tbuckley/cabot-search huggingface dataset:
Keratinocyte Growth Factor Promotes Epithelial Survival and Resolution in a Human Model of Lung Injury
Authors: Murali Shyamsundar, Daniel F. McAuley, Rebecca J. Ingram, David S. Gibson, Donal O’Kane, Scott T. McKeown, Alex Edwards, Cliff Taggart, Joseph S. Elborn, Carolyn S. Calfee, Michael A. Matthay, Cecilia M. O’Kane
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Rationale: Increasing epithelial repair and regeneration may hasten resolution of lung injury in patients with the acute respiratory distress syndrome (ARDS). In animal models of ARDS, keratinocyte growth factor (KGF) reduces injury and increases epithelial proliferation and repair. The effect of KGF in the human alveolus is unknown.Objectives: To test whether KGF can attenuate alveolar injury in a human model of ARDS.Methods: Volunteers were randomized to intravenous KGF (60 μg/kg) or placebo for 3 days, before inhaling 50 μg LPS. Six hours later, subjects underwent bronchoalveolar lavage (BAL) to quantify markers of alveolar inflammation and cell-specific injury.Measurements and Main Results: KGF did not alter leukocyte infiltration or markers of permeability in response to LPS. KGF increased BAL concentrations of surfactant protein D, matrix metalloproteinase (MMP)-9, IL-1Ra, granulocyte-macrophage colony–stimulating factor (GM-CSF), and C-reactive protein. In vitro, BAL fluid from KGF-treated subjects inhibited pulmonary fibroblast proliferation, but increased alveolar epithelial proliferation. Active MMP-9 increased alveolar epithelial wound repair. Finally, BAL from the KGF-pretreated group enhanced macrophage phagocytic uptake of apoptotic epithelial cells and bacteria compared with BAL from the placebo-treated group. This effect was blocked by inhibiting activation of the GM-CSF receptor.Conclusions: KGF treatment increases BAL surfactant protein D, a marker of type II alveolar epithelial cell proliferation in a human model of acute lung injury. Additionally, KGF increases alveolar concentrations of the antiinflammatory cytokine IL-1Ra, and mediators that drive epithelial repair (MMP-9) and enhance macrophage clearance of dead cells and bacteria (GM-CSF).Clinical trial registered with ISRCTN 98813895.
Biomarkers in respiratory tract infections: diagnostic guides to antibiotic prescription, prognostic markers and mediators
Authors: M. Christ-Crain, B. Müller
Journal: European Respiratory Journal (2007)

Used appropriately, biomarkers improve the assessment of respiratory tract infections and sepsis. Most prominently, circulating procalcitonin levels increase by a factor of several tens of thousands during sepsis. Using a sensitive assay, procalcitonin safely and markedly reduces antibiotic usage in respiratory tract infections and nonbacterial meningitis. Procalcitonin is the protopye of hormokine mediators. The term “hormokine” encompasses the cytokine-like behaviour of hormones during inflammation and infections. The concept is based on a ubiquitous expression of calcitonin peptides during sepsis. Adrenomedullin, another member of the calcitonin peptide superfamily, was shown to complement and improve the current prognostic assessment in lower respiratory tract infections. Other peptides share some features of hormokines, e.g. natriuretic peptide and copeptin. Hormokines are not only biomarkers of infection but are also pivotal inflammatory mediators. Like all mediators, their role during systemic infections is basically beneficial, possibly to combat invading microbes. However, at increased levels they can become harmful for their host. Multiple mechanisms of action were proposed. In several animal models the modulation and neutralisation of hormokines during infection was shown to improve survival, and thus might open new treatment options for severe infections, especially of the respiratory tract.
A Functional Screen Identifies Lateral Transfer of -Glucuronidase (gus) from Bacteria to Fungi
Authors: P. Wenzl
Journal: Molecular Biology and Evolution (2004)

Lateral gene transfer (LGT) from prokaryotes to microbial eukaryotes is usually detected by chance through genome-sequencing projects. Here, we explore a different, hypothesis-driven approach. We show that the fitness advantage associated with the transferred gene, typically invoked only in retrospect, can be used to design a functional screen capable of identifying postulated LGT cases. We hypothesized that beta-glucuronidase (gus) genes may be prone to LGT from bacteria to fungi (thought to lack gus) because this would enable fungi to utilize glucuronides in vertebrate urine as a carbon source. Using an enrichment procedure based on a glucose-releasing glucuronide analog (cellobiouronic acid), we isolated two gus(+) ascomycete fungi from soils (Penicillium canescens and Scopulariopsis sp.). A phylogenetic analysis suggested that their gus genes, as well as the gus genes identified in genomic sequences of the ascomycetes Aspergillus nidulans and Gibberella zeae, had been introgressed laterally from high-GC gram(+) bacteria. Two such bacteria (Arthrobacter spp.), isolated together with the gus(+) fungi, appeared to be the descendants of a bacterial donor organism from which gus had been transferred to fungi. This scenario was independently supported by similar substrate affinities of the encoded beta-glucuronidases, the absence of introns from fungal gus genes, and the similarity between the signal peptide-encoding 5' extensions of some fungal gus genes and the Arthrobacter sequences upstream of gus. Differences in the sequences of the fungal 5' extensions suggested at least two separate introgression events after the divergence of the two main Euascomycete classes. We suggest that deposition of glucuronides on soils as a result of the colonization of land by vertebrates may have favored LGT of gus from bacteria to fungi in soils.
P218 Is there any value in obtaining a tissue diagnosis in suspected lung cancer patients with a performance status 3-4?
Authors: M. Gautam, M. Haris, S. Huq, M. Shaw, M. Ledson, M. Walshaw
Journal: Thorax (2010)

<h3>Introduction</h3> The National Lung Cancer Audit stipulates a minimum 75% tissue diagnosis rate in order to meet the standard required for Peer Review. Whilst this is imperative in patients suitable for potentially curative treatment (PS=1–2), in those with a poorer performance state (PS=3–4) it has been suggested that investigations aimed at obtaining a tissue diagnosis lengthen the diagnostic process without improving the patient journey, thereby wasting resource and diminishing the quality of care. To look at this further, we studied patients with PS=3–4 diagnosed at our large lung cancer unit (all-patients tissue diagnosis rate &gt;80%), comparing their tissue diagnosis rate with treatment offered and ultimate outcome. <h3>Methods</h3> All 108 patients (57 male) with PS=3–4 (18 PS=4) diagnosed at our unit during 2009 formed the study population (25% of total diagnoses). Eighty-eight diagnostic procedures were attempted in 72 patients (66%), and were successful in 59 of these (82%) (15 small cell, 40 non-small cell, 4 other malignancies). <h3>Results</h3> Although a tissue diagnosis was more likely to be attempted in those with PS=3 than 4 (66/90 vs 6/18, χ<sup>2</sup>=10.8, p&lt;0.01), it was no more likely to be successful (54/66 vs 5/6, χ<sup>2</sup>=0.1, p=NS). Those with a tissue diagnosis were more likely to be offered chemo or radiotherapy (active treatment) (28/59 vs 5/49, χ<sup>2</sup>=17.5, p&lt;0.001), with the remaining patients benefiting from best supportive care (BSC). Furthermore, Kaplan–Meier plots (censored at 150 days) demonstrated that those who underwent active treatment had an improved clinical outcome (median survival: treated group 81 days [IQR 48–143] vs BSC group 16 days [6–56], p&lt;0.001). <h3>Conclusions</h3> This audit shows that patients with a poor performance state who undergo some form of active treatment gain a survival benefit. For clinical governance reasons, active treatment is unlikely to be offered to patients without a tissue diagnosis, underlining the need to appropriately investigate this patient group wherever possible. We achieved a tissue diagnosis rate of 55%, and exhort other lung cancer units to adopt a similar approach to improve the clinical journey of these unfortunate and sometimes under treated patients.
Multiplex Reverse Transcription-PCR Screening for <i>EML4-ALK</i> Fusion Transcripts
Authors: Kengo Takeuchi, Young Lim Choi, Manabu Soda, Kentaro Inamura, Yuki Togashi, Satoko Hatano, Munehiro Enomoto, Shuji Takada, Yoshihiro Yamashita, Yukitoshi Satoh, Sakae Okumura, Ken Nakagawa, Yuichi Ishikawa, Hiroyuki Mano
Journal: Clinical Cancer Research (2008)

EML4-ALK is a fusion-type protein tyrosine kinase that is generated by inv(2)(p21p23) in the genome of non-small cell lung cancer (NSCLC). To allow sensitive detection of EML4-ALK fusion transcripts, we have now developed a multiplex reverse transcription-PCR (RT-PCR) system that captures all in-frame fusions between the two genes.Primers were designed to detect all possible in-frame fusions of EML4 to exon 20 of ALK, and a single-tube multiplex RT-PCR assay was done with total RNA from 656 solid tumors of the lung (n = 364) and 10 other organs.From consecutive lung adenocarcinoma cases (n = 253), we identified 11 specimens (4.35%) positive for fusion transcripts, 9 of which were positive for the previously identified variants 1, 2, and 3. The remaining two specimens harbored novel transcript isoforms in which exon 14 (variant 4) or exon 2 (variant 5) of EML4 was connected to exon 20 of ALK. No fusion transcripts were detected for other types of lung cancer (n = 111) or for tumors from 10 other organs (n = 292). Genomic rearrangements responsible for the fusion events in NSCLC cells were confirmed by genomic PCR analysis and fluorescence in situ hybridization. The novel isoforms of EML4-ALK manifested marked oncogenic activity, and they yielded a pattern of cytoplasmic staining with fine granular foci in immunohistochemical analysis of NSCLC specimens.These data reinforce the importance of accurate diagnosis of EML4-ALK-positive tumors for the optimization of treatment strategies.
Modification of plant N-glycans processing: The future of producing therapeutic protein by transgenic plants
Authors: Min Chen, Xianwei Liu, Zhankun Wang, Jing Song, Qingsheng Qi, Peng George Wang
Journal: Medicinal Research Reviews (2004)

Transgenic plants are regarded as one of the most promising systems for the production of human therapeutic proteins. The number of therapeutic proteins successfully produced in plants is steadily arising. However, the glycoproteins normally produced from plants are not the same as native therapeutic proteins produced from mammals or humans. In addition to in vitro enzymatic modeling glycoproteins, there are two gene manipulation strategies to humanize plant N-glycans connected to the glycoproteins. One is retaining the recombinant glycoproteins in endoplasmic reticulum (ER), the site where few specific modifications of N-glycans occurs. The other is inhibiting the plant endogenous Golgi glycosyltransferase and/or adding new glycosyltransferase from mammalians. In this review, the biosynthesis of N-glycans in plants, the modification of the plant N-glycans processing will be discussed.
Stent underexpansion and residual reference segment stenosis are related to stent thrombosis after sirolimus-eluting stent implantation
Authors: Kenichi Fujii, Stéphane G. Carlier, Gary S. Mintz, Yi-ming Yang, Issam Moussa, Giora Weisz, George Dangas, Roxana Mehran, Alexandra J. Lansky, Edward M. Kreps, Michael Collins, Gregg W. Stone, Jeffrey W. Moses, Martin B. Leon
Journal: Journal of the American College of Cardiology (2005)
Treatment with etanercept of autoimmune hepatitis associated with rheumatoid arthritis: an open label proof of concept study
Authors: Gwendoline Toulemonde, Jean-Yves Scoazec, Pierre Miossec
Journal: Annals of the Rheumatic Diseases (2012)

Rheumatoid arthritis (RA) is a systemic disease, with extra-articular manifestations,1 including inflammatory liver disease.2 ,3 Our recent results indicate that elevated transaminase levels in RA patients on methotrexate (MTX) are rarely related to MTX-specific liver lesions (5%), but frequently to autoimmune hepatitis (AIH) histological lesions (41%).2 ,4 We have previously found that inhibition of tumour necrosis factor (TNF) with etanercept was well tolerated in patients with arthritis and hepatitis C virus infection.5 Since TNFα inhibition can control RA joint disease, we asked the question of a possible positive effect of TNFα inhibitors on RA-associated liver disease.

The objective of this proof of concept study was to evaluate the effect of 6 months of etanercept treatment on RA-associated AIH histological lesions.

Among a population of 1571 patients treated with MTX for chronic arthritis, 53 with persistent abnormal …
Regulatory T Cells and T Cell Depletion
Authors: Marina Noris, Federica Casiraghi, Marta Todeschini, Paolo Cravedi, Daniela Cugini, Giuseppe Monteferrante, Sistiana Aiello, Linda Cassis, Eliana Gotti, Flavio Gaspari, Dario Cattaneo, Norberto Perico, Giuseppe Remuzzi
Journal: Journal of the American Society of Nephrology (2007)

Allogeneic immune responses are modulated by a subset of host T cells with regulatory function (Treg) contained within the CD4(+)CD25(high) subset. Evidence exists that Treg expand after peritransplantation lymphopenia, inhibit graft rejection, and induce and maintain tolerance. Little, however, is known about the role of Treg in the clinical setting. IL-2 and activation by T cell receptor engagement are instrumental to generate and maintain Treg, but the influence of immunosuppressants on Treg homeostasis in humans in vivo has not been investigated. This study monitored Treg phenotype and function during immune reconstitution in renal transplant recipients who underwent profound T cell depletion with Campath-1H and received sirolimus or cyclosporine (CsA) as part of their maintenance immunosuppressive therapy. CD4(+)CD25(high) cells that expressed FOXP3 underwent homeostatic peripheral expansion during immune reconstitution, more intense in patients who received sirolimus than in those who were given CsA. T cells that were isolated from peripheral blood long term after transplantation were hyporesponsive to alloantigens in both groups. In sirolimus- but not CsA-treated patients, hyporesponsiveness was reversed by Treg depletion. T cells from CsA-treated patients were anergic. Thus, lymphopenia and calcineurin-dependent signaling seem to be primary mediators of CD4(+)CD25(high) Treg expansion in renal transplant patients. These findings will be instrumental in developing "tolerance permissive" immunosuppressive regimens in the clinical setting.
Changes in Gene Expression in Responders and Nonresponders to a Low-Intensity Walking Intervention
Authors: Megan E. Osler, Tomas Fritz, Kenneth Caidahl, Anna Krook, Juleen R. Zierath, Harriet Wallberg-Henriksson
Journal: Diabetes Care (2015)

OBJECTIVE Daily physical activity remains an effective strategy to prevent obesity and type 2 diabetes. However, the metabolic response to exercise training is variable, and the precise clinical and molecular determinants that mark the metabolic improvements remain unknown. We tested the hypothesis that clinical improvements in glucose control after low-intensity exercise in individuals with impaired glucose tolerance (IGT) are coupled to alterations in skeletal muscle gene expression. RESEARCH DESIGN AND METHODS We investigated 14 overweight individuals with IGT before and after a 4-month low-intensity unsupervised walking exercise intervention. Clinical and anthropometric measurements and glucose tolerance were determined before and after the intervention. Skeletal muscle biopsy specimens were obtained for mRNA expression analysis. RESULTS Waist circumference and work capacity during cycle ergometry were improved in individuals who achieved normal glucose tolerance (NGT) after exercise training (IGT-NGT; n = 9) but in not individuals who remained IGT (IGT-IGT; n = 5). Pretraining glycemic control was better in IGT-NGT compared with IGT-IGT. mRNA expression of mitochondrial markers and transcription factors was increased in IGT-NGT after exercise intervention and normalized to levels measured in a separate cohort of nonexercised individuals with NGT. Conversely, these markers were unaltered after exercise intervention in IGT-IGT. CONCLUSIONS Normalization of metabolic control can be achieved after low-intensity exercise in individuals with IGT. This can be tracked with increased mRNA expression of mitochondrial and metabolic genes in skeletal muscle. However, for individuals presenting with a greater derangement in glycemia, the potential for clinical and metabolic improvements after this low-intensity unsupervised exercise protocol appears to be limited.
RNA polymerase III transcription in cancer: the BRF2 connection
Authors: Stephanie Cabarcas, Laura Schramm
Journal: Molecular Cancer (2011)

RNA polymerase (pol) III transcription is responsible for the transcription of small, untranslated RNAs involved in fundamental metabolic processes such mRNA processing (U6 snRNA) and translation (tRNAs). RNA pol III transcription contributes to the regulation of the biosynthetic capacity of a cell and a direct link exists between cancer cell proliferation and deregulation of RNA pol III transcription. Accurate transcription by RNA pol III requires TFIIIB, a known target of regulation by oncogenes and tumor suppressors. There have been significant advances in our understanding of how TFIIIB-mediated transcription is deregulated in a variety of cancers. Recently, BRF2, a component of TFIIIB required for gene external RNA pol III transcription, was identified as an oncogene in squamous cell carcinomas of the lung through integrative genomic analysis. In this review, we focus on recent advances demonstrating how BRF2-TFIIIB mediated transcription is regulated by tumor suppressors and oncogenes. Additionally, we present novel data further confirming the role of BRF2 as an oncogene, extracted from the Oncomine database, a cancer microarray database containing datasets derived from patient samples, providing evidence that BRF2 has the potential to be used as a biomarker for patients at risk for metastasis. This data further supports the idea that BRF2 may serve as a potential therapeutic target in a variety of cancers.
Inhibitory Effect of 12-<b> <i>O</i> </b>-Tetradecanoylphorbol-13-acetate Alone or in Combination with All-<b> <i>trans</i> </b>-Retinoic Acid on the Growth of LNCaP Prostate Tumors in Immunodeficient Mice
Authors: Xi Zheng, Richard L. Chang, Xiao-Xing Cui, Gina E. Avila, Sabrina Lee, Yao Ping Lu, You Rong Lou, Weichung Joe Shih, Yong Lin, Kenneth Reuhl, Harold Newmark, Arnold Rabson, Allan H. Conney
Journal: Cancer Research (2004)

Clinically achievable concentrations of 12-O-tetradecanoylphorbol-13-acetate (TPA; 0.16-0.32 nM) and all-trans-retinoic acid (ATRA; 0.5-1 micro M) had a synergistic inhibitory effect on the growth of cultured LNCaP prostate cancer cells, and apoptosis was markedly stimulated. In additional studies, NCr immunodeficient mice received s.c. injection with LNCaP cells in Matrigel. After 4-6 weeks, mice with well-established tumors received i.p. injection with vehicle, TPA (0.16 nmol/g body weight), ATRA (0.5 nmol/g body weight), or TPA+ATRA in vehicle once a day for 46 days. Tumor growth occurred in all of the vehicle-treated control mice. The percentage of animals with some tumor regression after 21 days of treatment was 0% for the control group, 31% for the ATRA group, 62% for the TPA group, and 100% for the TPA+ATRA group (13 mice/group). Although treatment of the mice with TPA or TPA+ATRA continued to inhibit tumor growth for the duration of the 46-day study, treatment of the mice with ATRA alone did not inhibit tumor growth beyond 28 days of daily injections (6 mice/group). Mechanistic studies indicated that treatment of the mice with TPA or TPA+ATRA for 46 days increased apoptosis in the tumors, and treatment with TPA+ATRA also decreased the mitotic index. Because the dose of TPA used in this study was effective and resulted in clinically achievable blood levels, clinical trials with TPA alone or in combination with ATRA in patients with prostate cancer may be warranted.
Genetic Unmasking of an Epigenetically Silenced microRNA in Human Cancer Cells
Authors: Amaia Lujambio, Santiago Ropero, Esteban Ballestar, Mario F. Fraga, Celia Cerrato, Fernando Setién, Sara Casado, Ana Suarez-Gauthier, Montserrat Sanchez-Cespedes, Anna Gitt, Inmaculada Spiteri, Partha P. Das, Carlos Caldas, Eric Miska, Manel Esteller
Journal: Cancer Research (2007)

The mechanisms underlying microRNA (miRNA) disruption in human disease are poorly understood. In cancer cells, the transcriptional silencing of tumor suppressor genes by CpG island promoter hypermethylation has emerged as a common hallmark. We wondered if the same epigenetic disruption can "hit" miRNAs in transformed cells. To address this issue, we have used cancer cells genetically deficient for the DNA methyltransferase enzymes in combination with a miRNA expression profiling. We have observed that DNA hypomethylation induces a release of miRNA silencing in cancer cells. One of the main targets is miRNA-124a, which undergoes transcriptional inactivation by CpG island hypermethylation in human tumors from different cell types. Interestingly, we functionally link the epigenetic loss of miRNA-124a with the activation of cyclin D kinase 6, a bona fide oncogenic factor, and the phosphorylation of the retinoblastoma, a tumor suppressor gene.
Advantage of Premeal-Injected Insulin Glulisine Compared With Regular Human Insulin in Subjects With Type 1 Diabetes
Authors: Klaus Rave, Oliver Klein, Annke D. Frick, Reinhard H.A. Becker
Journal: Diabetes Care (2006)

OBJECTIVE—Insulin glulisine, a rapid-acting insulin analog, provides prandial insulin replacement. In this study, we compared postprandial blood glucose control after pre- and postmeal insulin glulisine with regular human insulin (RHI). RESEARCH DESIGN AND METHODS—In a single-dose, randomized, four-way complete cross-over study, subjects received standardized, 15-min meals, covered by subcutaneous injections of either insulin glulisine (immediately premeal or 15 min postmeal; 0.15 unit/kg per injection) or RHI (30 min or immediately premeal; 0.15 unit/kg per injection). Twenty-one patients with type 1 diabetes (mean age 36.4 years; mean BMI 26.0 kg/m2) were enrolled; 20 patients completed the study. Postprandial baseline-subtracted blood glucose exposure, maximum excursion, maximum and minimum blood glucose concentrations, and time to the maximum excursion and minimum concentration were assessed, along with serum insulin concentrations. RESULTS—Lower maximum blood glucose excursion (65 vs. 89 mg/dl), total blood glucose exposure within 2 h (279 vs. 334 mg · h/dl, maximum blood glucose concentration (180 vs. 209 mg/dl), and less time to maximum blood glucose excursion (48 vs. 70 min) were seen with immediately premeal insulin glulisine versus immediately premeal RHI. The maximum serum concentration of insulin glulisine was almost double that of RHI (82 vs. 45 μU/ml), achieved in approximately half the time (55 vs. 97 min). Conversely, insulin glulisine (15 min postmeal) versus RHI (immediately premeal) and RHI (30 min premeal) versus insulin glulisine (immediately premeal) resulted in comparable blood glucose control. CONCLUSIONS—Insulin glulisine renders postprandial glucose disposal closer to physiologic requirements compared with RHI and enables appropriate timing of prandial insulin administration.