tbuckley/cabot-search huggingface dataset:
Prognostic Model for Predicting Survival of Patients With Metastatic Urothelial Cancer Treated With Cisplatin-Based Chemotherapy
Authors: Andrea B. Apolo, Irina Ostrovnaya, Susan Halabi, Alexia Iasonos, George K. Philips, Jonathan E. Rosenberg, Jamie Riches, Eric J. Small, Matthew I. Milowsky, Dean F. Bajorin
Journal: JNCI Journal of the National Cancer Institute (2013)

A prognostic model that predicts overall survival (OS) for metastatic urothelial cancer (MetUC) patients treated with cisplatin-based chemotherapy was developed, validated, and compared with a commonly used Memorial Sloan-Kettering Cancer Center (MSKCC) risk-score model. Data from 7 protocols that enrolled 308 patients with MetUC were pooled. An external multi-institutional dataset was used to validate the model. The primary measurement of predictive discrimination was Harrell's c-index, computed with 95% confidence interval (CI). The final model included four pretreatment variables to predict OS: visceral metastases, albumin, performance status, and hemoglobin. The Harrell's c-index was 0.67 for the four-variable model and 0.64 for the MSKCC risk-score model, with a prediction improvement for OS (the U statistic and its standard deviation were used to calculate the two-sided P = .002). In the validation cohort, the c-indices for the four-variable and the MSKCC risk-score models were 0.63 (95% CI = 0.56 to 0.69) and 0.58 (95% CI = 0.52 to 0.65), respectively, with superiority of the four-variable model compared with the MSKCC risk-score model for OS (the U statistic and its standard deviation were used to calculate the two-sided P = .02).
Uremia Alters HDL Composition and Function
Authors: Michael Holzer, Ruth Birner-Gruenberger, Tatjana Stojakovic, Dalia El-Gamal, Veronika Binder, Christian Wadsack, Akos Heinemann, Gunther Marsche
Journal: Journal of the American Society of Nephrology (2011)

Functional impairment of HDL may contribute to the excess cardiovascular mortality experienced by patients with renal disease, but the effect of advanced renal disease on the composition and function of HDL is not well understood. Here, we used mass spectrometry and biochemical analyses to study alterations in the proteome and lipid composition of HDL isolated from patients on maintenance hemodialysis. We identified a significant increase in the amount of acute phase protein serum amyloid A1, albumin, lipoprotein-associated phospholipase A2, and apoC-III composing uremic HDL. Furthermore, uremic HDL contained reduced phospholipid and increased triglyceride and lysophospholipid. With regard to function, these changes impaired the ability of uremic HDL to promote cholesterol efflux from macrophages. In summary, the altered composition of HDL in renal disease seems to inhibit its cardioprotective properties. Assessing HDL composition and function in renal disease may help identify patients at increased risk for cardiovascular disease.
Transgenic and Infectious Animal Models of HIV-Associated Nephropathy
Authors: Paul Rosenstiel, Ali Gharavi, Vivette D'Agati, Paul Klotman
Journal: Journal of the American Society of Nephrology (2009)

HIV-associated nephropathy (HIVAN) is a major cause of HIV-related morbidity and mortality. Transgenic and infectious models of HIVAN faithfully recapitulate the human disease and are important tools in advancing our understanding of disease pathogenesis, genetic susceptibility, and therapeutic intervention beyond the inhibition of viral replication. This review discusses the available transgenic murine models and infectious models of HIVAN in mice, rats, nonhuman primates, and felines. Particular emphasis is given to cell type–specific HIV expression as well as partial HIV genome expression used to map HIV-1 Nef and Vpr as pathologic determinants.
“Bystander” Chest Compressions and Assisted Ventilation Independently Improve Outcome From Piglet Asphyxial Pulseless “Cardiac Arrest”
Authors: Robert A. Berg, Ronald W. Hilwig, Karl B. Kern, Gordon A. Ewy
Journal: Circulation (2000)

Bystander cardiopulmonary resuscitation (CPR) without assisted ventilation may be as effective as CPR with assisted ventilation for ventricular fibrillatory cardiac arrests. However, chest compressions alone or ventilation alone is not effective for complete asphyxial cardiac arrests (loss of aortic pulsations). The objective of this investigation was to determine whether these techniques can independently improve outcome at an earlier stage of the asphyxial process.After induction of anesthesia, 40 piglets (11.5+/-0.3 kg) underwent endotracheal tube clamping (6.8+/-0.3 minutes) until simulated pulselessness, defined as aortic systolic pressure <50 mm Hg. For the 8-minute "bystander CPR" period, animals were randomly assigned to chest compressions and assisted ventilation (CC+V), chest compressions only (CC), assisted ventilation only (V), or no bystander CPR (control group). Return of spontaneous circulation occurred during the first 2 minutes of bystander CPR in 10 of 10 CC+V piglets, 6 of 10 V piglets, 4 of 10 CC piglets, and none of the controls (CC+V or V versus controls, P<0.01; CC+V versus CC and V combined, P=0.01). During the first minute of CPR, arterial and mixed venous blood gases were superior in the 3 experimental groups compared with the controls. Twenty-four-hour survival was similarly superior in the 3 experimental groups compared with the controls (8 of 10, 6 of 10, 5 of 10, and 0 of 10, P<0.05 each).Bystander CPR with CC+V improves outcome in the early stages of apparent pulseless asphyxial cardiac arrest. In addition, this study establishes that bystander CPR with CC or V can independently improve outcome.
[296] DOWN-REGULATION OF SURVIVIN IN GROWTH INHIBITION OF HEPATOMA CELLS INDUCED BY SELECTIVE CYCLOOXYGENASE-2 INHIBITOR
Authors: I.H. Song, E.Y. Kim, M.J. Kim, S.Y. Yun, B.H. Kim, J.C. Kim, S.B. Kim, J.E. Shin, H.J. Kim
Journal: Journal of Hepatology (2007)
Impact of immunosuppressant therapy on early recurrence of hepatocellular carcinoma after liver transplantation
Authors: Ju-Yeun Lee, Yul Hee Kim, Nam-Joon Yi, Hyang Sook Kim, Hye Suk Lee, Byung Koo Lee, Hyeyoung Kim, Young Rok Choi, Geun Hong, Kwang-Woong Lee, Kyung-Suk Suh
Journal: Clinical and Molecular Hepatology (2014)

Background/Aims The most commonly used immunosuppressant therapy after liver transplantation (LT) is a combination of tacrolimus and steroid. Basiliximab induction has recently been introduced; however, the most appropriate immunosuppression for hepatocellular carcinoma (HCC) patients after LT is still debated. Methods Ninety-three LT recipients with HCC who took tacrolimus and steroids as major immunosuppressants were included. Induction with basiliximab was implemented in 43 patients (46.2%). Mycophenolate mofetil (MMF) was added to reduce the tacrolimus dosage (n=28, 30.1%). The 1-year tacrolimus exposure level was 7.2 ± 1.3 ng/mL (mean ± SD). Results The 1- and 3-year recurrence rates of HCC were 12.9% and 19.4%, respectively. Tacrolimus exposure, cumulative steroid dosages, and MMF dosages had no impact on HCC recurrence. Induction therapy with basiliximab, high alpha fetoprotein (AFP; >400 ng/mL) and protein induced by vitamin K absence/antagonist-II (PIVKA-II; >100 mAU/mL) levels, and microvascular invasion were significant risk factors for 1-year recurrence (P<0.05). High AFP and PIVKA-II levels, and positive 18fluoro-2-deoxy-d-glucose positron-emission tomography findings were significantly associated with 3-year recurrence (P<0.05). Conclusions Induction therapy with basiliximab, a strong immunosuppressant, may have a negative impact with respect to early HCC recurrence (i.e., within 1 year) in high-risk patients. Keywords: Immunosuppression; Basiliximab; Microvascular invasion; PIVKA-II; AFP; 18F-PET scan
The mechanism of the effect of aspirin on human platelets. I. Acetylation of a particulate fraction protein.
Authors: G J Roth, P W Majerus
Journal: Journal of Clinical Investigation (1975)

Aspirin (acetylsalicylic acid) inhibits platelet prostaglandin synthesis and the ADP- and collagen-induced platelet release reaction. The mechanism of the inhibitory effect is unknown but may involve protein acetylation, since aspirin acetylates a variety of substrates, including platelet protein. We have examined the relationship between protein acetylation and aspirin's physiologic effect on platelets. Suspensions of washed human platelets were incubated at 37 degrees C with (3H)aspirin, and incorporation of radioactivity into protein was analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Exposure to (acetyl-3H)aspirin but not (aromatic ring-3H)aspirin resulted in radioactive labeling of three platelet proteins, suggesting that the drug acetylates these three proteins. The acetylation of two of the proteins (located in the supernatant fraction) was not saturable, implying that these reactions may not be physiologically significant. Acetylation of the third protein, approximate mol wt 85,000 (located in the particulate fraction), saturated at an aspirin concentration of 30 muM and was complete within 20 min. Platelets prepared from aspirin-treated donors did not incorporate any (acetyl-3H)aspirin radioactivity into the particulate protein for 2 days after drug treatment and did not show full pretreatment uptake of radioactivity for 12 days thereafter. The course of increasing incorporation of (acetyl-3H)aspirin radioactivity parralleled that of platelet turnover. Therefore, in addition to its saturability, acetylation of the particulate fraction protein by aspirin was permanent. In two respects, the inhibition of platelet function by aspirin correlates well with the aspirin-mediated acetylation of the particulate fraction protein. Both persist for the life-span of the aspirin-treated platelet, and both occur at a similar saturating aspirin concentration. The evidence suggests that the physiologic effect of aspirin on human platelets is produced by acetylation of a single protein located in the particulate fraction. The acetylated protein may be related to cyclo-oxygenase, the prostaglandin G2 biosynthetic enzyme.
Somatic Chromosome Abnormalities in the Lungs of Patients with Pulmonary Arterial Hypertension
Authors: Micheala A. Aldred, Suzy A. Comhair, Marileila Varella-Garcia, Kewal Asosingh, Weiling Xu, George P. Noon, Patricia A. Thistlethwaite, Rubin M. Tuder, Serpil C. Erzurum, Mark W. Geraci, Christopher D. Coldren
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Vascular remodeling in pulmonary arterial hypertension (PAH) involves proliferation and migration of endothelial and smooth muscle cells, leading to obliterative vascular lesions. Previous studies have indicated that the endothelial cell proliferation is quasineoplastic, with evidence of monoclonality and instability of short DNA microsatellite sequences. Objectives: To assess whether there is larger-scale genomic instability.Methods: We performed genome-wide microarray copy number analysis on pulmonary artery endothelial cells and smooth muscle cells isolated from the lungs of patients with PAH.Measurements and Main Results: Mosaic chromosomal abnormalities were detected in PAEC cultures from five of nine PAH lungs but not in normal (n = 8) or disease control subjects (n = 5). Fluorescent in situ hybridization analysis confirmed the presence of these abnormalities in vivo in two of three cases. One patient harbored a germline mutation of BMPR2, the primary genetic cause of PAH, and somatic loss of chromosome-13, which constitutes a second hit in the same pathway by deleting Smad-8. In two female subjects with mosaic loss of the X chromosome, methylation analysis showed that the active X was deleted. One subject also showed completely skewed X-inactivation in the nondeleted cells, suggesting the pulmonary artery endothelial cell population was clonal before the acquisition of the chromosome abnormality.Conclusions: Our data indicate a high frequency of genetically abnormal subclones within PAH lung vessels and provide the first definitive evidence of a second genetic hit in a patient with a germline BMPR2 mutation. We propose that these chromosome abnormalities may confer a growth advantage and thus contribute to the progression of PAH.
Phosphorylation of Caveolin-1 Regulates Oxidant–Induced Pulmonary Vascular Permeability via Paracellular and Transcellular Pathways
Authors: Yu Sun, Guochang Hu, Xiumei Zhang, Richard D. Minshall
Journal: Circulation Research (2009)

Rationale: Oxidants are important signaling molecules known to increase endothelial permeability, although the mechanisms underlying permeability regulation are not clear. Objective: To define the role of caveolin-1 in the mechanism of oxidant-induced pulmonary vascular hyperpermeability and edema formation. Methods and Results: Using genetic approaches, we show that phosphorylation of caveolin-1 Tyr14 is required for increased pulmonary microvessel permeability induced by hydrogen peroxide (H 2 O 2 ). Caveolin-1–deficient mice ( cav-1 −/− ) were resistant to H 2 O 2 -induced pulmonary vascular albumin hyperpermeability and edema formation. Furthermore, the vascular hyperpermeability response to H 2 O 2 was completely rescued by expression of caveolin-1 in cav-1 −/− mouse lung microvessels but was not restored by the phosphorylation-defective caveolin-1 mutant. The increase in caveolin-1 phosphorylation induced by H 2 O 2 was dose-dependently coupled to both increased 125 I-albumin transcytosis and decreased transendothelial electric resistance in pulmonary endothelial cells. Phosphorylation of caveolin-1 following H 2 O 2 exposure resulted in the dissociation of vascular endothelial cadherin/β-catenin complexes and resultant endothelial barrier disruption. Conclusions: Caveolin-1 phosphorylation–dependent signaling plays a crucial role in oxidative stress-induced pulmonary vascular hyperpermeability via transcellular and paracellular pathways. Thus, caveolin-1 phosphorylation may be an important therapeutic target for limiting oxidant-mediated vascular hyperpermeability, protein-rich edema formation, and acute lung injury.
Weight Loss Strategies for Adolescents
Authors: David S. Ludwig
Journal: JAMA (2012)

With prevalence approaching 20% in the United States, adolescent obesity has become a common problem for patients, parents, and clinicians. Obese adolescents may experience physical and psychosocial complications, as illustrated by the case of Ms K, a 14-year-old girl with a body mass index of 40. Unfortunately, the effectiveness of pediatric obesity treatment is modest in younger children and declines in older children and adolescents, and few interventions involving adolescents have produced significant long-term weight loss. Nevertheless, novel strategies to alter energy balance have shown preliminary evidence of benefit in clinical trials, including a diet focused on food quality rather than fat restriction and a lifestyle approach to encourage enjoyable physical activity throughout the day rather than intermittent exercise. Parents can have an important influence on weight-related behaviors in adolescents despite typically complicated emotional dynamics at this age, especially through the use of noncoercive methods. A key parenting practice applicable to children of all ages is to create a protective environment in the home, substituting nutritious foods for unhealthful ones and facilitating physical activities instead of sedentary pursuits. Other behaviors that may promote successful long-term weight management include good sleep hygiene, stress reduction, and mindfulness. Ultimately, the obesity epidemic can be attributed to changes in the social environment that hinder healthful lifestyle habits, and prevention will require a comprehensive public health strategy.
Annexin A2 is involved in antiphospholipid antibody-mediated pathogenic effects in vitro and in vivo
Authors: Zurina Romay-Penabad, Maria Guadalupe Montiel-Manzano, Tuya Shilagard, Elizabeth Papalardo, Gracie Vargas, Arun B. Deora, Michael Wang, Andrew T. Jacovina, Ethel Garcia-Latorre, Elba Reyes-Maldonado, Katherine A. Hajjar, Silvia S. Pierangeli
Journal: Blood (2009)
Use of Whole-Exome Sequencing to Determine the Genetic Basis of Multiple Mitochondrial Respiratory Chain Complex Deficiencies
Authors: Robert W. Taylor, Angela Pyle, Helen Griffin, Emma L. Blakely, Jennifer Duff, Langping He, Tania Smertenko, Charlotte L. Alston, Vivienne C. Neeve, Andrew Best, John W. Yarham, Janbernd Kirschner, Ulrike Schara, Beril Talim, Haluk Topaloglu, Ivo Baric, Elke Holinski-Feder, Angela Abicht, Birgit Czermin, Stephanie Kleinle, Andrew A. M. Morris, Grace Vassallo, Grainne S. Gorman, Venkateswaran Ramesh, Douglass M. Turnbull, Mauro Santibanez-Koref, Robert McFarland, Rita Horvath, Patrick F. Chinnery
Journal: JAMA (2014)

<h3>Importance</h3> Mitochondrial disorders have emerged as a common cause of inherited disease, but their diagnosis remains challenging. Multiple respiratory chain complex defects are particularly difficult to diagnose at the molecular level because of the massive number of nuclear genes potentially involved in intramitochondrial protein synthesis, with many not yet linked to human disease. <h3>Objective</h3> To determine the molecular basis of multiple respiratory chain complex deficiencies. <h3>Design, Setting, and Participants</h3> We studied 53 patients referred to 2 national centers in the United Kingdom and Germany between 2005 and 2012. All had biochemical evidence of multiple respiratory chain complex defects but no primary pathogenic mitochondrial DNA mutation. Whole-exome sequencing was performed using 62-Mb exome enrichment, followed by variant prioritization using bioinformatic prediction tools, variant validation by Sanger sequencing, and segregation of the variant with the disease phenotype in the family. <h3>Results</h3> Presumptive causal variants were identified in 28 patients (53%; 95% CI, 39%-67%) and possible causal variants were identified in 4 (8%; 95% CI, 2%-18%). Together these accounted for 32 patients (60% 95% CI, 46%-74%) and involved 18 different genes. These included recurrent mutations in<i>RMND1, AARS2</i>, and<i>MTO1</i>, each on a haplotype background consistent with a shared founder allele, and potential novel mutations in 4 possible mitochondrial disease genes (<i>VARS2, GARS, FLAD1</i>, and<i>PTCD1</i>). Distinguishing clinical features included deafness and renal involvement associated with<i>RMND1</i>and cardiomyopathy with<i>AARS2</i>and<i>MTO1.</i>However, atypical clinical features were present in some patients, including normal liver function and Leigh syndrome (subacute necrotizing encephalomyelopathy) seen in association with<i>TRMU</i>mutations and no cardiomyopathy with founder<i>SCO2</i>mutations. It was not possible to confidently identify the underlying genetic basis in 21 patients (40%; 95% CI, 26%-54%). <h3>Conclusions and Relevance</h3> Exome sequencing enhances the ability to identify potential nuclear gene mutations in patients with biochemically defined defects affecting multiple mitochondrial respiratory chain complexes. Additional study is required in independent patient populations to determine the utility of this approach in comparison with traditional diagnostic methods.
Support for a Monophyletic Lemuriformes: Overcoming Incongruence Between Data Partitions
Authors: K. Stanger-Hall, C. W. Cunningham
Journal: Molecular Biology and Evolution (1998)

The Malagasy lemurs (Lemuriformes), represented today by 32 extant species (Mittermeier et al. 1994), are thought to have diverged approximately 60 MYA from their last common ancestor with the Lorisiformes in Africa and Asia (Yoder et al. 1996). Despite a great deal of morphological and molecular data, the family-level relationships—and even the monophyly—of the Lemuriformes remain controversial (e.g., Tattersall and Schwartz 1974; Cartmill 1975; Szalay 1975; Dene et al. 1976; Sarich and Cronin 1976; Dene, Goodman, and Prychodko 1980; Schwartz and Tattersall 1985; MacPhee and Cartmill 1986; Adkins and Honeycutt 1994; Yoder 1994; Del Pero et al. 1995; Porter et al. 1995; Yoder et al. 1996; Yoder, Vilgalys, and Ruvolo 1996; Stanger-Hall 1997). In this paper, we focus on resolving a remarkable pattern of incongruence between codon positions found in two mitochondrial DNA genes, cytochrome b (Cyt b) (Yoder, Vilgalys, and Ruvolo 1996) and cytochrome c oxidase subunit II (COII) (Adkins and Honeycutt 1994). To test the hypothesis that first and second codon positions of these genes are misleading in their support for a diphyletic Lemuriformes (Yoder, Vilgalys, and Ruvolo 1996), we collected partial sequences of the mitochondrial large ribosomal subunit (16S) from 17 species and subspecies of the Lemuriformes. Our sequences represented the 39 portions of the gene (33%), which are known to be far more conserved than the 59 portions (Hillis and Dixon 1991). This study represents the largest taxon sampling to date of the Lemuriformes for any gene. We chose the 16S gene, because, as a mitochondrial gene, it is guaranteed to have had the same history as the two protein-coding genes, but, as a ribosomal gene, it presumably operates under different selective constraints. As many taxa as possible were analyzed in an effort to resolve the long deep branches found in previous analyses with fewer taxa. After analyzing the 16S gene by itself, we used an iterative procedure to investigate whether the incongruence between data partitions is aggravated by inadequate phylogenetic reconstruction methods (Cunningham 1997). Three different phylogenetic reconstruction models were applied to the data using PAUP* 4.0d63 (written by D. L. Swofford, Smithsonian Institution): the best-fit model under maximum likelihood (ML), equally weighted parsimony, and six-parameter parsimony. The
Correlation of Osteopontin Protein Expression and Pathological Stage across a Wide Variety of Tumor Histologies
Authors: Domenico Coppola, Marianna Szabo, David Boulware, Patrick Muraca, Marwan Alsarraj, Ann F. Chambers, Timothy J. Yeatman
Journal: Clinical Cancer Research (2004)

Osteopontin (OPN) is an integrin-binding protein overexpressed in various experimental models of malignancy and appears to be involved in tumorigenesis and metastasis. Although various studies have assessed OPN protein levels in several tumor types, a broad survey of OPN expression in human neoplasia under the same experimental conditions has not been carried out.We used immunohistochemistry to detect OPN in a selection of 350 human tumors and 113 normal tissues, from a variety of body sites, using stage-oriented human cancer tissue arrays. Tumors included malignancies from breast (26), ovary (22), endometrium (14), esophagus (10), stomach (11), pancreas (16), bile duct (1), liver (9), colon (20), kidney (53), bladder (33), prostate (28), head and neck (60), salivary glands (14), lung (17), skin (6), and brain (10).High cytoplasmic OPN staining was observed in 100% of gastric carcinomas, 85% of colorectal carcinomas, 82% of transitional cell carcinomas of the renal pelvis, 81% of pancreatic carcinomas, 72% of renal cell carcinomas, 71% of lung and endometrial carcinomas, 70% of esophageal carcinomas, 58% of squamous cell carcinomas of the head and neck, and 59% of ovarian carcinomas. Although OPN expression was identified in a good number of bladder, prostate, and brain tumors, the majority of 6 skin cancers, 11 of 14 salivary gland cancers, 2 thyroid carcinomas, and 23 of 26 breast cancers revealed low OPN positivity or were negative. When considering all sites, OPN expression significantly correlated with tumor stage (Spearman's correlation coefficient, P = 0.0002). OPN score and stage were also significantly correlated for specific cancer sites including bladder (P = 0.01), colon (P = 0.004), kidney (P = 0.0001), larynx (P = 0.035), mouth (P = 0.046), and salivary gland (P = 0.011).This study reports the broad distribution of OPN in human tumors from different body sites, suggesting involvement of this protein in tumor formation. The strong correlation between pathological stage and OPN across multiple tumor types suggests a role for OPN in tumor progression.