

Purpose This is the first study in which the NK 1 -receptor antagonist, aprepitant (APR), was evaluated for the prevention of chemotherapy-induced nausea and vomiting (CINV) with moderately emetogenic chemotherapy. Patients and Methods Eligible breast cancer patients were naive to emetogenic chemotherapy and treated with cyclophosphamide ± doxorubicin or epirubicin. Patients were randomly assigned to either an aprepitant regimen (day 1, APR 125 mg, ondansetron (OND) 8 mg, and dexamethasone 12 mg before chemotherapy and OND 8 mg 8 hours later; days 2 through 3, APR 80 qd) or a control regimen (day 1, OND 8 mg and dexamethasone 20 mg before chemotherapy and OND 8 mg 8 hours later; days 2 through 3, OND 8 mg bid). Data on nausea, vomiting, and use of rescue medication were collected with a self-report diary. The primary efficacy end point was the proportion of patients with complete response, defined as no vomiting and no use of rescue therapy, during 120 hours after initiation of chemotherapy in cycle 1. The secondary end point was the proportion of patients with an average item score higher than 6 of 7 on the Functional Living Index–Emesis questionnaire. Results Of 866 patients randomized, 857 patients (99%) were assessable. Overall complete response was greater with the aprepitant regimen than with the control regimen (50.8% v 42.5%; P = .015). More patients in the aprepitant group reported minimal or no impact of CINV on daily life (63.5% v 55.6%; P = .019). Both treatments were generally well tolerated. Conclusion The aprepitant regimen was more effective than the control regimen for prevention of CINV in patients receiving both an anthracycline and cyclophosphamide.
Acetazolamide and chronic hypoxia: effects on haemorheology and pulmonary haemodynamics
Authors: Aurélien Pichon, Philippe Connes, Patricia Quidu, Dominique Marchant, Julien Brunet, Bernard I. Levy, José Vilar, Innocent Safeukui, Florence Cymbalista, Maxime Maignan, Jean-Paul Richalet, Fabrice Favret
Journal: European Respiratory Journal (2012)

We tested the effect of acetazolamide on blood mechanical properties and pulmonary vascular resistance (PVR) during chronic hypoxia. Six groups of rats were either treated or not treated with acetazolamide (curative: treated after 10 days of hypoxic exposure; preventive: treated before hypoxic exposure with 40 mg·kg −1 ·day −1 ) and either exposed or not exposed to 3 weeks of hypoxia (at altitude &gt;5,500 m). They were then used to assess the role of acetazolamide on pulmonary artery pressure, cardiac output, blood volume, haematological and haemorheological parameters. Chronic hypoxia increased haematocrit, blood viscosity and PVR, and decreased cardiac output. Acetazolamide treatment in hypoxic rats decreased haematocrit (curative by -10% and preventive by -11%), PVR (curative by -36% and preventive by -49%) and right ventricular hypertrophy (preventive -20%), and increased cardiac output (curative by +60% and preventive by +115%). Blood viscosity was significantly decreased after curative acetazolamide treatment (-16%) and was correlated with PVR (r=0.87, p&lt;0.05), suggesting that blood viscosity could influence pulmonary haemodynamics. The fall in pulmonary vascular hindrance (curative by -27% and preventive by -45%) after treatment suggests that acetazolamide could decrease pulmonary vessels remodelling under chronic hypoxia. The effect of acetazolamide is multifactorial by acting on erythropoiesis, pulmonary circulation, haemorheological properties and cardiac output, and could represent a pertinent treatment of chronic mountain sickness.
Gene Expression-Based Prognostic Signatures in Lung Cancer: Ready for Clinical Use?
Authors: J. Subramanian, R. Simon
Journal: JNCI Journal of the National Cancer Institute (2010)

A substantial number of studies have reported the development of gene expression–based prognostic signatures for lung cancer. The ultimate aim of such studies should be the development of well-validated clinically useful prognostic signatures that improve therapeutic decision making beyond current practice standards. We critically reviewed published studies reporting the development of gene expression–based prognostic signatures for non–small cell lung cancer to assess the progress made toward this objective. Studies published between January 1, 2002, and February 28, 2009, were identified through a PubMed search. Following hand-screening of abstracts of the identified articles, 16 were selected as relevant. Those publications were evaluated in detail for appropriateness of the study design, statistical validation of the prognostic signature on independent datasets, presentation of results in an unbiased manner, and demonstration of medical utility for the new signature beyond that obtained using existing treatment guidelines. Based on this review, we found little evidence that any of the reported gene expression signatures are ready for clinical application. We also found serious problems in the design and analysis of many of the studies. We suggest a set of guidelines to aid the design, analysis, and evaluation of prognostic signature studies. These guidelines emphasize the importance of focused study planning to address specific medically important questions and the use of unbiased analysis methods to evaluate whether the resulting signatures provide evidence of medical utility beyond standard of care–based prognostic factors.
New connections in the prokaryotic toxin-antitoxin network: relationship with the eukaryotic nonsense-mediated RNA decay system
Authors: Vivek Anantharaman, L Aravind
Journal: Genome biology (2003)

Several prokaryotic plasmids maintain themselves in their hosts by means of diverse post-segregational cell killing systems. Recent findings suggest that chromosomally encoded copies of toxins and antitoxins of post-segregational cell killing systems - such as the RelE system - might function as regulatory switches under stress conditions. The RelE toxin cleaves ribosome-associated transcripts, whereas another post-segregational cell killing toxin, ParE, functions as a gyrase inhibitor.Using sequence profile analysis we were able unify the RelE- and ParE-type toxins with several families of small, uncharacterized proteins from diverse bacteria and archaea into a single superfamily. Gene neighborhood analysis showed that the majority of these proteins were encoded by genes in characteristic neighborhoods, in which genes encoding toxins always co-occurred with genes encoding transcription factors that are also antitoxins. The transcription factors accompanying the RelE/ParE superfamily may belong to unrelated or distantly related superfamilies, however. We used this conserved neighborhood template to transitively search genomes and identify novel post-segregational cell killing-related systems. One of these novel systems, observed in several prokaryotes, contained a predicted toxin with a PilT-N terminal (PIN) domain, which is also found in proteins of the eukaryotic nonsense-mediated RNA decay system. These searches also identified novel transcription factors (antitoxins) in post-segregational cell killing systems. Furthermore, the toxin Doc defines a potential metalloenzyme superfamily, with novel representatives in bacteria, archaea and eukaryotes, that probably acts on nucleic acids.The tightly maintained gene neighborhoods of post-segregational cell killing-related systems appear to have evolved by in situ displacement of genes for toxins or antitoxins by functionally equivalent but evolutionarily unrelated genes. We predict that the novel post-segregational cell killing-related systems containing a PilT-N terminal domain toxin and the eukaryotic nonsense-mediated RNA decay system are likely to function via a common mechanism, in which the PilT-N terminal domain cleaves ribosome-associated transcripts. The core of the eukaryotic nonsense-mediated RNA decay system has probably evolved from a post-segregational cell killing-related system.
Body Fat Distribution and Breast Cancer in the Framingham Study
Authors: R. Ballard-Barbash, A. Schatzkin, C. L. Carter, W. B. Kannel, B. E. Kreger, R. B. D'Agostino, G. L. Splansky, K. M. Anderson, W. E. Helsel
Journal: JNCI Journal of the National Cancer Institute (1990)

We examined the relation between central body fat distribution and breast cancer in a prospective cohort of women who participated in the Framingham Study. At the baseline examination in 1948, a total of 2,201 women aged 30-62 years were analyzed. An index of central to peripheral body fat (the central adiposity ratio) was calculated from the sum of the trunkal skinfolds (chest, subscapular, and abdominal) divided by the sum of the extremity skinfolds (triceps and thigh). These skinfolds were measured at the fourth examination in 1954. The cohort was followed for up to 28 years and yielded 106 cases of breast cancer. When divided into quartiles based on the central adiposity ratio, only women in the fourth quartile (those with the highest central to peripheral body fat distribution) demonstrated an increased risk for breast cancer. The age- and adiposity-adjusted relative risk estimate for having an increased central adiposity ratio (fourth quartile) compared to lower central adiposity ratios was 1.8 (95% confidence interval, 1.2-2.6). Adjustment for potential confounders of height, parity, and education did not appreciably alter this estimate (1.7, 1.1-2.5). There was no association between degree of adiposity, as measured by the sum of the five skinfolds or by body mass index (weight in kg divided by height in m2), and subsequent breast cancer. The results of this study suggest that increased central to peripheral body fat distribution predicts breast cancer risk independently of the degree of adiposity and may be a more specific marker of a premalignant hormonal pattern than degree of adiposity.
Free radicals trigger TNF?-induced cardioprotection
Authors: S LECOUR, L ROCHETTE, L OPIE
Journal: Cardiovascular Research (2004)

Tumor Necrosis Factor alpha (TNF alpha) induces programmed cell death and contributes to cardiac ischemia/reperfusion injury. Paradoxically, we have recently demonstrated that low doses of TNF alpha can induce cardiac preconditioning (PC). We hypothesized that the production of free radicals participates in this cardioprotective program.Control isolated rat hearts underwent 30 min regional ischemia and 120 min of reperfusion. A second group of hearts received a low dose of TNF alpha (0.5 ng/ml) for 7 min followed by 10 min washout prior to I/R. In other groups, the antioxidant N-2-mercaptopropionyl glycine (MPG) (1 mM) was given for 15 min prior to I/R alone or during TNF alpha perfusion. Infarct size was determined at the end of the reperfusion period. Ventricular catalase and superoxide dismutase activities were assessed as an index of oxidative stress and free radical production was directly measured by the oxidation of 1-hydroxy-3-carboxy-pyrrolidine (CP-H) to paramagnetic 3-carboxy-proxyl (CP.) using electron spin resonance spectroscopy.TNF alpha reduced the infarct/area at risk (I/AAR) ratio (7.2+/-1.7% vs. 36.5+/-1.7% for controls, p<0.05). MPG reduced the cardioprotective effect of TNF alpha (I/AAR ratio: 20.5+/-3.3%, p<0.05). TNF alpha-perfusion increased catalase activity in the ventricles (15.8+/-1.2 I.U./mg for controls vs. 19.9+/-1.1 I.U/mg for TNF alpha, p<0.05). Proof of formation of free radicals was increased CP formation in the coronary effluent during TNF alpha infusion (24.2+/-4.5 for TNF alpha vs. 11.9+/-1.5 arbitrary units for controls, p<0.05), with decreased CP after addition of MPG.Our data provide firm evidence for a production and role of free radicals in TNF alpha-induced cardioprotection.
A Three-microRNA Signature Predicts Responses to Platinum-Based Doublet Chemotherapy in Patients with Lung Adenocarcinoma
Authors: Motonobu Saito, Kouya Shiraishi, Kenji Matsumoto, Aaron J. Schetter, Hiroko Ogata-Kawata, Naoto Tsuchiya, Hideo Kunitoh, Hiroshi Nokihara, Shun-ichi Watanabe, Koji Tsuta, Kensuke Kumamoto, Seiichi Takenoshita, Jun Yokota, Curtis C. Harris, Takashi Kohno
Journal: Clinical Cancer Research (2014)

Abstract Purpose: To examine the clinical utility of intratumor microRNAs (miRNA) as a biomarker for predicting responses to platinum-based doublet chemotherapy in patients with recurring lung adenocarcinoma (LADC). Experimental Design: The expression of miRNAs was examined in LADC tissues surgically resected from patients treated with platinum-based doublet chemotherapy at the time of LADC recurrence. Microarray-based screening of 904 miRNAs followed by quantitative reverse transcription-PCR–based verification in 40 test cohort samples, including 16 (40.0%) responders, was performed to identify miRNAs that are differentially expressed in chemotherapy responders and nonresponders. Differential expression was confirmed in a validation cohort (n = 63 samples), including 18 (28.6%) responders. An miRNA signature that predicted responses to platinum-based doublet chemotherapy was identified and its accuracy was examined by principal component and support vector machine analyses. Genotype data for the TP53-Arg72Pro polymorphism, which is associated with responses to platinum-based doublet chemotherapy, were subsequently incorporated into the prediction analysis. Results: A signature comprising three miRNAs (miR1290, miR196b, and miR135a*) enabled the prediction of a chemotherapeutic response (rather than progression-free and overall survival) with high accuracy in both the test and validation cohorts (82.5% and 77.8%). Examination of the latter was performed using miRNAs extracted from archived formalin-fixed paraffin-embedded tissues. Combining this miRNA signature with the TP53-Arg72Pro polymorphism genotype marginally improved the predictive power. Conclusion: The three-miRNA signature in surgically resected primary LADC tissues may by clinically useful for predicting responsiveness to platinum-based doublet chemotherapy in patients with LADC recurrence. Clin Cancer Res; 20(18); 4784–93. ©2014 AACR.
Effect of Atorvastatin on High-Density Lipoprotein Apolipoprotein A-I Production and Clearance in the New Zealand White Rabbit
Authors: Shirya Rashid, Kristine D. Uffelman, P. Hugh R. Barrett, Gary F. Lewis
Journal: Circulation (2002)

HMG-CoA reductase inhibitors reduce the incidence of cardiovascular disease predominantly by their LDL-lowering effect. Recently, there has been great interest in the pleiotropic effects of statins, which appear to differ among the various agents in this class. Unlike other statins, atorvastatin exhibits a decline in its HDL-raising effect at higher doses in humans. Whether atorvastatin-mediated alterations in HDL turnover in vivo contribute to this effect has not previously been investigated. We therefore studied the effect of atorvastatin on HDL apolipoprotein (apo) A-I production and clearance in normolipidemic male New Zealand White rabbits.Kinetic studies of HDL-apoA-I radiolabeled with 131I were performed in chow-fed rabbits after 3 weeks of atorvastatin treatment of 5 mg x kg(-1) x d(-1) (n=7) versus placebo-treated rabbits (n=7). Our results showed a significantly (P<0.001) more rapid clearance ( approximately 2-fold) of HDL apoA-I in atorvastatin-treated animals compared with the control group (0.121+/-0.012 versus 0.061+/-0.004 pools/h, respectively), accompanied by a lesser 48% increase in the apoA-I production rate (3.84+/-0.38 versus 2.59+/-0.41 mg x kg(-1) x h(-1), P=0.06). Accordingly, plasma apoA-I levels in atorvastatin-treated animals declined significantly (P<0.05, n=8 animals) after 3 weeks of treatment (173.5+/-1.8 mg/dL) from baseline values.These data suggest that the effect on apoA-I levels observed with atorvastatin at higher drug doses in humans may be caused at least in part by enhanced HDL apoA-I catabolism, which is not entirely offset by a concomitant increase in apoA-I production. Whether this finding results from an effect of atorvastatin on HDL particle composition or on receptors involved in circulating HDL holoparticle clearance will require further study.
The Potential Role of Neutrophils in Promoting the Metastatic Phenotype of Tumors Releasing Interleukin-8
Authors: Joseph E. De Larco, Beverly R. K. Wuertz, Leo T. Furcht
Journal: Clinical Cancer Research (2004)

In the last decade, several groups have shown a direct correlation between the inappropriate or ectopic release of interleukin (IL)-8 by tumor cells in vitro and their growth and metastatic potential using in vivo models of tumor growth. IL-8 is a potent neutrophil chemoattractant. Neutrophils, as "early responders" to wounds and infections, release enzymes to remodel the extracellular matrix of the tissues through which they migrate to reach the site of the wound or infection. It is proposed that the host's cellular response to IL-8 released by tumor cells enhances angiogenesis and contributes to tumor growth and progression. The activities released by the responding neutrophils could serve as enablers of tumor cell migration through the extracellular matrix, helping them enter the vasculature and journey to new, metastatic sites. The reactive oxygen species produced by neutrophilic oxidases to kill invading organisms have the potential to interact with tumor cells to attenuate their apoptotic cascade and increase their mutational rate. It is proposed that the increase in metastatic potential of tumors ectopically releasing IL-8 is, in part, attributable to their ability to attract neutrophils. Discussed here are possible mechanisms by which the neutrophils responding to ectopic IL-8 contribute to the in vivo growth, progression, and metastatic potential of tumor cells. Possible targets are also presented for the development of therapies to attenuate the effects of the ectopic IL-8 release by tumor cells.