tbuckley/cabot-search huggingface dataset:
Mitochondrial mutagenesis correlates with the local inflammatory environment in arthritis
Authors: Leonard C Harty, Monika Biniecka, Jacintha O'Sullivan, Edward Fox, Kevin Mulhall, Douglas J Veale, Ursula Fearon
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background</h3> To examine the association between mitochondrial mutagenesis and the proinflammatory microenvironment in patients with inflammatory arthritis. <h3>Methods</h3> Fifty patients with inflammatory arthritis underwent arthroscopy and synovial tissue biopsies, synovial fluid and clinical assessment were obtained. Fifteen patients pre/post-TNFi therapy were also recruited. Normal synovial biopsies were obtained from 10 subjects undergoing interventional arthroscopy. Macroscopic synovitis/vascularity was measured by visual analogue scale. Cell-specific markers CD3 (T cells) and CD68 (macrophages) were quantified by immunohistology. TNFα, IL-6, IFNγ and IL-1β were measured in synovial fluids by MSD multiplex assays. Synovial tissue mitochondrial mutagenesis was quantified using a mitochondrial random mutation capture assay (RMCA). The direct effect of TNFα on oxidative stress and mitochondrial function was assessed in primary cultures of rheumatoid arthritis synovial fibroblast cells (RASFCs). Mitochondrial mutagenesis, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and mitochondrial mass (MM) were quantified using the RMCA and specific cell fluorescent probes. <h3>Results</h3> A significant increase in mtDNA mutation frequency was demonstrated in inflamed synovial tissue compared with control (p&lt;0.05), an effect that was independent of age. mtDNA mutations positively correlated with macroscopic synovitis (r=0.52, p&lt;0.016), vascularity (r=0.54, p&lt;0.01) and with synovial fluid cytokine levels of TNFα (r=0.74, p&lt;0.024) and IFNγ (r=0.72, p&lt;0.039). mtDNA mutation frequency post-TNFi therapy was significantly lower in patients with a DAS&lt;3.2 (p&lt;0.05) and associated with clinical and microscopic measures of disease (p&lt;0.05). In vitro TNFα significantly induced mtDNA mutations, ROS, MM and MMP in RASFCs (all p&lt;0.05). <h3>Conclusion</h3> High mitochondrial mutations are strongly associated with synovial inflammation showing a direct link between mitochondrial mutations and key proinflammatory pathways.
The Liver Is a Site for Tumor-Induced Myeloid-Derived Suppressor Cell Accumulation and Immunosuppression
Authors: Dan Ilkovitch, Diana M. Lopez
Journal: Cancer Research (2009)

Abstract Tumor-induced immunosuppression plays a key role in tumor evasion of the immune system. A key cell population recognized as myeloid-derived suppressor cells (MDSC) contributes and helps orchestrate this immunosuppression. MDSC can interact with T cells, macrophages, and natural killer cells to create an environment favorable for tumor progression. In various tumor models, their presence at high levels has been reported in the bone marrow, blood, spleen, and tumor. We report for the first time that MDSC accumulate and home to the liver in addition to the other organs. Liver MDSC suppress T cells and accumulate to levels comparable with splenic MDSC. Additionally, hematopoiesis in the liver contributes to the dramatic expansion of MDSC in this organ. Furthermore, MDSC in the liver interact with macrophages, also known as Kupffer cells, and cause their up-regulation of PD-L1, a negative T-cell costimulatory molecule. The liver is thus an organ in which MDSC accumulate and can contribute to immunosuppression directly and indirectly. MDSC play a role in various pathologic states in addition to cancer, and these results contribute to our understanding of their biology and interactions with immune-related cells. [Cancer Res 2009;69(13):5514–21]
Breast Cancer–Specific mRNA Transcripts Presence in Peripheral Blood After Adjuvant Chemotherapy Predicts Poor Survival Among High-Risk Breast Cancer Patients Treated With High-Dose Chemotherapy With Peripheral Blood Stem Cell Support
Authors: Miguel Quintela-Fandino, Joaquín Martínez López, Ricardo Hitt, Soledad Gamarra, Antonio Jimeno, Rosa Ayala, Javier Hornedo, Cecilia Guzman, Florinda Gilsanz, Hernán Cortés-Funes
Journal: Journal of Clinical Oncology (2006)

Purpose To study the prognostic significance of the presence of breast cancer–specific mRNA transcripts in peripheral blood (PB), defined by serial analysis of gene expression, in high-risk breast cancer (HRBC) patients undergoing high-dose chemotherapy after receiving adjuvant chemotherapy. Methods From 1994 to 2000, 84 HRBC patients (median age, 44 years; &gt; 10 nodes; 74%) received adjuvant chemotherapy (fluorouracil, epirubicin, and cyclophosphamide for six cycles [83%] or doxorubicin and cyclophosphamide followed by paclitaxel) before undergoing one course of cyclophosphamide plus thiotepa plus carboplatin (STAMP V). Radiotherapy or hormone therapy was administered whenever indicated. Aliquots of apheresis-mononuclear blood cells were frozen from each patient. mRNA was isolated using an automatic nucleic acid extractor based on the magnetic beads technology; reverse transcription was performed using random hexamers. Cytokeratin 19, HER-2, P1B, PS2, and EGP2 transcripts were quantified to B-glucuronidase by real-time polymerase chain reaction (RT-PCR) using a linear DNA probe marked with a quencher and reporter fluorophores used in RT-PCR. Presence of PB micrometastases, estrogen receptor and progesterone receptor status, tumor size, age, tumor grade, number of nodes affected, and treatment with paclitaxel were included in the statistical analysis. Results Median follow-up was 68.3 months (range, 6 months to 103 months). Forty-seven relapses (56%) and 35 deaths (41.7%) were registered. Both tumor size and presence of micrometastases reached statistical significance according to the Cox multivariate model. Relapse hazard ratio (HR) for those patients with PB micrometastases was 269% (P = .006); death HR, 300% (P = .011). Time relapse was 53 months longer for patients without micrometastases: 31.3 v 84.2 months (P = .021). Conclusion PB micrometastases presence after adjuvant chemotherapy predicts both relapse and death more powerful than classical factors in HRBC patients undergoing high-dose chemotherapy. Micrometastases search using a gene panel appears to be a more accurate procedure than classical approaches involving only one or two genes.
Hepatocyte Growth Factor Reduces Susceptibility to an Irreversible Epidermal Growth Factor Receptor Inhibitor in <i>EGFR</i>-T790M Mutant Lung Cancer
Authors: Tadaaki Yamada, Kunio Matsumoto, Wei Wang, Qi Li, Yasuhiko Nishioka, Yoshitaka Sekido, Saburo Sone, Seiji Yano
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The secondary T790M mutation in epidermal growth factor receptor (EGFR) is the most frequent cause of acquired resistance to the reversible EGFR tyrosine kinase inhibitors (EGFR-TKI), gefitinib and erlotinib, in lung cancer. Irreversible EGFR-TKIs are expected to overcome the reversible EGFR-TKI resistance of lung cancer harboring T790M mutation in EGFR. However, it is clear that resistance may also develop to this class of inhibitors. We showed previously that hepatocyte growth factor (HGF) induced gefitinib resistance of lung cancer harboring EGFR-activating mutations. Here, we investigated whether HGF induced resistance to the irreversible EGFR-TKI, CL-387,785, in lung cancer cells (H1975) harboring both L858R activating mutation and T790M secondary mutation in EGFR. Experimental Design: CL-387,785 sensitivity and signal transduction in H1975 cells were examined in the presence or absence of HGF or HGF-producing fibroblasts with or without HGF-MET inhibitors. Results: HGF reduced susceptibility to CL-387,785 in H1975 cells. Western blotting and small interfering RNA analyses indicated that HGF-induced hyposensitivity was mediated by the MET/phosphoinositide 3-kinase/Akt signaling pathway independent of EGFR, ErbB2, ErbB3, and ErbB4. Hyposensitivity of H1975 cells to CL-387,785 was also induced by coculture with high-level HGF-producing lung fibroblasts. The hyposensitivity was abrogated by treatment with anti-HGF neutralizing antibody, HGF antagonist NK4, or MET-TKI. Conclusions: We showed HGF-mediated hyposensitivity as a novel mechanism of resistance to irreversible EGFR-TKIs. It will be clinically valuable to investigate the involvement of HGF-MET–mediated signaling in de novo and acquired resistance to irreversible EGFR-TKIs in lung cancer harboring T790M mutation in EGFR. Clin Cancer Res; 16(1); 174–83
Comparative analysis of chimpanzee and human Y chromosomes unveils complex evolutionary pathway
Authors: Yoko Kuroki, Atsushi Toyoda, Hideki Noguchi, Todd D Taylor, Takehiko Itoh, Dae-Soo Kim, Dae-Won Kim, Sang-Haeng Choi, Il-Chul Kim, Han Ho Choi, Yong Sung Kim, Yoko Satta, Naruya Saitou, Tomoyuki Yamada, Shinichi Morishita, Masahira Hattori, Yoshiyuki Sakaki, Hong-Seog Park, Asao Fujiyama
Journal: Nature Genetics (2006)
Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo
Authors: Omar Abdel-Wahab, Jie Gao, Mazhar Adli, Anwesha Dey, Thomas Trimarchi, Young Rock Chung, Cem Kuscu, Todd Hricik, Delphine Ndiaye-Lobry, Lindsay M. LaFave, Richard Koche, Alan H. Shih, Olga A. Guryanova, Eunhee Kim, Sheng Li, Suveg Pandey, Joseph Y. Shin, Leon Telis, Jinfeng Liu, Parva K. Bhatt, Sebastien Monette, Xinyang Zhao, Christopher E. Mason, Christopher Y. Park, Bradley E. Bernstein, Iannis Aifantis, Ross L. Levine
Journal: The Journal of Experimental Medicine (2013)

Somatic Addition of Sex Combs Like 1 (ASXL1) mutations occur in 10-30% of patients with myeloid malignancies, most commonly in myelodysplastic syndromes (MDSs), and are associated with adverse outcome. Germline ASXL1 mutations occur in patients with Bohring-Opitz syndrome. Here, we show that constitutive loss of Asxl1 results in developmental abnormalities, including anophthalmia, microcephaly, cleft palates, and mandibular malformations. In contrast, hematopoietic-specific deletion of Asxl1 results in progressive, multilineage cytopenias and dysplasia in the context of increased numbers of hematopoietic stem/progenitor cells, characteristic features of human MDS. Serial transplantation of Asxl1-null hematopoietic cells results in a lethal myeloid disorder at a shorter latency than primary Asxl1 knockout (KO) mice. Asxl1 deletion reduces hematopoietic stem cell self-renewal, which is restored by concomitant deletion of Tet2, a gene commonly co-mutated with ASXL1 in MDS patients. Moreover, compound Asxl1/Tet2 deletion results in an MDS phenotype with hastened death compared with single-gene KO mice. Asxl1 loss results in a global reduction of H3K27 trimethylation and dysregulated expression of known regulators of hematopoiesis. RNA-Seq/ChIP-Seq analyses of Asxl1 in hematopoietic cells identify a subset of differentially expressed genes as direct targets of Asxl1. These findings underscore the importance of Asxl1 in Polycomb group function, development, and hematopoiesis.
Exhaled nitric oxide among pulpmill workers reporting gassing incidents involving ozone and chlorine dioxide
Authors: A-C. Olin, G. Ljungkvist, B Bake, S Hagberg, L. Henriksson, K Torén
Journal: European Respiratory Journal (1999)

The aim of the study was to investigate whether measurement of nitric oxide in exhaled air could be used for assessing the effects of irritants on the respiratory system, in this case recurrent ozone gassing in an occupational setting. The study population comprised bleachery workers (n=56) from a Swedish pulpmill carrying out ozone-based pulp bleaching since 1992 and controls (n=39). Both groups were investigated by measuring NO in exhaled air, methacholine challenge test and answers to a questionnaire concerning history of respiratory symptoms and accidental exposure to ozone peaks. There was no significant difference in NO output between exposed subjects and controls (median 67.2 versus 55.0 nL x min(-1), p=0.64). However, among bleachery workers reporting ozone gassings, the median NO output was 90.0 nL x min(-1) compared to 58.8 nL x min(-1) among those not reporting such incidents (p=0.019). There was no relation between exhaled NO and the prevalence of respiratory symptoms or bronchial hyperresponsiveness. In a multiple regression model, only reported ozone gassings were associated (p=0.016) with NO output. The results indicate an association between previous response to ozone gassing and nitric oxide output. The increased nitric oxide output among the bleachery workers reporting peak ozone exposure may indicate that chronic airway inflammation is present. Further studies are needed to evaluate the extent to which nitric oxide can be used for biological monitoring of respiratory health effects, and to relate it to other markers of airway inflammation.
Therapy in Helicobacter pylori infection
Authors: C.K. Ching, H.A. Leake, S.P. Misra, M. Dwivedi, Vatsala Misra, FrankI. Tovey, Louise Baker, ElizabethM. Husband, Graham Mcphail, YiuChu Yiu, A.Paul Jayaraj
Journal: The Lancet (1990)
Survival of COPD patients after their first episode of acute exacerbation treated with non-invasive ventilation
Authors: Yu Hon Man
Journal: European Respiratory Journal (2011)

Objective: To describe the survival of patients surviving the first episode of COPD exacerbation requiring the use of Non-invasive positive ventilation (NIV) in 2002 and 2007 with secondary aim of comparing survival difference between these two one-year periods.

Background: Data on long term survival of patients surviving their first episode of acute exacerbation treated with NIV are scarce. Advances in COPD management may improve survival over the years.

Method: Patients surviving their first episode of acute exacerbation treated with NIV in a regional hospital in the years of 2002 and 2007 were retrospectively reviewed. Two Kaplan-Meier curves were plotted by Epi Info which are compared using log-rank test.

Results: A total of 90 and 73 patients requiring NIV were identified in 2002 and 2007 respectively: 13 and 41 patients died within the same admission; 26 and 9 patients were not first time users; 18 and 17 patients suffered from medical diseases other than COPD. As a result, 33 and 15 patients surviving the first episode of COAD exacerbation requiring the use of NIV in 2002 and 2007 were identified. Overall, the mean age of enrolled cohorts were 76.48 (7.60) and 73.60 (7.00) respectively, with 78.8% and 80.0% males. The median survival was 665 and 539 days. Survival at 1, 2 and 3 years was 61% and 53%, 45% and 33%, 39% and 33%. The predominant cause of death was COPD and contributed to 16 and 8 patients. The Kaplan-Meier survival curves were statistically equivalent with p value of 0.07.

Conclusion: The survival of patients surviving the first episode of COAD exacerbation requiring NIV remains poor, and does not differ between the two one-year periods.
Protein S blocks the extrinsic apoptotic cascade in tissue plasminogen activator/N-methyl D-aspartate-treated neurons via Tyro3-Akt-FKHRL1 signaling pathway
Authors: Huang Guo, Theresa M Barrett, Zhihui Zhong, José A Fernández, John H Griffin, Robert S Freeman, Berislav V Zlokovic
Journal: Molecular Neurodegeneration (2011)

Abstract Background Thrombolytic therapy with tissue plasminogen activator (tPA) benefits patients with acute ischemic stroke. However, tPA increases the risk for intracerebral bleeding and enhances post-ischemic neuronal injury if administered 3-4 hours after stroke. Therefore, combination therapies with tPA and neuroprotective agents have been considered to increase tPA's therapeutic window and reduce toxicity. The anticoagulant factor protein S (PS) protects neurons from hypoxic/ischemic injury. PS also inhibits N-methyl-D-aspartate (NMDA) excitotoxicity by phosphorylating Bad and Mdm2 which blocks the downstream steps in the intrinsic apoptotic cascade. To test whether PS can protect neurons from tPA toxicity we studied its effects on tPA/NMDA combined injury which in contrast to NMDA alone kills neurons by activating the extrinsic apoptotic pathway. Neither Bad nor Mdm2 which are PS's targets and control the intrinsic apoptotic pathway can influence the extrinsic cascade. Thus, based on published data one cannot predict whether PS can protect neurons from tPA/NMDA injury by blocking the extrinsic pathway. Neurons express all three TAM ( T yro3, A xl, M er) receptors that can potentially interact with PS. Therefore, we studied whether PS can activate TAM receptors during a tPA/NMDA insult. Results We show that PS protects neurons from tPA/NMDA-induced apoptosis by suppressing Fas-ligand (FasL) production and FasL-dependent caspase-8 activation within the extrinsic apoptotic pathway. By transducing neurons with adenoviral vectors expressing the kinase-deficient Akt mutant Akt K179A and a triple FKHRL1 Akt phosphorylation site mutant (FKHRL1-TM), we show that Akt activation and Akt-mediated phosphorylation of FKHRL1, a member of the Forkhead family of transcription factors, are critical for FasL down-regulation and caspase-8 inhibition. Using cultured neurons from Tyro3, Axl and Mer mutants, we show that Tyro3, but not Axl and Mer, mediates phosphorylation of FHKRL1 that is required for PS-mediated neuronal protection after tPA/NMDA-induced injury. Conclusions PS blocks the extrinsic apoptotic cascade through a novel mechanism mediated by Tyro3-dependent FKHRL1 phosphorylation which inhibits FasL-dependent caspase-8 activation and can control tPA-induced neurotoxicity associated with pathologic activation of NMDA receptors. The present findings should encourage future studies in animal stroke models to determine whether PS can increase the therapeutic window of tPA by reducing its post-ischemic neuronal toxicity.
Serum Uric Acid Levels Improve Prediction of Incident Type 2 Diabetes in Individuals With Impaired Fasting Glucose
Authors: Caroline Kaercher Kramer, Denise von Mühlen, Simerjot Kaur Jassal, Elizabeth Barrett-Connor
Journal: Diabetes Care (2009)

OBJECTIVE To determine whether serum uric acid predicts incident type 2 diabetes by glucose tolerance status in older community-dwelling adults. RESEARCH DESIGN AND METHODS Participants without diabetes at baseline were evaluated for incident type 2 diabetes 13 years later. Baseline glucose tolerance status was defined as normoglycemia, impaired fasting glucose, and impaired postchallenge glucose tolerance. RESULTS A total of 566 participants were included (mean age 63.3 ± 8.6 years; 41% men). Regression models adjusted for age, sex, BMI, diuretic use, and estimated glomerular filtration rate showed that for each 1 mg/dl increment in uric acid levels, incident type 2 diabetes risk increased by ∼60%. When analyses were stratified by glucose status, uric acid levels independently predicted incident type 2 diabetes among participants who had impaired fasting glucose (odds ratio 1.75, 95% CI 1.1–2.9, P = 0.02). CONCLUSIONS Uric acid may be a useful predictor of type 2 diabetes in older adults with impaired fasting glucose.
Approach to hypersensitivity reactions to chemotherapeutics in patients with lung cancer
Authors: Ozlem Goksel, Tuncay Goksel, Gursel Cok, Haydar Karakus, Munevver Erdinc
Journal: European Respiratory Journal (2013)

Background: Hypersensitivity reactions(HSRs) to chemotherapeutic drugs can be vital.  Aim: To determine frequency of HSRs during chemotherapy and review current our approaches.  Method: Medical records of patients received chemotherapy due to lung cancer in our clinic during 2012 examined retrospectively. Patients who developed immediate -according to Ring and Messmer classifications- or delayed HSRs were included into the study. The efficacy of a standardized 12-steps desensitization procedure was investigated in patients with immediate HSRs.  Results: Total 1099 cycles of chemotherapy was given in 292 patients in one year. We observed 10 HSRs during 10 cycles in 10 patients. Two reactions were delayed type (one was proven with skin biopsy), while other 7 reactions were immediate with degree of Grade 2-3. The most frequent HSRs was observed among patients received docetaxel (2.6%/cycles) and pemetrexed (2.4%/cycles). Four of the patients with HSRs were changed protocol, one patient was continued the same carboplatin protocol after intensive premedication with slow infusion. Remain 5 patients were not able to tolerate chemotherapeutic drug despite intensive premedication and slow infusion. A standardized 12-steps desensitization procedure was performed in 19 cycles of those. No life-threatening HSRs or deaths occurred during the desensitization procedures, and all patients received their full target dose at the end.  Conclusion: This study shows that HSRs to chemotherapeutics is not rare. In this case, a standardized desensitization protocol administered by an experienced team seems safe and effective for overcoming hypersensitivity and continuing treatment with preferred therapeutic agents.
From catastrophe to complexity: a novel model of integrative central neural regulation of effort and fatigue during exercise in humans: summary and conclusions
Authors: T D Noakes, A St Clair Gibson, E V Lambert
Journal: British Journal of Sports Medicine (2005)

It is hypothesised that physical activity is controlled by a central governor in the brain and that the human body functions as a complex system during exercise. Using feed forward control in response to afferent feedback from different physiological systems, the extent of skeletal muscle recruitment is controlled as part of a continuously altering pacing strategy, with the sensation of fatigue being the conscious interpretation of these homoeostatic, central governor control mechanisms.
Nail psoriasis in Germany: epidemiology and burden of disease
Authors: M. Augustin, K. Reich, C. Blome, I. Schäfer, A. Laass, M.A. Radtke
Journal: British Journal of Dermatology (2010)

Although nail psoriasis affects a marked proportion of patients with psoriasis and causes significant psychological stress, only few epidemiological data characterizing patients with nail involvement are available.To gain robust data on the epidemiology and disease burden of nail psoriasis in Germany.Two nationwide, noninterventional, cross-sectional studies on psoriasis health care were conducted in 2005 and 2007, involving 48 (2005) and 130 (2007) German office-based and clinic-based dermatological centres. Data of n=3531 patients with psoriasis were collected using standardized questionnaires and physical examinations by trained dermatologists. Patients with nail psoriasis were compared with patients without any nail involvement concerning sex, age, disease duration, family history, disease severity, presence of psoriatic arthritis (PsA), health-related quality of life (HRQoL), number of inpatient therapies, and days off work.Nail psoriasis was diagnosed in 40·9% of the patients; prevalence was 11·2 percentage points higher in men than in women. Patients with nail involvement had a longer disease duration (21·9 vs. 18·1 years), higher disease severity (mean Psoriasis Area and Severity Index 12·7 vs. 9·3), higher frequency of PsA (26·0% vs. 12·7%), stronger impairment of HRQoL (mean Dermatology Life Quality Index 8·9 vs. 7·3), and a 2·5-fold higher rate of inpatient treatments.Nail involvement is a relevant manifestation of psoriasis and is associated with a higher disease severity and quality of life impairment. Accordingly, management of psoriasis should include a special focus on nail involvement.
Response to Letter Regarding Article, “Coronary Multidetector Computed Tomography in the Assessment of Patients With Acute Chest Pain”
Authors: Udo Hoffmann, Fabian Moselewski, Antonio Pena, Maros Ferencik, Sujith K. Seneviratne, Ricardo C. Cury, Javed Butler, Suhny Abbara, John H. Nichols, Thomas J. Brady, John T. Nagurney, David F. Brown, Alex Manini, Claudia U. Chae, Stephan Achenbach
Journal: Circulation (2007)