tbuckley/cabot-search huggingface dataset:
Genomics of Loa loa, a Wolbachia-free filarial parasite of humans
Authors: Christopher A Desjardins, Gustavo C Cerqueira, Jonathan M Goldberg, Julie C Dunning Hotopp, Brian J Haas, Jeremy Zucker, José M C Ribeiro, Sakina Saif, Joshua Z Levin, Lin Fan, Qiandong Zeng, Carsten Russ, Jennifer R Wortman, Doran L Fink, Bruce W Birren, Thomas B Nutman
Journal: Nature Genetics (2013)

Thomas Nutman and colleagues report the draft genome of the filarial pathogen Loa loa, the African eyeworm. They also report coverage of two other filarial pathogens, Wuchereria bancrofti and Onchocerca volvulus. Unlike most filariae, L. loa lacks an obligate intracellular Wolbachia endosymbiont, and comparative genomic analyses suggest that the L. loa genome does not contain new metabolic synthesis or transport pathways compared to other filariae. Loa loa, the African eyeworm, is a major filarial pathogen of humans. Unlike most filariae, L. loa does not contain the obligate intracellular Wolbachia endosymbiont. We describe the 91.4-Mb genome of L. loa and that of the related filarial parasite Wuchereria bancrofti and predict 14,907 L. loa genes on the basis of microfilarial RNA sequencing. By comparing these genomes to that of another filarial parasite, Brugia malayi, and to those of several other nematodes, we demonstrate synteny among filariae but not with nonparasitic nematodes. The L. loa genome encodes many immunologically relevant genes, as well as protein kinases targeted by drugs currently approved for use in humans. Despite lacking Wolbachia, L. loa shows no new metabolic synthesis or transport capabilities compared to other filariae. These results suggest that the role of Wolbachia in filarial biology is more subtle than previously thought and reveal marked differences between parasitic and nonparasitic nematodes.
The Spectrum of Mutations in <i>TSC1</i> and <i>TSC2</i> in Women with Tuberous Sclerosis and Lymphangiomyomatosis
Authors: GALINA D. STRIZHEVA, THOMAS CARSILLO, WARREN D. KRUGER, EUGENE J. SULLIVAN, JAY H. RYU, ELIZABETH PETRI HENSKE
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Lymphangiomyomatosis (LAM) is a progressive and often fatal interstitial lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. LAM is of unusual interest biologically because it affects almost exclusively young women. LAM can occur as an isolated disorder (sporadic LAM) or in association with tuberous sclerosis complex (TSC). Because only a minority of women with TSC develops symptomatic LAM, we hypothesized that a relationship might exist between the type of germline TSC1 or TSC2 gene mutation and the risk of developing LAM. We examined all 41 exons of the TSC2 gene and 21 coding exons of the TSC1 gene for mutations in a group of 14 women with both TSC and LAM using single-strand conformation polymorphism analysis. Seven mutations were found in TSC2 and one in TSC1. Of the seven patients with TSC2 mutations, two had the same in-frame exon 40 deletion and one had an exon 41 missense change. We conclude that germline mutations in the extreme carboxy-terminus of tuberin can result in LAM. Further studies will be required to determine whether mutations in exons 40 and 41 are associated with an increased incidence and/or severity of LAM in women with TSC.
Microarray Analysis of Colorectal Cancer Stromal Tissue Reveals Upregulation of Two Oncogenic miRNA Clusters
Authors: Naohiro Nishida, Makoto Nagahara, Tetsuya Sato, Koshi Mimori, Tomoya Sudo, Fumiaki Tanaka, Kohei Shibata, Hideshi Ishii, Kenichi Sugihara, Yuichiro Doki, Masaki Mori
Journal: Clinical Cancer Research (2012)

Cancer stroma plays an important role in the progression of cancer. Although alterations in miRNA expression have been explored in various kinds of cancers, the expression of miRNAs in cancer stroma has not been explored in detail.Using a laser microdissection technique, we collected RNA samples specific for epithelium or stroma from 13 colorectal cancer tissues and four normal tissues, and miRNA microarray and gene expression microarray were carried out. The expression status of miRNAs was confirmed by reverse transcriptase PCR. Furthermore, we investigated whether miRNA expression status in stromal tissue could influence the clinicopathologic factors.Oncogenic miRNAs, including two miRNA clusters, miR-17-92a and miR-106b-25 cluster, were upregulated in cancer stromal tissues compared with normal stroma. Gene expression profiles from cDNA microarray analyses of the same stromal tissue samples revealed that putative targets of these miRNA clusters, predicted by Target Scan, such as TGFBR2, SMAD2, and BMP family genes, were significantly downregulated in cancer stromal tissue. Downregulated putative targets were also found to be involved in cytokine interaction and cellular adhesion. Importantly, expression of miR-25 and miR-92a in stromal tissues was associated with a variety of clinicopathologic factors.Oncogenic miRNAs were highly expressed in cancer stroma. Although further validation is required, the finding that stromal miRNA expression levels were associated with clinicopathologic factors suggests the possibility that miRNAs in cancer stroma are crucially involved in cancer progression.
Extensive Chromosomal Breaks Are Induced by Tamoxifen and Estrogen in DNA Repair-Deficient Cells
Authors: Aki Mizutani, Takashi Okada, Shinya Shibutani, Eiichiro Sonoda, Helfrid Hochegger, Chikako Nishigori, Yoshiki Miyachi, Shunichi Takeda, Mitsuyoshi Yamazoe
Journal: Cancer Research (2004)

Abstract Tamoxifen (TAM) possesses antiestrogen activity and is widely used for the treatment or prevention of breast cancer. However, it is also carcinogenic in human uterus and rat liver, highlighting the profound complexity of its actions. To explore the molecular mechanisms of TAM-induced mutagenesis, we analyzed the effects of this drug on gene-disrupted chicken B lymphocyte (DT40) clones deficient in various DNA repair pathways. Rad18, Rev3, and Polκ are involved in translesion DNA synthesis (TLS), which facilitates recovery from replication blocks on damaged template strands. DT40 cells deficient in TLS were found to be hypersensitive to TAM, exhibiting an increase in chromosomal breaks. Furthermore, these mutants were also hypersensitive to 4-hydroxyestradiol, a physiological metabolite of estrogen. These data suggest a contribution of TLS to the prevention of chromosomal breaks by TAM and estrogen, and they therefore indicate that such error-prone DNA synthesis underlies mutagenesis induced by these agents.
In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia.
Authors: G L Vega, S M Grundy
Journal: Journal of Clinical Investigation (1986)

The causes of primary moderate hypercholesterolemia are not understood, but some patients have reduced fractional clearance rates (FCRs) for low density lipoproteins (LDL). This could be due to either decreased activity of LDL receptors or to a defect in structure (or composition) of LDL that reduces its affinity for receptors. To distinguish between these causes, simultaneous turnover rates of autologous and normal homologous LDL were determined in 15 patients with primary moderate hypercholesterolemia. In 10, turnover rates of both types of LDL were indistinguishable, which indicated that autologous LDL was cleared as efficiently as normal homologous LDL. In five others, FCRs for autologous LDL were significantly lower than for homologous LDL. Two of the latter five were treated with mevinolin, and although FCRs for both types of LDL rose during treatment, differences in FCRs between the two types of LDL persisted. In these five patients, autologous LDL appeared to be a poor ligand for LDL receptors.
Scientists challenge companies' dubious marketing claims
Authors: Adrian O'Dowd
Journal: BMJ (2007)

Young scientists have challenged 11 big companies over their marketing claims about the health benefits of their products, ranging from yogurts to spa treatments, which have been described as “extraordinary.”

These 11 named companies are making “unproven and pseudoscientific” claims about their products, according to a report funded by Sense About Science, a charity that promotes good science and evidence for the public.

In the report There Goes the Science Bit: A Guide to Standing up for Science for Early Career Researchers , the authors say that they decided it was time to question some of the claims and see …
Physical and functional association of the high affinity immunoglobulin G receptor (Fc gamma RI) with the kinases Hck and Lyn.
Authors: A V Wang, P R Scholl, R S Geha
Journal: The Journal of Experimental Medicine (1994)

The high affinity immunoglobulin G (IgG) receptor Fc gamma RI (CD64) is expressed constitutively on monocytes and macrophages, and is inducible on neutrophils. Fc gamma RI has recently been shown to be associated with the signal transducing gamma subunit of the high-affinity IgE receptor (Fc epsilon RI gamma). Induction of cytoplasmic protein tyrosine phosphorylation by Fc gamma RI cross-linking is known to be important in mediating Fc gamma RI-coupled effector functions. Recently, syk has been implicated in this role. We now report that the src-type kinases hck and lyn are physically and functionally associated with Fc gamma RI. Hck and lyn coimmunoprecipitated with Fc gamma RI from detergent lysates of normal human monocytes and of the monocytic line THP-1. Hck and lyn showed rapidly increased phosphorylation and increased exogenous substrate kinase activity after cross-linking of Fc gamma RI. These results demonstrate both physical and functional association of the Fc gamma RI/Fc epsilon RI gamma receptor complex with hck and lyn, and suggest a potential signal transducing role for these kinases in monocyte/macrophage activation.
Getting from Genes to Function in Lung Disease
Authors: Carole Ober, Atul J. Butte, Jack A. Elias, A. Jake Lusis, Weiniu Gan, Susan Banks-Schlegel, David Schwartz
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Section:ChooseTop of pageAbstract <<SESSION 1: DATA INTEGRATI...SESSION 2: SYSTEMS GENETI...SESSION 3A: FUNCTIONAL VA...SESSION 3B: FUNCTIONAL VA...SESSION 4: INTEGRATION AC...ReferencesCITING ARTICLES
The Hydra Phenomenon of Cancer: Why Tumors Recur Locally after Microscopically Complete Resection
Authors: Michael Höckel, Nadja Dornhöfer
Journal: Cancer Research (2005)

Abstract After surgical resection with microscopically clear margins, solid malignant tumors recur locally in up to 50%. Although the effect of a local tumor recurrence on the overall survival may be low in common cancers such as carcinoma of the breast or prostate, the affected patients suffer from exacerbated fear and the burden of the secondary treatment. With some tumor entities such as carcinoma of the uterine cervix or carcinoma of the head and neck, a local recurrence indicates incurability in the majority of cases. The pathomechanisms of local tumor spread and relapse formation are still unclear and comparatively little research has been devoted to their elucidation. Through the analysis of clinical and molecular data, we propose the concept of two pathogenetically and prognostically different local relapse types (i) in situ recurrences that arise in the residual organ/organ system not involved in the surgery for the primary tumor and (ii) scar recurrences that develop at the site of previous tumor resection. Whereas field cancerization, the monoclonal or multiclonal displacement of normal epithelium by a genetically altered but microscopically undistinguishable homologue, may explain the origin of in situ recurrences, most scar recurrences are regarded as the result of the interaction of minimal residual microscopically occult cancer with the surgical wound environment inside a developmentally defined tissue or organ compartment. The therapeutic implications derived from these concepts and areas of future research aimed to reduce local relapses are discussed in this perspective.
Response to Comments on "The Predictive Capacity of Personal Genome Sequencing"
Authors: Bert Vogelstein, Nicholas J. Roberts, Joshua T. Vogelstein, Giovanni Parmigiani, Kenneth W. Kinzler, Victor E. Velculescu
Journal: Science Translational Medicine (2012)

The power of personal genome sequencing to elucidate disease pathogenesis will ensure that it will become an essential tool in medical practice, but recognizing its limitations for improving public health will minimize false expectations and foster the most fruitful investigations.
Myocardial injury and induction of arrhythmia by direct current shock delivered via endocardial catheters in dogs.
Authors: B B Lerman, J L Weiss, B H Bulkley, L C Becker, M L Weisfeldt
Journal: Circulation (1984)

Although electrical ablation of ventricular tachycardia via percutaneous catheters has been recently accomplished in human beings, little is known of its pathologic or arrhythmogenic effects. We studied 21 open-chest anesthetized dogs in which an endocardial electrode catheter was percutaneously introduced into the left ventricle. Direct current (DC) shock was delivered by a standard defibrillator through the distal electrode to a back paddle. Cross-sectional two-dimensional echocardiographic studies were performed in the plane of the catheter (confirmed by epicardial metal beads), and blood flow was determined by the microsphere technique before DC shock and when the animals were killed 2 to 8 days later. Of 11 dogs receiving a total of 100 to 400 J, only three survived 48 hr compared with nine of 10 receiving 50 J and all three control dogs. Holter monitoring demonstrated sustained ventricular tachycardia (VT) (greater than or equal to 30 sec) in all 11 dogs monitored (six received greater than or equal to 100 J), beginning within 5 hr of the DC shock; three control dogs had no VT. Two dogs that died suddenly while being monitored showed ventricular fibrillation. Histologic examination revealed hemorrhagic contraction band necrosis in the shock zone, a type of injury similar to that observed in reperfusion necrosis. Necrosis of the left ventricle was 0.5% to 5%. There was no significant difference in necrosis between dogs receiving 100 J or more and those receiving 50 J (2.5 vs 1.7 g; p greater than .10). Percent systolic thickening determined in eight equally divided regions around the left ventricle showed no difference between the shock zone, perishock zone, or remote normal zone in dogs receiving 50 J.(ABSTRACT TRUNCATED AT 250 WORDS)
Tropical respiratory medicine. 4. Acute tropical infections and the lung.
Authors: S Johnson, R Wilkinson, R N Davidson
Journal: Thorax (1994)

Imported diseases are increasingly common and may present in many ways.A number of infections which are classically associated with non-pulmonary manifestations but which may cause acute pulmonary disease and thus pre- sent to chest physicians are described. Falciparum malaria and respiratory failureIn severe Plasmodiumfalciparum malaria acute respiratory failure'-5 may occur.It is relatively uncommon and generally the patient will have an additional complication such as cerebral malaria.Acute respiratory failure is rarely seen in African children, but is more common in south east Asian adults and non-immune whites.Characteristically it occurs 2-3 days into treatment when the peripheral parasit- aemia is falling.It is heralded by the develop- ment of tachypnoea, orthopnoea, hypoxia, and cough.Inspiratory crackles and frothy sputum may be present, and the chest radiograph shows interstitial and alveolar oedema with a normal size heart (fig 1).In one series, seven of 11 patients with this complication of falci- parum malaria died5 despite aggressive treat- ment.Whilst frequently referred to in the literature as pulmonary oedema, the most detailed haemodynamic study' found the con-
Rapid electrical stimulation of contraction modulates gap junction protein in neonatal rat cultured cardiomyocytes
Authors: Noriko Inoue, Tomoko Ohkusa, Tomoko Nao, Jong-Kook Lee, Tomo Matsumoto, Yuji Hisamatsu, Takashi Satoh, Masafumi Yano, Kenji Yasui, Itsuo Kodama, Masunori Matsuzaki
Journal: Journal of the American College of Cardiology (2004)
Long-term results of Intergroup RTOG 91–11: A phase III trial to preserve the larynx—Induction cisplatin/5-FU and radiation therapy versus concurrent cisplatin and radiation therapy versus radiation therapy
Authors: A. A. Forastiere, M. Maor, R. S. Weber, T. Pajak, B. Glisson, A. Trotti, J. Ridge, J. Ensley, C. Chao, J. Cooper
Journal: Journal of Clinical Oncology (2006)

5517 Background: The 2-year results of Intergroup RTOG 91–11 were published in 2003 (NEJM 349:2091–8,2003). We now present the 5-year results (after median follow-up for surviving patients of 6.9 years) of 515 eligible pts with resectable stage III or IV (excluding T1 and high volume T4), cancer of the glottic or supraglottic larynx. Methods: Patients were randomized to induction cisplatin/5-FU (CF) with responders then receiving RT (I+RT) (n = 173); or concurrent cisplatin (100 mg/m 2 q 21 days × 3) and RT (CRT) (n = 171); or RT alone (R) (n = 171). Laryngectomy was performed for &lt; partial response to induction CF, for persistent/recurrent disease or for laryngeal dysfunction. Results: At 5 years, laryngectomy-free survival (LFS) was significantly better with either I+RT (44.6%, p = 0.011) or CRT (46.6%, p = 0.011) compared to R (33.9%). There was no difference in LFS between I+RT and CRT (p = 0.98). Laryngeal preservation (LP) was significantly better with CRT (83.6%) compared to I+RT (70.5%, p = 0.0029) or R (65.7%, p = 0.00017). Local-regional control (LRC) was significantly better with CRT (68.8%) compared to I+RT (54.9%, p = 0.0018) or R (51%, p = 0.0005). I+RT compared to R for LP and LRC showed no significant difference (p = 0.37 and 0.62, respectively). The distant metastatic rate was low (I+RT 14.3%, CRT 13.2%, R 22.3%) with a trend (p ∼0.06) for benefit from chemotherapy. Disease-free survival (DFS) was significantly better with either I+RT (38.6%, p = 0.016) or CRT (39%, p = 0.0058) compared to R (27.3%). Overall survival rates were similar for the first 5 years (I+RT 59.2%, CRT 54.6%, R 53.5%); thereafter I+RT had a non-significant lower death rate. Compared to CRT, significantly more pts in the R group died of their cancer (34% vs 58.3%, p = 0.0007); the rate for I+RT was 43.8%. Conclusion: These 5-year results differ from the 2-year analysis by a significant improvement in LFS now seen for both I+RT and CRT treatments compared to R. For the endpoints of LP and LRC, CRT is still the superior treatment with no advantage seen to the addition of induction CF to R. There is no significant difference in overall survival. [Table: see text]
Carcinogenicity of tetrachlorvinphos, parathion, malathion, diazinon, and glyphosate
Authors: Kathryn Z Guyton, Dana Loomis, Yann Grosse, Fatiha El Ghissassi, Lamia Benbrahim-Tallaa, Neela Guha, Chiara Scoccianti, Heidi Mattock, Kurt Straif
Journal: The Lancet Oncology (2015)
<i>KRAS</i>Mutation Is an Important Predictor of Resistance to Therapy with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer
Authors: Erminia Massarelli, Marileila Varella-Garcia, Ximing Tang, Ana C. Xavier, Natalie C. Ozburn, Diane D. Liu, Benjamin N. Bekele, Roy S. Herbst, Ignacio I. Wistuba
Journal: Clinical Cancer Research (2007)

EGFR gene mutations and increased EGFR copy number have been associated with favorable response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) in patients with non-small-cell lung cancer (NSCLC). In contrast, KRAS mutation has been shown to predict poor response to such therapy. We tested the utility of combinations of these three markers in predicting response and survival in patients with NSCLC treated with EGFR-TKIs.Patients with advanced NSCLC treated with EGFR-TKI with available archival tissue specimens were included. EGFR and KRAS mutations were analyzed using PCR-based sequencing. EGFR copy number was analyzed using fluorescence in situ hybridization.The study included 73 patients, 59 of whom had all three potential markers successfully analyzed. EGFR mutation was detected in 7 of 71 patients (9.8%), increased EGFR copy number in 32 of 59 (54.2%), and KRAS mutation in 16 of 70 (22.8%). EGFR mutation (P<0.0001) but not increased EGFR copy number (P=0.48) correlated with favorable response. No survival benefit was detected in patients with either of these features. KRAS mutation correlated with progressive disease (P=0.04) and shorter median time to progression (P=0.0025) but not with survival. Patients with both EGFR mutation and increased EGFR copy number had a >99.7% chance of objective response, whereas patients with KRAS mutation with or without increased EGFR copy number had a >96.5% chance of disease progression.KRAS mutation should be included as indicator of resistance in the panel of markers used to predict response to EGFR-TKIs in NSCLC.
Effect of Luminal Atrial Natriuretic Peptide on Chloride Reabsorption in Mouse Cortical Thick Ascending Limb
Authors: CLAIRE BAILLY
Journal: Journal of the American Society of Nephrology (2000)

Insofar as neutral endopeptidase inhibition has afforded evidence for a tubular luminal action of atrial natriuretic peptide (ANP), the present study was undertaken to investigate a possible effect of the peptide on chloride reabsorption (JCl) in thick ascending limb (TAL). Luminal addition of ANP to in vitro microperfused cortical TAL (CTAL) significantly decreased JCl with a threshold and a maximum concentration of 10(-12) M and 10(-9) M, respectively. A similar effect of 10(-9) M ANP was observed in medullary TAL (MTAL). The effect of luminal ANP was significantly reduced by HS-142-1, a specific inhibitor of guanylyl cyclase receptor, and by H-8, a protein kinase G inhibitor, but was not affected by the protein kinase C inhibitor bisindolylmaleimide I. Unexpectedly, the effect of ANP was not additive with that of endothelin (ET), a peptide that was previously shown to decrease JCl in TAL through a calcium-independent, protein kinase C-mediated pathway. Indeed, ET-1 (10(-8) M in the lumen) significantly decreased JCl and prevented a further effect of ANP on the same tubule. Similarly, the decrease of JCl induced by simultaneous addition of ET and ANP was not higher than that obtained with each agent alone. Conversely, the inhibitory effect of ANP was enhanced in the presence of cyclic guanosine monophosphate (cGMP; 10(-6) M in the lumen). ET-1 significantly attenuated the ANP-stimulated generation of cGMP in microdissected CTAL and failed to prevent a further decrease of JCl promoted by a permeant cGMP analogue. It is concluded that luminal ANP decreased Cl reabsorption in mouse CTAL and MTAL. This effect was abrogated by ET-1 as a result of the inhibition of ANP-stimulated cGMP generation.
Dynamics and ethics of comprehensive preimplantation genetic testing: a review of the challenges
Authors: Kristien Hens, Wybo Dondorp, Alan H. Handyside, Joyce Harper, Ainsley J. Newson, Guido Pennings, Christoph Rehmann-Sutter, Guido de Wert
Journal: Human Reproduction Update (2013)

BACKGROUNDGenetic testing of preimplantation embryos has been used for preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS). Microarray technology is being introduced in both these contexts, and whole genome sequencing of blastomeres is also expeted to become possible soon. The amount of extra information such tests will yield may prove to be beneficial for embryo selection, will also raise various ethical issues. We present an overview of the developments and an agenda-setting exploration of the ethical issues.
Acute beta-blockade reduces the extent and severity of myocardial perfusion defects with dipyridamole Tc-99m sestamibi SPECT imaging
Authors: Raymond Taillefer, Alan W Ahlberg, Yasmin Masood, C.Michael White, Isabella Lamargese, Jeffrey F Mather, Carol C McGill, Gary V Heller
Journal: Journal of the American College of Cardiology (2003)