tbuckley/cabot-search huggingface dataset:
Leflunomide: mode of action in the treatment of rheumatoid arthritis
Authors: F C Breedveld
Journal: Annals of the Rheumatic Diseases (2000)

Leflunomide is a selective inhibitor of de novo pyrimidine synthesis. In phase II and III clinical trials of active rheumatoid arthritis, leflunomide was shown to improve primary and secondary outcome measures with a satisfactory safety profile. The active metabolite of leflunomide, A77 1726, at low, therapeutically applicable doses, reversibly inhibits dihydroorotate dehydrogenase (DHODH), the rate limiting step in the de novo synthesis of pyrimidines. Unlike other cells, activated lymphocytes expand their pyrimidine pool by approximately eightfold during proliferation; purine pools are increased only twofold. To meet this demand, lymphocytes must use both salvage and de novo synthesis pathways. Thus the inhibition of DHODH by A77 1726 prevents lymphocytes from accumulating sufficient pyrimidines to support DNA synthesis. At higher doses, A77 1726 inhibits tyrosine kinases responsible for early T cell and B cell signalling in the G<sub>0</sub>/G<sub>1</sub> phase of the cell cycle. Because the immunoregulatory effects of A77 1726 occur at doses that inhibit DHODH but not tyrosine kinases, the interruption of de novo pyrimidine synthesis may be the primary mode of action. Recent evidence suggests that the observed anti-inflammatory effects of A77 1726 may relate to its ability to suppress interleukin 1 and tumour necrosis factor α selectively over their inhibitors in T lymphocyte/monocyte contact activation. A77 1726 has also been shown to suppress the activation of nuclear factor κB, a potent mediator of inflammation when stimulated by inflammatory agents. Continuing research indicates that A77 1726 may downregulate the glycosylation of adhesion molecules, effectively reducing cell-cell contact activation during inflammation.
A MEK Inhibitor Abrogates Myeloproliferative Disease in <i>Kras</i> Mutant Mice
Authors: Natalya Lyubynska, Matthew F. Gorman, Jennifer O. Lauchle, Wan Xing Hong, Jon K. Akutagawa, Kevin Shannon, Benjamin S. Braun
Journal: Science Translational Medicine (2011)

Inhibiting the Raf/MEK/ERK pathway reverses the harmful effects of oncogenic Kras on hematopoietic differentiation, suggesting a strategy for treating myeloproliferative neoplasms.
Connexin43 Remodeling Caused by Inhibition of Plakophilin-2 Expression in Cardiac Cells
Authors: Eva M. Oxford, Hassan Musa, Karen Maass, Wanda Coombs, Steven M. Taffet, Mario Delmar
Journal: Circulation Research (2007)

Desmosomes and gap junctions are distinct structural components of the cardiac intercalated disc. Here, we asked whether the presence of plakophilin (PKP)2, a component of the desmosome, is essential for the proper function and distribution of the gap junction protein connexin (Cx)43. We used RNA silencing technology to decrease the expression of PKP2 in cardiac cells (ventricular myocytes, as well as epicardium-derived cells) obtained from neonatal rat hearts. We evaluated the content, distribution, and function of Cx43 gap junctions. Our results show that loss of PKP2 expression led to a decrease in total Cx43 content, a significant redistribution of Cx43 to the intracellular space, and a decrease in dye coupling between cells. Separate experiments showed that Cx43 and PKP2 can coexist in the same macromolecular complex. Our results support the notion of a molecular crosstalk between desmosomal and gap junction proteins. The results are discussed in the context of arrhythmogenic right ventricular cardiomyopathy, an inherited disease involving mutations in desmosomal proteins, including PKP2.
Conductances and Selective Permeability of Connexin43 Gap Junction Channels Examined in Neonatal Rat Heart Cells
Authors: Virginijus Valiunas, Feliksas F. Bukauskas, Robert Weingart
Journal: Circulation Research (1997)

Abstract Myocytes from neonatal rat hearts were used to assess the conductive properties of gap junction channels by means of the dual voltage-clamp method. The experiments were carried out on three types (groups) of preparations: (1) induced cell pairs, (2) preformed cell pairs with few gap junction channels (1 to 3 channels), and (3) preformed cell pairs with many channels (100 to 200 channels) after treatment with uncoupling agents such as SKF-525A (75 μmol/L), heptanol (3 mmol/L), and arachidonic acid (100 μmol/L). In group 1, the first opening of a newly formed channel was slow (20 to 65 ms) and occurred 7 to 25 minutes after physical cell contact. The rate of channel insertion was 1.3 channels/min. Associated with a junctional voltage gradient (V j ), the channels revealed multiple conductances, a main open state [γ j (main state)], several substates [γ j (substates)], and a residual state [γ j (residual state)]. On rare occasions, the channels closed completely. The same phenomena were observed in groups 2 and 3. The existence of γ j (residual state) provides an explanation for the incomplete inactivation of the junctional current (I j ) at large values of V j in cell pairs with many gap junction channels. The values of γ j (main state) and γ j (residual state) gained from groups 1, 2, and 3 turned out to be comparable and hence were pooled. The fit of the data to a Gaussian distribution revealed a narrow single peak for both conductances. The values of γ j were dependent on the composition of the pipette solution. Solutions were as follows: (1) KCl solution, γ j (main state)=96 pS and γ j (residual state)=23 pS; (2) Cs + aspartate − solution, γ j (main state)=61 pS and γ j (residual state)=12 pS; and (3) tetraethylammonium + aspartate − solution, γ j (main state)=19 pS and γ j (residual state)=3 pS. The respective γ j (main state)-to-γ j (residual state) ratios were 4.2, 5.1, and 6.3. This indicates that the residual state restricts ion permeation more efficiently than does the main state. Transitions of I j between open states (main open state, substates, and residual state) were fast (&lt;2 ms), and transitions involving the closed state and an open state were slow (15 to 65 ms). This implies the existence of two gating mechanisms. The residual state may be regarded as the ground state of electrical gating controlled by V j ; the closed state, as the ground state of chemical gating.
Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with <i>EGFR</i>-Mutant Lung Cancers
Authors: Helena A. Yu, Maria E. Arcila, Natasha Rekhtman, Camelia S. Sima, Maureen F. Zakowski, William Pao, Mark G. Kris, Vincent A. Miller, Marc Ladanyi, Gregory J. Riely
Journal: Clinical Cancer Research (2013)

Abstract Purpose: All patients with EGF receptor (EGFR)–mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Smaller series have identified various mechanisms of resistance, but systematic evaluation of a large number of patients to definitively establish the frequency of various mechanisms has not been conducted. Experimental Design: Patients with lung adenocarcinomas and acquired resistance to erlotinib or gefitinib enrolled onto a prospective biopsy protocol and underwent a rebiopsy after the development of acquired resistance. Histology was reviewed. Samples underwent genotyping for mutations in EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS and PIK3CA, and FISH for MET and HER2. Results: Adequate tumor samples for molecular analysis were obtained in 155 patients. Ninety-eight had second-site EGFR T790M mutations [63%; 95% confidence interval (CI), 55%–70%] and four had small cell transformation (3%, 95% CI, 0%–6%). MET amplification was seen in 4 of 75 (5%; 95% CI, 1%–13%). HER2 amplification was seen in 3 of 24 (13%; 95% CI, 3%–32%). We did not detect any acquired mutations in PIK3CA, AKT1, BRAF, ERBB2, KRAS, MEK1, or NRAS (0 of 88, 0%; 95% CI, 0%–4%). Overlap among mechanisms of acquired resistance was seen in 4%. Conclusions: This is the largest series reporting mechanisms of acquired resistance to EGFR-TKI therapy. We identified EGFR T790M as the most common mechanism of acquired resistance, whereas MET amplification, HER2 amplification, and small cell histologic transformation occur less frequently. More comprehensive methods to characterize molecular alterations in this setting are needed to improve our understanding of acquired resistance to EGFR-TKIs. Clin Cancer Res; 19(8); 2240–7. ©2013 AACR.
Developmental and hormonal regulation of sarcomeric myosin heavy chain gene family.
Authors: V Mahdavi, S Izumo, B Nadal-Ginard
Journal: Circulation Research (1987)

Sarcomeric myosin heavy chain (MHC), the main component of the sarcomere, contains the ATPase activity that generates the contractile force of cardiac and skeletal muscles. The different MHC isoforms are encoded by a closely related multigene family. Most members (seven) of this gene family have been isolated and characterized in the rat, including the alpha- and beta-cardiac, skeletal embryonic, neonatal, fast IIA, fast IIB, and extraocular specific MHC. The slow type I skeletal MHC is encoded by the same gene that codes for the cardiac beta-MHC. Each MHC gene studied displays a pattern of expression that is tissue and developmental stage specific, both in cardiac and skeletal muscles. Furthermore, more than one MHC gene is expressed in each muscle while each gene is expressed in more than one tissue. The expression of each MHC gene in cardiac and skeletal muscles is modulated by thyroid hormone. Surprisingly, however, the same MHC gene can be regulated by the hormone in a significantly different manner, even in opposite directions, depending on the muscle in which it is expressed. Moreover, the skeletal embryonic and neonatal MHC genes, so far considered specific to these 2 developmental stages, are normally expressed in certain adult muscles and can be reinduced by hypothyroidism in specific muscles. This complex pattern of expression and regulation of the MHC gene family in cardiac and skeletal muscle sheds new light on the mechanisms involved in determining the biochemical basis of the contractile state. It also indicates that the cardiac contractile system needs to be examined in a broader context, including skeletal muscles, in order to understand fully its developmental and physiologic regulation.
Importance of genotype-phenotype correlation in xeroderma pigmentosum
Authors: H. Fassihi
Journal: British Journal of Dermatology (2015)

Journal Article Importance of genotype–phenotype correlation in xeroderma pigmentosum Get access H. Fassihi H. Fassihi UK National XP Service St John's Institute of Dermatology Guy's and St Thomas' NHS Trust London U.K Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 172, Issue 4, 1 April 2015, Pages 859–860, https://doi.org/10.1111/bjd.13577 Published: 01 April 2015
Evolutionary divergence in the fungal response to fluconazole revealed by soft clustering
Authors: Dwight Kuo, Kai Tan, Guy Zinman, Timothy Ravasi, Ziv Bar-Joseph, Trey Ideker
Journal: Genome biology (2010)

Fungal infections are an emerging health risk, especially those involving yeast that are resistant to antifungal agents. To understand the range of mechanisms by which yeasts can respond to anti-fungals, we compared gene expression patterns across three evolutionarily distant species - Saccharomyces cerevisiae, Candida glabrata and Kluyveromyces lactis - over time following fluconazole exposure. Conserved and diverged expression patterns were identified using a novel soft clustering algorithm that concurrently clusters data from all species while incorporating sequence orthology. The analysis suggests complementary strategies for coping with ergosterol depletion by azoles - Saccharomyces imports exogenous ergosterol, Candida exports fluconazole, while Kluyveromyces does neither, leading to extreme sensitivity. In support of this hypothesis we find that only Saccharomyces becomes more azole resistant in ergosterol-supplemented media; that this depends on sterol importers Aus1 and Pdr11; and that transgenic expression of sterol importers in Kluyveromyces alleviates its drug sensitivity. We have compared the dynamic transcriptional responses of three diverse yeast species to fluconazole treatment using a novel clustering algorithm. This approach revealed significant divergence among regulatory programs associated with fluconazole sensitivity. In future, such approaches might be used to survey a wider range of species, drug concentrations and stimuli to reveal conserved and divergent molecular response pathways.
CSNK1A1 mutations and isolated del(5q) abnormality in myelodysplastic syndrome: a retrospective mutational analysis
Authors: Alexander E Smith, Austin G Kulasekararaj, Jie Jiang, Syed Mian, Azim Mohamedali, Joop Gaken, Robin Ireland, Barbara Czepulkowski, Steven Best, Ghulam J Mufti
Journal: The Lancet Haematology (2015)
Large-Scale Molecular Comparison of Human Schwann Cells to Malignant Peripheral Nerve Sheath Tumor Cell Lines and Tissues
Authors: Shyra J. Miller, Fatima Rangwala, Jon Williams, Peter Ackerman, Sue Kong, Anil G. Jegga, Sergio Kaiser, Bruce J. Aronow, Silke Frahm, Lan Kluwe, Victor Mautner, Meena Upadhyaya, David Muir, Margaret Wallace, Jussara Hagen, Dawn E. Quelle, Mark A. Watson, Arie Perry, David H. Gutmann, Nancy Ratner
Journal: Cancer Research (2006)

Abstract Malignant peripheral nerve sheath tumors (MPNST) are highly invasive soft tissue sarcomas that arise within the peripheral nerve and frequently metastasize. To identify molecular events contributing to malignant transformation in peripheral nerve, we compared eight cell lines derived from MPNSTs and seven normal human Schwann cell samples. We found that MPNST lines are heterogeneous in their in vitro growth rates and exhibit diverse alterations in expression of pRb, p53, p14Arf, and p16INK4a proteins. All MPNST cell lines express the epidermal growth factor receptor and lack S100β protein. Global gene expression profiling using Affymetrix oligonucleotide microarrays identified a 159-gene molecular signature distinguishing MPNST cell lines from normal Schwann cells, which was validated in Affymetrix microarray data generated from 45 primary MPNSTs. Expression of Schwann cell differentiation markers (SOX10, CNP, PMP22, and NGFR) was down-regulated in MPNSTs whereas neural crest stem cell markers, SOX9 and TWIST1, were overexpressed in MPNSTs. Previous studies have implicated TWIST1 in apoptosis inhibition, resistance to chemotherapy, and metastasis. Reducing TWIST1 expression in MPNST cells using small interfering RNA did not affect apoptosis or chemoresistance but inhibited cell chemotaxis. Our results highlight the use of gene expression profiling in identifying genes and molecular pathways that are potential biomarkers and/or therapeutic targets for treatment of MPNST and support the use of the MPNST cell lines as a primary analytic tool. (Cancer Res 2006; 66(5): 2584-91)
Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial
Authors: Jordi Giralt, Jose Trigo, Sandra Nuyts, Mahmut Ozsahin, Krzysztof Skladowski, Georges Hatoum, Jean-Francois Daisne, Alejandro César Yunes Ancona, Anthony Cmelak, Ricard Mesía, Alicia Zhang, Kelly S Oliner, Ari VanderWalde
Journal: The Lancet Oncology (2015)
The prevention and management of rabies
Authors: N. S. Crowcroft, N. Thampi
Journal: BMJ (2015)

Box 2 Schedule for pre-exposure vaccination (day 0 is date of first dose) Intramuscular-one dose on each of days 0, 7, and 21 or 28* Intradermal-one injection on each of days 0, 7, and 21 or 28 † *WHO recommends following the schedule as closely as possible.The series need not be restarted if doses are not given exactly to schedule †Vials should be used within six hours of opening.To maximize cost savings, sessions should involve enough people to avoid vaccine wastage Box 3 Examples of national sources of advice on rabies diagnosis, prevention, and post-exposure prophylaxis Australia-Australian immunization handbook www.health.gov.au/internet/immunise/publishing.
Impact of severe acute respiratory syndrome (SARS) on pulmonary function, functional capacity and quality of life in a cohort of survivors
Authors: D S Hui
Journal: Thorax (2005)

<b>Objective:</b> To examine the impact of severe acute respiratory syndrome (SARS) on pulmonary function, exercise capacity, and health-related quality of life (HRQoL) among survivors. <b>Methods:</b> 110 survivors with confirmed SARS were evaluated at the Prince of Wales Hospital, HK at the end of 3 and 6 months after symptom onset. The assessment included lung volumes (TLC, VC, RV, FRC), spirometry (FVC, FEV<sub>1</sub>), carbon monoxide transfer factor (Tlco adjusted for haemoglobin), inspiratory and expiratory respiratory muscle strength (Pimax and Pemax), 6 minute walk distance (6MWD), chest radiographs, and HRQoL by SF-36 questionnaire. <b>Results:</b> There were 44 men and 66 women with a mean (SD) age of 35.6 (9.8) years and body mass index of 23.1 (4.8) kg/m<sup>2</sup>. Seventy (64%) were healthcare workers. At 6 months 33 subjects (30%) had abnormal chest radiographs; four (3.6%), eight (7.4%), and 17 (15.5%) patients had FVC, TLC, and Tlco below 80% of predicted values; and 15 (13.9%) and 24 (22.2%) had Pimax and Pemax values below 80 cm H<sub>2</sub>O, respectively. The 6MWD increased from a mean (SD) of 464 (83) m at 3 months to 502 (95) m (95% CI 22 to 54 m, p&lt;0.001), but the results were lower than normal controls in the same age groups. There was impairment of HRQoL at 6 months. Patients who required ICU admission (n = 31) had significantly lower FVC, TLC, and Tlco than those who did not. <b>Conclusion:</b> The exercise capacity and health status of SARS survivors was considerably lower than that of a normal population at 6 months. Significant impairment in surface area for gas exchange was noted in 15.5% of survivors. The functional disability appears out of proportion to the degree of lung function impairment and may be related to additional factors such as muscle deconditioning and steroid myopathy.
Socioeconomic factors and cardiovascular disease: a review of the literature.
Authors: G A Kaplan, J E Keil
Journal: Circulation (1993)

Despite recent declines in mortality, cardiovascular diseases are the leading cause of death in the United States today. It appears that many of the major risk factors for coronary disease have been identified. Researchers are still learning about different modifiable factors that may influence cardiovascular diseases. Socioeconomic status may provide a new focus. The principal measures of SES have been education, occupation, and income or combinations of these. Education has been the most frequent measure because it does not usually change (as occupation or income might) after young adulthood, information about education can be obtained easily, and it is unlikely that poor health in adulthood influences level of education. However, other measures of SES have merit, and the most informative strategy would incorporate multiple indicators of SES. A variety of psychosocial measures--for example, certain aspects of occupational status--may be important mediators of SES and disease. The hypothesis that high job strain may adversely affect health status has a rational basis and is supported by evidence from a limited number of studies. There is a considerable body of evidence for a relation between socioeconomic factors and all-cause mortality. These findings have been replicated repeatedly for 80 years across measures of socioeconomic level and in geographically diverse populations. During 40 years of study there has been a consistent inverse relation between cardiovascular disease, primarily coronary heart disease, and many of the indicators of SES. Evidence for this relation has been derived from prevalence, prospective, and retrospective cohort studies. Of particular importance to the hypothesis that SES is a risk factor for cardiovascular disease was the finding by several investigators that the patterns of association of SES with coronary disease had changed in men during the past 30 to 40 years and that SES has been associated with the decline of coronary mortality since the mid-1960s. However, the declines in coronary mortality of the last few decades have not affected all segments of society equally. There is some evidence that areas with the poorest socioenvironmental conditions experience later onset in the decline in cardiovascular mortality. A number of studies suggest that poor living conditions in childhood and adolescence contribute to increased risk of arteriosclerosis. Some of these studies have been criticized because of their nature, and others for inadequate control of confounding factors.(ABSTRACT TRUNCATED AT 400 WORDS)
One naive T cell, multiple fates in CD8+ T cell differentiation
Authors: Carmen Gerlach, Jeroen W.J. van Heijst, Erwin Swart, Daoud Sie, Nicola Armstrong, Ron M. Kerkhoven, Dietmar Zehn, Michael J. Bevan, Koen Schepers, Ton N.M. Schumacher
Journal: The Journal of Experimental Medicine (2010)

The mechanism by which the immune system produces effector and memory T cells is largely unclear. To allow a large-scale assessment of the development of single naive T cells into different subsets, we have developed a technology that introduces unique genetic tags (barcodes) into naive T cells. By comparing the barcodes present in antigen-specific effector and memory T cell populations in systemic and local infection models, at different anatomical sites, and for TCR-pMHC interactions of different avidities, we demonstrate that under all conditions tested, individual naive T cells yield both effector and memory CD8+ T cell progeny. This indicates that effector and memory fate decisions are not determined by the nature of the priming antigen-presenting cell or the time of T cell priming. Instead, for both low and high avidity T cells, individual naive T cells have multiple fates and can differentiate into effector and memory T cell subsets.
Magnetic resonance imaging of intracranial tumors: intra-patient comparison of gadoteridol and ferumoxytol
Authors: E. Dosa, D. J. Guillaume, M. Haluska, C. A. Lacy, B. E. Hamilton, J. M. Njus, W. D. Rooney, D. F. Kraemer, L. L. Muldoon, E. A. Neuwelt
Journal: Neuro-Oncology (2010)

This study aims to compare gadoteridol with ferumoxytol for contrast-enhanced and perfusion-weighted (PW) MRI of intracranial tumors.The final analysis included 26 patients, who underwent 3 consecutive days of 3T MRI.Day 1 consisted of anatomical pre-and postcontrast images, and PW MRI was acquired using gadoteridol (0.1 mmol/kg).On Day 2, the same MRI sequences were obtained with ferumoxytol (510 mg) and on Day 3, the anatomical images were repeated to detect delayed ferumoxytol-induced signal changes.The T 1 -weighted images were evaluated qualitatively and quantitatively for enhancement volume and signal intensity (SI) changes; PW data were used to estimate the relative cerebral blood volume (rCBV).All 26 lesions showed 24-hour T 1 -weighted ferumoxytol enhancement; 16 also had T 2 -weighted hypointensities.In 6 patients, ferumoxytol-induced signal changes were noted in areas with no gadoteridol enhancement.Significantly greater (P < .0001)SI changes were seen with gadoteridol, and qualitative analyses (lesion border delineation, internal morphology, contrast enhancement) also showed significant preferences (P 5 .0121;P 5 .0015;P < .0001,respectively) for this agent.There was no significant difference in lesion enhancement volumes between contrast materials.The ferumoxytol-rCBV values were significantly higher (P 5 .0016)compared with the gadoteridol-rCBV values.In conclusion, ferumoxytol provides important information about tumor biology that complements gadoteridol imaging.The rCBV measurements indicate areas of tumor undergoing rapid growth, whereas the 24-hour scans mark the presence of inflammatory cells.Both of these functions provide useful information about tumor response to treatment.We suggest that dynamic and anatomical imaging with ferumoxytol warrant further assessment in brain tumor therapy.