tbuckley/cabot-search huggingface dataset:
Down-regulation of Myeloid Cell Leukemia-1 through Inhibiting Erk/Pin 1 Pathway by Sorafenib Facilitates Chemosensitization in Breast Cancer
Authors: Qingqing Ding, Longfei Huo, Jer-Yen Yang, Weiya Xia, Yongkun Wei, Yong Liao, Chun-Ju Chang, Yan Yang, Chien-Chen Lai, Dung-Fang Lee, Chia-Jui Yen, Yun-Ju Rita Chen, Jung-Mao Hsu, Hsu-Ping Kuo, Chun-Yi Lin, Fuu-Jen Tsai, Long-Yuan Li, Chang-Hai Tsai, Mien-Chie Hung
Journal: Cancer Research (2008)

Abstract Myeloid cell leukemia-1 (Mcl-1), a Bcl-2–like antiapoptotic protein, plays a role in cell immortalization and chemoresistance in a number of human malignancies. A peptidyl-prolyl cis/trans isomerase, Pin1 is involved in many cellular events, such as cell cycle progression, cell proliferation, and differentiation through isomerizing prophosphorylated substrates. It has been reported that down-regulation of Pin1 induces apoptosis, and that Erk phosphorylates and up-regulates Mcl-1; however, the underlying mechanisms for the two phenomena are not clear yet. Here, we showed that Pin 1 stabilizes Mcl-1, which is required for Mcl-1 posphorylation by Erk. First, we found expression of Mcl-1 and Pin1 were positively correlated and associated with poor survival in human breast cancer. We then showed that Erk could phosphorylate Mcl-1 at two consensus residues, Thr 92 and 163, which is required for the association of Mcl-1 and Pin1, resulting in stabilization of Mcl-1. Moreover, Pin1 is also required for the up-regulation of Mcl-1 by Erk activation. Based on this newly identified mechanism of Mcl-1 stabilization, two strategies were used to overcome Mcl-1–mediated chemoresistance: inhibiting Erk by Sorafenib, an approved clinical anticancer drug, or knocking down Pin1 by using a SiRNA technique. In conclusion, the current report not only unravels a novel mechanism to link Erk/Pin1 pathway and Mcl-1–mediated chemoresistance but also provides a plausible combination therapy, Taxol (Paclitaxel) plus Sorafenib, which was shown to be effective in killing breast cancer cells. [Cancer Res 2008;68(15):6109–17]
Why Is Wallerian Degeneration in the CNS So Slow?
Authors: Mauricio E. Vargas, Ben A. Barres
Journal: Annual Review of Neuroscience (2007)

Wallerian degeneration (WD) is the set of molecular and cellular events by which degenerating axons and myelin are cleared after injury. Why WD is rapid and robust in the PNS but slow and incomplete in the CNS is a longstanding mystery. Here we review current work on the mechanisms of WD with an emphasis on deciphering this mystery and on understanding whether slow WD in the CNS could account for the failure of CNS axons to regenerate.
One-Year Clinical Results With the Slow-Release, Polymer-Based, Paclitaxel-Eluting TAXUS Stent
Authors: Gregg W. Stone, Stephen G. Ellis, David A. Cox, James Hermiller, Charles O’Shaughnessy, James Tift Mann, Mark Turco, Ronald Caputo, Patrick Bergin, Joel Greenberg, Jeffrey J. Popma, Mary E. Russell
Journal: Circulation (2004)

The safety and efficacy of the slow-release, polymer-based, paclitaxel-eluting stent after implantation in a broad cross section of de novo coronary lesions at 1 year are unknown.In the TAXUS-IV trial, 1314 patients with single de novo coronary lesions 10 to 28 mm in length, with reference-vessel diameter 2.5 to 3.75 mm, coverable by a single study stent, were prospectively randomized to the slow-release, polymer-based, paclitaxel-eluting TAXUS stent or an identical-appearing bare-metal EXPRESS stent. By actuarial analysis, the TAXUS stent compared with the bare-metal stent reduced the 12-month rates of target-lesion revascularization by 73% (4.4% versus 15.1%, P<0.0001), target-vessel revascularization by 62% (7.1% versus 17.1%, P<0.0001), target-vessel failure by 52% (10.0% versus 19.4%, P<0.0001), and composite major adverse cardiac events by 49% (10.8% versus 20.0%, P<0.0001). The 1-year rates of cardiac death (1.4% versus 1.3%), myocardial infarction (3.5% versus 4.7%), and subacute thrombosis (0.6% versus 0.8%) were similar between the paclitaxel-eluting and control stents, respectively. Between 9 and 12 months, there were significantly fewer myocardial infarctions (0% versus 1.1%, P=0.007), target-vessel revascularizations (2.4% versus 5.8%, P=0.002), and major adverse cardiac events (2.4% versus 6.3%, P=0.0009) in the paclitaxel-eluting stent than in the control stent group, respectively.The relative efficacy reported at 9 months for the polymer-based, paclitaxel-eluting TAXUS stent compared with the EXPRESS stent is preserved and continues to increase at 1 year, with no safety concerns apparent.
Targeting Eukaryotic Translation Initiation Factor 4E (eIF4E) in Cancer
Authors: Andrew C. Hsieh, Davide Ruggero
Journal: Clinical Cancer Research (2010)

Recent advances in understanding the role of eukaryotic translation initiator factor 4E (eIF4E) in tumorigenesis and cancer progression have generated significant interest in therapeutic agents that indirectly or directly target aberrant activation of eIF4E in cancer. Here, we address the general function of eIF4E in translation initiation and cancer, present evidence supporting its role in cancer initiation and progression, and highlight emerging therapeutics that efficiently target hyperactivated eIF4E. In doing so, we also highlight the major differences between these therapeutics that may influence their mechanism of action.
Molecular Pathways: Involvement of <i>Helicobacter pylori</i>–Triggered Inflammation in the Formation of an Epigenetic Field Defect, and Its Usefulness as Cancer Risk and Exposure Markers
Authors: Toshikazu Ushijima, Naoko Hattori
Journal: Clinical Cancer Research (2011)

Infection-associated cancers account for a large proportion of human cancers, and gastric cancer, the vast majority of which is associated with Helicobacter pylori infection, is a typical example of such cancers. Epigenetic alterations are known to occur frequently in gastric cancers, and H. pylori infection has now been shown to induce aberrant DNA methylation in gastric mucosae. Accumulation of aberrant methylation in gastric mucosae produces a field for cancerization, and methylation levels correlate with gastric cancer risk. H. pylori infection induces methylation of specific genes, and such specificity is determined by the epigenetic status in normal cells, including the presence of H3K27me3 and RNA polymerase II (active or stalled). Specific types of inflammation, such as that induced by H. pylori infection, are important for methylation induction, and infiltration of monocytes appears to be involved. The presence of an epigenetic field defect is not limited to gastric cancers and is observed in various types of cancers. It provides translational opportunities for cancer risk diagnosis incorporating life history, assessment of past exposure to carcinogenic factors, and cancer prevention.
Thyrocyte-specific Gq/G11 deficiency impairs thyroid function and prevents goiter development
Authors: Jukka Kero, Kashan Ahmed, Nina Wettschureck, Sorin Tunaru, Tim Wintermantel, Erich Greiner, Günther Schütz, Stefan Offermanns
Journal: Journal of Clinical Investigation (2007)

The function of the adult thyroid is regulated by thyroid-stimulating hormone (TSH), which acts through a G protein-coupled receptor. Overactivation of the TSH receptor results in hyperthyroidism and goiter. The Gs-mediated stimulation of adenylyl cyclase-dependent cAMP formation has been regarded as the principal intracellular signaling mechanism mediating the action of TSH. Here we show that the Gq/G11-mediated signaling pathway plays an unexpected and essential role in the regulation of thyroid function. Mice lacking the alpha subunits of Gq and G11 specifically in thyroid epithelial cells showed severely reduced iodine organification and thyroid hormone secretion in response to TSH, and many developed hypothyroidism within months after birth. In addition, thyrocyte-specific Galphaq/Galpha11-deficient mice lacked the normal proliferative thyroid response to TSH or goitrogenic diet, indicating an essential role of this pathway in the adaptive growth of the thyroid gland. Our data suggest that Gq/G11 and their downstream effectors are promising targets to interfere with increased thyroid function and growth.
Anti-β1-adrenergic receptor autoantibodies are potent stimulators of the ERK1/2 pathway in cardiac cells
Authors: A TUTOR, P PENELA, F MAYORJR
Journal: Cardiovascular Research (2007)

Objective Antibodies specific for the β1-adrenergic receptor (β1AR) are highly prevalent in patients with idiopathic dilated cardiomyopathy (DCM) and known to contribute to the pathogenesis of heart failure, though the precise molecular mechanisms involved are largely unknown.
Genetic Sources of Subcomponents of Event-Related Potential in the Dimension of Psychosis Analyzed From the B-SNIP Study
Authors: Balaji Narayanan, Lauren E. Ethridge, Kasey O’Neil, Sabra Dunn, Ian Mathew, Neeraj Tandon, Vince D. Calhoun, Gualberto Ruaño, Mohan Kocherla, Andreas Windemuth, Brett A. Clementz, Carol A. Tamminga, John A. Sweeney, Matcheri S. Keshavan, Godfrey D. Pearlson
Journal: American Journal of Psychiatry (2015)

Biological risk factors underlying psychosis are poorly understood. Biological underpinnings of the dimension of psychosis can be derived using genetic associations with intermediate phenotypes such as subcomponents of auditory event-related potentials (ERPs). Various ERP subcomponent abnormalities in schizophrenia and psychotic bipolar disorder are heritable and are expressed in unaffected relatives, although studies investigating genetic contributions to ERP abnormalities are limited. The authors used a novel parallel independent component analysis (para-ICA) to determine which empirically derived gene clusters are associated with data-driven ERP subcomponents, assuming a complex etiology underlying psychosis.The authors examined the multivariate polygenic association of ERP subcomponents from 64-channel auditory oddball data in 144 individuals with schizophrenia, 210 psychotic bipolar disorder probands, and 95 healthy individuals from the multisite Bipolar-Schizophrenia Network on Intermediate Phenotypes study. Data were reduced by principal components analysis to two target and one standard ERP waveforms. Multivariate association of compressed ERP waveforms with a set of 20,329 single-nucleotide polymorphisms (SNPs) (reduced from a 1-million-SNP array) was examined using para-ICA. Genes associated with SNPs were further examined using pathway analysis tools.Para-ICA identified four ERP components that were significantly correlated with three genetic components. Enrichment analysis revealed complement immune response pathway and multiple processes that significantly mediate ERP abnormalities in psychosis, including synaptic cell adhesion, axon guidance, and neurogenesis.This study identified three genetic components comprising multiple genes mediating ERP subcomponent abnormalities in schizophrenia and psychotic bipolar disorder. The data suggest a possible polygenic structure comprising genes influencing key neurodevelopmental processes, neural circuitry, and brain function mediating biological pathways plausibly associated with psychosis.
THE REACTIONS BETWEEN BACTERIA AND ANIMAL TISSUES UNDER CONDITIONS OF ARTIFICIAL CULTIVATION
Authors: Henry Field Smyth
Journal: The Journal of Experimental Medicine (1916)

The results here reported confirm those of the former papers and strengthen the conclusions drawn therefrom. They may be summarized as follows: Chicken plasma has a marked bactericidal action on Bacillus typhosus, which may be in some slight degree overcome by the presence of growing tissue, especially splenic tissue, in the cultures. On Bacillus dysenterioe this bactericidal action of chicken plasma is present, but much less marked, and the same counteracting action of tissue, especially splenic tissue, is evident. On Bacillus coli verus chicken plasma has little or no bactericidal action. On Bacterium diphtheriticum chicken plasma has a very strong bactericidal action which may be strongly counteracted by the presence of growing tissue in the cultures. In all cases the bactericidal action of the plasma is decidedly diminished by dilution, as shown by the comparative results of these and the cultures formerly reported. The migrating white cells from splenic cultures, or substances closely associated with these cells, have a distinctly bactericidal influence on all organisms tested except Bacillus coli verus. Murphy states that lymphocytes first appear in the general circulation of the chick embryo on the 18th to 20th day, but in my cultures of splenic tissue cells resembling lymphocytes in morphology and behavior begin to appear in cultures of 11 or 12 day spleen and are abundant in cultures of spleen from 14 day or older embryos.
CyberKnife radiosurgery for inoperable stage IA non-small cell lung cancer: 18F-fluorodeoxyglucose positron emission tomography/computed tomography serial tumor response assessment
Authors: Saloomeh Vahdat, Eric K Oermann, Sean P Collins, Xia Yu, Malak Abedalthagafi, Pedro DeBrito, Simeng Suy, Shadi Yousefi, Constanza J Gutierrez, Thomas Chang, Filip Banovac, Eric D Anderson, Giuseppe Esposito, Brian T Collins
Journal: Journal of Hematology & Oncology (2010)

Abstract Objective To report serial 18F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET)/computed tomography (CT) tumor response following CyberKnife radiosurgery for stage IA non-small cell lung cancer (NSCLC). Methods Patients with biopsy-proven inoperable stage IA NSCLC were enrolled into this IRB-approved study. Targeting was based on 3-5 gold fiducial markers implanted in or near tumors. Gross tumor volumes (GTVs) were contoured using lung windows; margins were expanded by 5 mm to establish the planning treatment volumes (PTVs). Doses ranged from 42-60 Gy in 3 equal fractions. 18 F-FDG PET/CT was performed prior to and at 3-6-month, 9-15 months and 18-24 months following treatment. The tumor maximum standardized uptake value (SUV max ) was recorded for each time point. Results Twenty patients with an average maximum tumor diameter of 2.2 cm were treated over a 3-year period. A mean dose of 51 Gy was delivered to the PTV in 3 to 11 days (mean, 7 days). The 30-Gy isodose contour extended an average of 2 cm from the GTV. At a median follow-up of 43 months, the 2-year Kaplan-Meier overall survival estimate was 90% and the local control estimate was 95%. Mean tumor SUV max before treatment was 6.2 (range, 2.0 to 10.7). During early follow-up the mean tumor SUV max remained at 2.3 (range, 1.0 to 5.7), despite transient elevations in individual tumor SUV max levels attributed to peritumoral radiation-induced pneumonitis visible on CT imaging. At 18-24 months the mean tumor SUV max for controlled tumors was 2.0, with a narrow range of values (range, 1.5 to 2.8). A single local failure was confirmed at 24 months in a patient with an elevated tumor SUV max of 8.4. Conclusion Local control and survival following CyberKnife radiosurgery for stage IA NSCLC is exceptional. Early transient increases in tumor SUV max are likely related to radiation-induced pneumonitis. Tumor SUV max values return to background levels at 18-24 months, enhancing 18 F-FDG PET/CT detection of local failure. The value of 18 F-FDG PET/CT imaging for surveillance following lung SBRT deserves further study.
Diagnosing cystic fibrosis in patients with non-diagnostic results: the case for intestinal current measurements
Authors: J. P. Clancy
Journal: Thorax (2010)

Cystic fibrosis (CF) is a well-described genetic disease with characteristic defects in ion transport in disease-affected tissues. CF results from dysfunction of the cystic fibrosis transmembrane conductance regulator protein (CFTR) which is an ATP binding cassette protein that, in addition to chloride channel function, regulates other ion transport pathways such as sodium channels, other chloride channels and bicarbonate transport.1 Diagnosing CF is generally straightforward in patients with classic disease and builds upon these basic ion transport features, with well-defined clinical manifestations combined with elevated sweat chloride values, nasal ion transport abnormalities and/or common CFTR mutations.2 Newborn screening algorithms have added elevated serum immunoreactive trypsinogen levels to the diagnostic pathway (typically prior to symptoms), and together allow healthcare providers to confidently provide diagnostic and prognostic information to the majority of families and patients with CF.3

Unfortunately, there is a spectrum of disorders that have been linked to CFTR dysfunction which may not fulfil the diagnostic criteria for CF. In general, these milder manifestations of CFTR dysfunction can present in numerous ways such as recurrent upper and lower airway respiratory symptoms, pancreatic disease, male infertility, liver disease and vague gastrointestinal symptoms.3–5 Standard CF diagnostic testing may provide information that is conflicting or sits squarely in the ‘grey zone’, with intermediate sweat chloride values (above the normal range but below the CF diagnostic cut-off), nasal potential difference measurements with both CF and non-CF features, inconclusive genetic testing and additional (less specific) clinical measurements that may support …
Therapeutic Consequences from Molecular Biology for Gastrointestinal Stromal Tumor Patients Affected by Neurofibromatosis Type 1
Authors: Chiara Mussi, Hans-Ulrich Schildhaus, Alessandro Gronchi, Eva Wardelmann, Peter Hohenberger
Journal: Clinical Cancer Research (2008)

Patients affected by neurofibromatosis type 1 (NF-1) have an increased risk of developing gastrointestinal stromal tumors (GIST). NF-1-associated GISTs are usually wild type for c-KIT and platelet-derived growth factor receptor-alpha (PDGFR-alpha) mutations and harbor a different oncogenic molecular mechanism. The lack of data on imatinib activity raises the question whether to enroll these patients in clinical trials. We analyzed a large series of NF-1 related GISTs to discuss the therapeutic implications.Clinical, pathologic (IHC to CD34, S100, bcl-2, PDGFRA), and molecular features (exons 9, 11, 13, 14, 17 in c-kit and exons 12, 14, 18 in PDGFRA) of 28 patients were analyzed.The most common site of primary lesions was the small bowel (75%). Twelve patients (43%) had multiple tumors. Most tumors belonged to the high (30.5%) or intermediate risk group for malignant behavior (39%). Three patients developed peritoneal and liver metastases; another four had peritoneal spread only. All tumors were immunohistochemically strongly positive for CD117. Three primary KIT/PDGFRA activating mutations were found. Three metastatic patients treated with imatinib experienced progression, and only one had temporary stable disease. Median survival after starting treatment with imatinib was 21 months.This study is the largest series available and confirms that KIT/PDGFRA mutations in NF-1-associated GISTs are sporadic. Prognosis of metastatic tumors is poor, and imatinib response rate is low. Patients with NF-1-GIST of high or intermediate risk should not be eligible for adjuvant trials of imatinib. Imatinib should not be used in a neoadjuvant intent in these patients, and molecular analysis of activating mutations is strongly recommended.
Persistence of Leukemia-Initiating Cells in a Conditional Knockin Model of an Imatinib-Responsive Myeloproliferative Disorder
Authors: Katherine I. Oravecz-Wilson, Steven T. Philips, Ömer H. Yilmaz, Heather M. Ames, Lina Li, Brendan D. Crawford, Alice M. Gauvin, Peter C. Lucas, Kajal Sitwala, James R. Downing, Sean J. Morrison, Theodora S. Ross
Journal: Cancer Cell (2009)
Preferential rearrangement of V kappa 4 gene segments in pre-B cell lines.
Authors: S L Kalled, P H Brodeur
Journal: The Journal of Experimental Medicine (1990)

Examination of the in vitro V kappa gene rearrangements of murine adult bone marrow-derived pre-B cell lines reveals that 21 of 25 (84%) cell lines have rearranged a member of the V kappa 4 family. In contrast, analysis of two V kappa cDNA libraries prepared from LPS-stimulated adult spleen cells indicates that only 17% of the Ig kappa cDNAs contain sequences belonging to the V kappa 4 gene family. Half of the pre-B cell lines examined also share an 8-kbp BamHI reciprocal product (rp). However, these rp do not involve the same V kappa gene, indicating that conserved BamHI sites exist 3' of some V kappa genes. This rp is also readily detected in DNA from normal adult spleen cells, suggesting that the in vitro rearrangements examined in this study are representative of kappa rearrangements that occur in vivo. We suggest that, unlike the diverse V kappa repertoire expressed by mature B cells, the germline V kappa segments involved in initial rearrangements of the Ig kappa locus are highly restricted, and that an initial V kappa 4 rearrangement is probably followed by other, more random recombination events.
Emergency Treatment of Asthma
Authors: Stephen C. Lazarus
Journal: New England Journal of Medicine (2010)

A 46-year-old woman who has had two admissions to the intensive care unit for asthma during the past year presents with a 4-day history of upper respiratory illness and a 6-hour history of shortness of breath and wheezing. An inhaled corticosteroid has been prescribed, but she takes it only when she has symptoms, which is rarely. She generally uses albuterol twice per day but has increased its use to six to eight times per day for the past 3 days. How should this case be managed in the emergency department?
Mammalian Housekeeping Genes Evolve More Slowly than Tissue-Specific Genes
Authors: Liqing Zhang, Wen-Hsiung Li
Journal: Molecular Biology and Evolution (2004)

Do housekeeping genes, which are turned on most of the time in almost every tissue, evolve more slowly than genes that are turned on only at specific developmental times or tissues? Recent large-scale gene expression studies enable us to have a better definition of housekeeping genes and to address the above question in detail. In this study, we examined 1,581 human-mouse orthologous gene pairs for their patterns of sequence evolution, contrasting housekeeping genes with tissue-specific genes. Our results show that, in comparison to tissue-specific genes, housekeeping genes on average evolve more slowly and are under stronger selective constraints as reflected by significantly smaller values of Ka/Ks. Besides stronger purifying selection, we explored several other factors that can possibly slow down nonsynonymous rates in housekeeping genes. Although mutational bias might slightly slow the nonsynonymous rates in housekeeping genes, it is unlikely to be the major cause of the rate difference between the two types of genes. The codon usage pattern of housekeeping genes does not seem to differ from that of tissue-specific genes. Moreover, contrary to the old textbook concept, we found that ∼74% of the housekeeping genes in our study belong to multigene families, not significantly different from that of the tissue-specific genes (∼70%). Therefore, the stronger selective constraints on housekeeping genes are not due to a lower degree of genetic redundancy.
Response to Temozolomide in Patients With Metastatic Colorectal Cancer With Loss of MGMT Expression: A New Approach in the Era of Personalized Medicine?
Authors: Einat Shacham-Shmueli, Alexander Beny, Ravit Geva, Arye Blachar, Arie Figer, Dan Aderka
Journal: Journal of Clinical Oncology (2011)