tbuckley/cabot-search huggingface dataset:
Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia
Authors: Sharon E. Maynard, Jiang-Yong Min, Jaime Merchan, Kee-Hak Lim, Jianyi Li, Susanta Mondal, Towia A. Libermann, James P. Morgan, Frank W. Sellke, Isaac E. Stillman, Franklin H. Epstein, Vikas P. Sukhatme, S. Ananth Karumanchi
Journal: Journal of Clinical Investigation (2003)

Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF. Additionally, VEGF and PlGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia.
The Protein Import Channel in the Outer Mitosomal Membrane of Giardia intestinalis
Authors: M. J. Dagley, P. Dolezal, V. A. Likic, O. Smid, A. W. Purcell, S. K. Buchanan, J. Tachezy, T. Lithgow
Journal: Molecular Biology and Evolution (2009)

The identification of mitosomes in Giardia generated significant debate on the evolutionary origin of these organelles, whether they were highly reduced mitochondria or the product of a unique endosymbiotic event in an amitochondrial organism. As the protein import pathway is a defining characteristic of mitochondria, we sought to discover a TOM (translocase in the outer mitochondrial membrane) complex in Giardia. A Hidden Markov model search of the Giardia genome identified a Tom40 homologous sequence (GiTom40), where Tom40 is the protein translocation channel of the TOM complex. The GiTom40 protein is located in the membrane of mitosomes in a approximately 200-kDa TOM complex. As Tom40 was derived in the development of mitochondria to serve as the protein import channel in the outer membrane, its presence in Giardia evidences the mitochondrial ancestry of mitosomes.
No Child Left Behind in <i>SDHB</i> Testing for Paragangliomas and Pheochromocytomas
Authors: Joshua D. Schiffman
Journal: Journal of Clinical Oncology (2011)

treatment in advanced non-small-cell lung cancer: A multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 11:521-529, 2010 10. Bradbury PA, Tu D, Seymour L, et al: Economic analysis: Randomized placebo-controlled clinical trial of erlotinib in advanced non-small cell lung cancer. J Natl Cancer Inst 102:298-306, 2010 11. Coate LE, Shepherd FA: Maintenance therapy in advanced non-small cell lung cancer. J Thorac Oncol 5:723-734, 2010
Low miR-145 and high miR-367 are associated with unfavourable prognosis in resected nonsmall cell lung cancer
Authors: Marc Campayo, Alfons Navarro, Nuria Viñolas, Tania Diaz, Rut Tejero, Josep M. Gimferrer, Laureano Molins, Maria L. Cabanas, Jose Ramirez, Mariano Monzo, Ramon Marrades
Journal: European Respiratory Journal (2012)

The transcription factors SRY-related HMG box (SOX)2 and octamer-binding transcription factor (OCT)4 regulate the expression of the miR-302–367 cluster. miR-145 regulates SOX2 and OCT4 translation and p53 regulates miR-145 expression. We analysed the expression of the miR-302–367 cluster and miR-145 and the mutational status of p53 in resected nonsmall cell lung cancer (NSCLC) patients and correlated results with time to relapse (TTR). Tumour and paired normal tissue samples were obtained from 70 NSCLC patients. MicroRNA expression was assessed with TaqMan MicroRNA Assays. p53 exons 5 to 8 were sequenced. miR-145 was downregulated (p&lt;0.0001) and miR-367 was upregulated (p&lt;0.0001) in tumour compared with normal tissue. Mean TTR was 18.4 months for patients with low miR-145 levels and 28.2 months for those with high levels (p=0.015). Mean TTR was 29.1 months for patients with low miR-367 levels and 23.4 months for those with high levels (p=0.048). TTR was shorter for patients with both unfavourable variables (p=0.009). Low miR-145 expression (p=0.049), the combination of unfavourable microRNA levels (p=0.02) and the combination of low miR-145 with p53 mutations (p=0.011) were independent markers of shorter TTR. In conclusion, miR-145 and miR-367 expression could be novel markers for relapse in surgically treated NSCLC. p53 may play a role in modulating miR-145 expression in NSCLC.
Lipids and Renal Disease
Authors: Roberto Trevisan, Alessandro R. Dodesini, Giuseppe Lepore
Journal: Journal of the American Society of Nephrology (2006)

Chronic renal disease is accompanied by characteristic abnormalities of lipid metabolism, which appear as a consequence of nephrotic syndrome or renal insufficiency and are reflected in an altered apolipoprotein profile as well as elevated plasma lipid levels. Experimental and clinical studies have suggested a correlation between the progression of renal disease and dyslipidemia. High cholesterol and triglyceride plasma levels have been demonstrated to be independent risk factors for progression of renal disease in humans. The underlying pathophysiologic mechanisms for the relationship between lipid levels and progression of renal disease are not yet fully understood, although there are data that oxidative stress and insulin resistance may mediate the lipid-induced renal damage. In the animal model, lipid-lowering agents seem to ameliorate glomerular damage, preventing glomerulosclerosis and interstitial fibrosis. Although evidence from clinical studies indicates that statin therapy is associated with significant benefit in individuals with established chronic renal failure, whether lipid reduction can slow the renal functional decline awaits a primary renal outcome lipid-lowering therapy study.
LSC 2013 abstract - Volatile compounds of exhaled breath in lung cancer and lung inflammatory disease
Authors: Agnese Kislina, Liga Balode, Maris Bukovskis, Gunta Strazda, Normunds Jurka, Uldis Kopeika, Liene Logina, Immanuels Taivans
Journal: European Respiratory Journal (2013)

Challenging approach is to try to diagnose lung diseases by analysis of exhaled breath that contains volatile organic compounds (VOCs).   The aims:  of this study was to compare the concentrations of VOCs in exhaled air of lung cancer patients and patients with inflammatory lung diseases and healthy controls.   Materials and methods:  four study groups were formed – 31 patients - lung cancer, 19 with COPD, 11 - pneumonia and 10 healthy volunteers. Before collection of exhaled air patients lungs were washed for 5 minutes with filtered air. Exhaled breath samples were collected on termodesorbtion tubes and later analyzed on gas chromatograph / mass spectrometer.   Results:  Mean concentrations of VOCs are shown in the table.  p  95% CI – 95% confidence interval of mean value   Conclusions:  Exhaled air of lung cancer patients contain less amounts of light spirits and hydrocarbons, compared to controls. VOCs spectrum from patients with lung inflammatory diseases doesn9t differ significantly from normal controls.
HIF-Dependent Antitumorigenic Effect of Antioxidants In Vivo
Authors: Ping Gao, Huafeng Zhang, Ramani Dinavahi, Feng Li, Yan Xiang, Venu Raman, Zaver M. Bhujwalla, Dean W. Felsher, Linzhao Cheng, Jonathan Pevsner, Linda A. Lee, Gregg L. Semenza, Chi V. Dang
Journal: Cancer Cell (2007)
Withanolide D induces apoptosis in leukemia by targeting the activation of neutral sphingomyelinase-ceramide cascade mediated by synergistic activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase
Authors: Susmita Mondal, Chandan Mandal, Rajender Sangwan, Sarmila Chandra, Chitra Mandal
Journal: Molecular Cancer (2010)

Ceramide is an important second messenger that has diverse cellular and biological effect. It is a specific and potent inducer of apoptosis and suppressor of cell growth. In leukemia, chemoresistance generally developed due to deregulated ceramide metabolism. In combinatorial treatment strategies of leukemia, few components have the capability to increases ceramide production. Manipulation in ceramide production by physiological and pharmacological modulators therefore will give additive effect in leukemia chemotherapy.Here, we show that Withanolide D (C4β-C5β,C6β-epoxy-1-oxo-,20β, dihydroxy-20S,22R-witha-2,24-dienolide; WithaD), a pure herbal compound isolated from Withania somnifera could effectively induces apoptosis in a dose and time dependant manner both in myeloid (K562) and lymphoid (MOLT-4) cells being nontoxic to normal lymphocytes and control proliferative cells. WithaD potentially augment ceramide production in these cells. Downstream of ceramide, WithaD acted on MKK group of proteins and significantly increased JNK and p38MAPK phosphorylation. Pharmacological inhibition of p38MAPK and JNK proves their cooperative action on WithaD-induced cell death. Dissecting the cause of ceramide production, we found activation of neutral sphingomyelinase and showed neutral-sphingomyelinase 2 (N-SMase 2) is a critical mediator of WithaD-induced apoptosis. Knockdown of N-SMase 2 by siRNA and inhibitor of N-SMase (GW4869) significantly reduced WithaD-induced ceramide generation and phosphorylation of MKK4 and MKK3/6, whereas phosphorylation of MKK7 was moderately regulated in leukemic cells. Also, both by silencing of N-SMase 2 and/or blocking by GW4869 protects these cells from WithaD-mediated death and suppressed apoptosis, whereas Fumonisin B1, an inhibitor of ceramide synthase, did not have any effect. Additionally, WithaD effectively induced apoptosis in freshly isolated lymphoblasts from patients and the potent cell killing activity was through JNK and p38MAPK activation.Our results demonstrate that WithaD enhance the ceramide accumulation by activating N-SMase 2, modulate phosphorylation of the JNK and p38MAPK and induced apoptosis in both myeloid and lymphoid cells along with primary cells derived from leukemia patients. Taken together, this pure herbal compound (WithaD) may consider as a potential alternative tool with additive effects in conjunction with traditional chemotherapeutic treatment, thereby accelerate the process of conventional drug development.
Searching for the Closest Living Relative(s) of Tetrapods Through Evolutionary Analysis of Mitochondrial and Nuclear Data
Authors: R. Zardoya, Y. Cao, M. Hasegawa, A. Meyer
Journal: Molecular Biology and Evolution (1998)

The phylogenetic relationships of the African lungfish (Protopterus dolloi) and the coelacanth (Latimeria chalumnae) with respect to tetrapods were analyzed using complete mitochondrial genome DNA sequences. A lungfish + coelancanth clade was favored by maximum parsimony (although this result is dependent on which transition:transversion weights are applied), and a lungfish + tetrapod clade was supported by neighbor-joining and maximum-likelihood analyses. These two hypotheses received the strongest statistical and bootstrap support to the exclusion of the third alternative, the coelacanth + tetrapod sister group relationship. All mitochondrial protein coding genes combined favor a lungfish + tetrapod grouping. We can confidently reject the hypothesis that the coelacanth is the closest living relative of tetrapods. When the complete mitochondrial sequence data were combined with nuclear 28S rRNA gene data, a lungfish + coelacanth clade was supported by maximum parsimony and maximum likelihood, but a lungfish + tetrapod clade was favored by neighbor-joining. The seeming conflicting results based on different data sets and phylogenetic methods were typically not statistically strongly supported based on Kishino-Hasegawa and Templeton tests, although they were often supported by strong bootstrap values. Differences in rate of evolution of the different mitochondrial genes (slowly evolving genes such as the cytochrome oxidase and tRNA genes favored a lungfish + coelacanth clade, whereas genes of relatively faster substitution rate, such as several NADH dehydrogenase genes, supported a lungfish + tetrapod grouping), as well as the rapid radiation of the lineages back in the Devonian, rather than base compositional biases among taxa seem to be directly responsible for the remaining uncertainty in accepting one of the two alternate hypotheses.
Genome sequence of ground tit Pseudopodoces humilis and its adaptation to high altitude
Authors: Qingle Cai, Xiaoju Qian, Yongshan Lang, Yadan Luo, Jiaohui Xu, Shengkai Pan, Yuanyuan Hui, Caiyun Gou, Yue Cai, Meirong Hao, Jinyang Zhao, Songbo Wang, Zhaobao Wang, Xinming Zhang, Rongjun He, Jinchao Liu, Longhai Luo, Yingrui Li, Jun Wang
Journal: Genome biology (2013)

The mechanism of high-altitude adaptation has been studied in certain mammals. However, in avian species like the ground tit Pseudopodoces humilis, the adaptation mechanism remains unclear. The phylogeny of the ground tit is also controversial. Using next generation sequencing technology, we generated and assembled a draft genome sequence of the ground tit. The assembly contained 1.04 Gb of sequence that covered 95.4% of the whole genome and had higher N50 values, at the level of both scaffolds and contigs, than other sequenced avian genomes. About 1.7 million SNPs were detected, 16,998 protein-coding genes were predicted and 7% of the genome was identified as repeat sequences. Comparisons between the ground tit genome and other avian genomes revealed a conserved genome structure and confirmed the phylogeny of ground tit as not belonging to the Corvidae family. Gene family expansion and positively selected gene analysis revealed genes that were related to cardiac function. Our findings contribute to our understanding of the adaptation of this species to extreme environmental living conditions. Our data and analysis contribute to the study of avian evolutionary history and provide new insights into the adaptation mechanisms to extreme conditions in animals.
Congenital heart defects in Fgfr2-IIIb and Fgf10 mutant mice
Authors: A MARGUERIE, F BAJOLLE, S ZAFFRAN, N BROWN, C DICKSON, M BUCKINGHAM, R KELLY
Journal: Cardiovascular Research (2006)

Objective Myocardial progenitor cells expressing Fgf10 give rise to the outflow tract and right ventricle of the mammalian heart. In order to define the role of fibroblast growth factor (FGF) signaling in this process we investigated whether Fgf10 or the major Fgf10 receptor Fgfr2-IIIb are required for normal heart development. Methods The cardiac phenotype of Fgf10 and Fgfr2-IIIb mutant mice was analysed by histology, scanning electron microscopy and gene and transgene expression studies. Results Outflow tract formation from Fgf10 expressing progenitor cells occurs normally in Fgf10 mutant embryos and in the majority of Fgfr2-IIIb mutant embryos; a proportion of Fgfr2-IIIb mutant embryos, however, display outflow tract and right ventricular hypoplasia. The predominant cardiac defects in Fgfr2-IIIb mutant embryos are ventricular septal defects associated with overriding aorta or double outlet right ventricle. In addition, loss of Fgfr2-IIIb is associated with ventricular anomalies including a thin myocardial wall, abnormal trabeculation and muscular ventricular septal defects. In contrast, Fgf10 is required to correctly position the heart in the thoracic cavity but not for outflow tract septation. Both Fgf10 and Fgfr2-IIIb mutant embryos lack pulmonary arteries and veins. ConclusionsFgfr2-IIIb and Fgf10 mutant mice have distinct roles during cardiac morphogenesis, although neither gene is essential for outflow tract elongation from Fgf10 expressing progenitor cells. Fgfr2-IIIb and Fgf10 mutant mice provide new models for common components of congenital heart disease.
Cadherin-11 Provides Specific Cellular Adhesion between Fibroblast-like Synoviocytes
Authors: Xavier Valencia, Jonathan M.G. Higgins, Hans P. Kiener, David M. Lee, Theresa A. Podrebarac, Christopher C. Dascher, Gerald F.M. Watts, Emiko Mizoguchi, Barry Simmons, Dhavalkumar D. Patel, Atul K. Bhan, Michael B. Brenner
Journal: The Journal of Experimental Medicine (2004)

Cadherins are integral membrane proteins expressed in tissue-restricted patterns that mediate homophilic intercellular adhesion. During development, they orchestrate tissue morphogenesis and, in the adult, they determine tissue integrity and architecture. The synovial lining is a condensation of fibroblast-like synoviocytes (FLS) and macrophages one to three cells thick. These cells are embedded within the extracellular matrix, but the structure is neither an epithelium nor an endothelium. Previously, the basis for organization of the synovium into a tissue was unknown. Here, we cloned cadherin-11 from human rheumatoid arthritis (RA)-derived FLS. We developed L cell transfectants expressing cadherin-11, cadherin-11 fusion proteins, and anti–cadherin-11 mAb. Cadherin-11 was found to be expressed mainly in the synovial lining by immunohistologic staining of human synovium. FLS adhered to cadherin-11–Fc, and transfection of cadherin-11 conferred the formation of tissue-like sheets and lining-like structures upon fibroblasts in vitro. These findings support a key role for cadherin-11 in the specific adhesion of FLS and in synovial tissue organization and behavior in health and RA.
Self recognition in allogeneic thymic chimeras. Self recognition by T helper cells from thymus-engrafted nude mice is restricted to the thymic H-2 haplotype.
Authors: A Singer, K S Hathcock, R J Hodes
Journal: The Journal of Experimental Medicine (1982)

To examine the possibility that the thymus determines the I region-restricted self-recognition repertoire expressed by T helper (TH) cells, thymic chimeras were constructed by transplanting allogeneic neonatal thymic lobes into congenitally athymic nude mice. Spleen TH cells from the thymic chimeras were themselves of nude host origin but only cooperated with B+ accessory cells of the thymic haplotype for primary in vitro responses to sheep erythrocytes and trinitrophenyl conjugate of keyhole limpet hemocyanin. Thus, these experiments demonstrate that the self-recognition repertoire expressed by TH cells is determined by the H-2 phenotype of the intrathymic environment in which the TH cells had differentiated.
Identifying breast cancer patients at risk for Central Nervous System (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG)
Authors: B.C. Pestalozzi, D. Zahrieh, K.N. Price, S.B. Holmberg, J. Lindtner, J. Collins, D. Crivellari, M.F. Fey, E. Murray, O. Pagani, E. Simoncini, M. Castiglione-Gertsch, R.D. Gelber, A.S. Coates, A. Goldhirsch
Journal: Annals of Oncology (2006)
Are Fire Policies Fair When They Mandate the Use of Chemical Flame Retardants Without Mandating Their Safety Testing?
Authors: Eric M. Hecht, Julien Thomas, David C. Landy
Journal: JAMA Pediatrics (2015)

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Phase I study of the effects of hepatic impairment on the pharmacokinetic (PK) and safety of satraplatin in patients with refractory non-hematologic cancer
Authors: R. F. Setlik, G. Preston, C. B. Jones, J. Sarantopoulos, T. Dufresne, M. E. Petrone, F. E. Nathan, D. Greene, T. Anthony, C. Takemoto
Journal: Journal of Clinical Oncology (2006)

2045 Background: Satraplatin (S) is a third-generation oral platinum analog that has demonstrated activity in the treatment of patients with platinum-sensitive malignancies. A worldwide double-blind, placebo controlled randomized phase III trial evaluating S as 2nd line therapy for HRPC has recently completed enrollment. The current study was designed to determine the effect of hepatic impairment on S pharmacokinetics in patients with refractory cancer, as well as treatment efficacy and toxicity. Methods: S was administered orally at a dose of 80mg/m 2 /day (d) on d1–5 every 35 days. Study groups (cohorts) were defined at 4 levels of hepatic impairment - Group 1 (G1) = control; G2 = Child-Pugh Class A; G3 = Child-Pugh Class B; and Group 4 = Child-Pugh Class C. Results: 19 pts have been enrolled to date (11 M/ 8 F); median age is 57 (range 44–80). Pts with prostate (2), pancreas (4), colorectal (3), adenocystic (2), and 1 each neuroendocrine, hepatocellular, melanoma, breast, ovarian, SCLC, and anal cancers were enrolled. 8 pts were in G1, 3 pts in G2, 4 pts in G3, and 5 pts in G4. Accrual is ongoing in this study with a total of 8 pts planned for each group. The median number of prior regimens was 5 (range 2–8). A total of 35 cycles of S have been given: median 2/pt (range 1–4). 9 pts have completed 2 cycles of S. Hematologic toxicities during the first 2 cycles included grade (G) 3/4 thrombocytopenia in 15 %. There were no cases of G 3/4 neutropenia or anemia. One case of G3 hypokalemia, was reported. Two patients developed acute renal failure; one of which was due to uncontrolled nausea (N) and vomiting (V) and the other was associated with rapid disease progression in the liver. Both were G4 patients. Otherwise, N, V, and diarrhea were mild to moderate, and controlled with oral therapy. Conclusions: S is, in general, well tolerated in patients with mild or moderate liver impairment. Severe thrombocytopenia is the most common side-effect. Of the patients enrolled to date 15% did not have progression of disease. PK data will also be presented. [Table: see text]