tbuckley/cabot-search huggingface dataset:
Pirfenidone suppresses proinflammatory and antiangiogenetic cytokine production by alveolar macrophages (AMs) in idiopathic non specific interstitial pneumonia (iNSIP)
Authors: Xuan He, Xiaoping Long, Thomas E. Wessendorf, Dirk Theegarten, Josune Guzman, Ulrich Costabel, Francesco Bonella
Journal: European Respiratory Journal (2014)

Background:  Pirfenidone (PFD), the first approved treatment for idiopathic pulmonary fibrosis (IPF), exhibits antifibrotic and antiinflammatory activity. The efficacy of PFD for iNSIP in vitro and in vivo is poorly understood. Aim of this study was to verify whether the effect of PFD on cytokine production by AMs from iNSIP patients is different from the effect seen in IPF patients.   Methods:  AMs from bronchoalveolar lavage (BAL) of 10 iNSIP and 11 IPF patients were cultured with and without lipopolysaccharide (LPS). The production of cytokines in the culture supernatants were measured by Luminex bead based assay. The effect of PFD on the cytokine production was tested at increasing concentrations (0, 0.03, 0.1, 0.3 mg/ml).   Results:  In agreement with our previous preliminary results, PFD suppressed the release of TNF-α, IL-1β, IL-10, IL-18 and GMCSF from AM isolated from iNSIP patients in a similar way as in IPF. The only difference was that production of MIP-1β and IP-10 by LPS stimulated AMs was significantly higher in iNSIP than IPF (p= 0.021 and p=0.01 respectively). PFD suppressed the spontaneous and LPS stimulated release of MIP-1β and IP-10 in iNSIP in a dose-dependent manner at concentrations of 0.1 and 0.3 mg/ml (pl0.05 for each PFD concentration vs basal).   Conclusions:  AMs from iNSIP patients produce higher levels of MIP-1β and IP-10 than those from IPF. The suppression of these cytokines by PFD could be of therapeutic relevance.
In Vivo Enhancement of 5-Fluorouracil Cytotoxicity to AKR Leukemia Cells by Thymidine in Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Giovanni Santelli, Fred Valeriote
Journal: JNCI Journal of the National Cancer Institute (1978)

The spleen colony assay was used to examine the effect of thymidine (dThd) on 5-fluorouracil (FUra) cytotoxicity in two transplantable leukemias, AKR (in AKR mice) and L1210 [in (BALB/c x DBA/2)F1 mice], in vivo. A large dose of dThd (10 mg/mouse) could not rescue these cell lines from FUra toxicity. Instead, when dThd was given within 1 hour before FUra, it enhanced FUra cytotoxicity by a factor between 100 and 1,000 in AKR leukemia. That dThd increased the cytotoxicity of FUra only by a factor of 3 in L1210 leukemia suggested a different mechanism of interaction of the two drugs in the two cell lines. Examination in hybrid mice capable of supporting the growth of both leukemias showed the enhancement to be tumor related rather than host related. We also demonstrated a dose-dependent effect of dThd injection 15 minutes before FUra in AKR leukemia. Concerning the kinetics of killing of AKR leukemia colony-forming units (LCFU) following the administration of dThd 15 minutes before FUra, LCFU survival continued to decrease for 24--36 hours following drug administration.
Perioperative international normalized ratio level is a poor predictor of postoperative bleeding complications in dermatological surgery patients taking warfarin
Authors: C. Blasdale, C.M. Lawrence
Journal: British Journal of Dermatology (2008)

When planning dermatological surgery with patients on warfarin, clinicians must balance the risk of bleeding complications against that of a thrombotic event if anticoagulation is interrupted.To evaluate the frequency of bleeding complications in warfarinized subjects undergoing cutaneous surgery, and to correlate the risk of bleeding with the international normalized ratio (INR) at the time of surgery.In this prospective controlled observational study, 65 patients on warfarin underwent excision of 70 cutaneous tumours. Mean perioperative INR was 2.1 (range 1.0-4.2). A group of 92 nonwarfarinized controls underwent excision of 100 tumours by the same surgeons. The INR of those on warfarin was checked at the time of surgery. Intraoperative and postoperative bleeding was recorded by the operating surgeon.No increase in bleeding tendency during surgery was seen in those on warfarin when compared with controls. Five patients on warfarin (8%) reported moderate or severe postoperative bleeding. No significant postoperative bleeding was reported by controls (P=0.01). All patients on warfarin with bleeding complications had an INR of <2.6 at the time of surgery.Bleeding risk could not be correlated with INR and this study demonstrates that even when INR is in the therapeutic range the risk of postoperative bleeding is increased for warfarinized patients. The need for meticulous haemostasis in all patients on warfarin should not be forgotten and patients should be made aware preoperatively of the small but significant risk of postoperative bleeding complications.
MitoTALEN: A General Approach to Reduce Mutant mtDNA Loads and Restore Oxidative Phosphorylation Function in Mitochondrial Diseases
Authors: Masami Hashimoto, Sandra R Bacman, Susana Peralta, Marni J Falk, Anne Chomyn, David C Chan, Sion L Williams, Carlos T Moraes
Journal: Molecular Therapy (2015)

We have designed mitochondrially targeted transcription activator-like effector nucleases or mitoTALENs to cleave specific sequences in the mitochondrial DNA (mtDNA) with the goal of eliminating mtDNA carrying pathogenic point mutations. To test the generality of the approach, we designed mitoTALENs to target two relatively common pathogenic mtDNA point mutations associated with mitochondrial diseases: the m.8344A>G tRNALys gene mutation associated with myoclonic epilepsy with ragged red fibers (MERRF) and the m.13513G>A ND5 mutation associated with MELAS/Leigh syndrome. Transmitochondrial cybrid cells harbouring the respective heteroplasmic mtDNA mutations were transfected with the respective mitoTALEN and analyzed after different time periods. MitoTALENs efficiently reduced the levels of the targeted pathogenic mtDNAs in the respective cell lines. Functional assays showed that cells with heteroplasmic mutant mtDNA were able to recover respiratory capacity and oxidative phosphorylation enzymes activity after transfection with the mitoTALEN. To improve the design in the context of the low complexity of mtDNA, we designed shorter versions of the mitoTALEN specific for the MERRF m.8344A>G mutation. These shorter mitoTALENs also eliminated the mutant mtDNA. These reductions in size will improve our ability to package these large sequences into viral vectors, bringing the use of these genetic tools closer to clinical trials. We have designed mitochondrially targeted transcription activator-like effector nucleases or mitoTALENs to cleave specific sequences in the mitochondrial DNA (mtDNA) with the goal of eliminating mtDNA carrying pathogenic point mutations. To test the generality of the approach, we designed mitoTALENs to target two relatively common pathogenic mtDNA point mutations associated with mitochondrial diseases: the m.8344A>G tRNALys gene mutation associated with myoclonic epilepsy with ragged red fibers (MERRF) and the m.13513G>A ND5 mutation associated with MELAS/Leigh syndrome. Transmitochondrial cybrid cells harbouring the respective heteroplasmic mtDNA mutations were transfected with the respective mitoTALEN and analyzed after different time periods. MitoTALENs efficiently reduced the levels of the targeted pathogenic mtDNAs in the respective cell lines. Functional assays showed that cells with heteroplasmic mutant mtDNA were able to recover respiratory capacity and oxidative phosphorylation enzymes activity after transfection with the mitoTALEN. To improve the design in the context of the low complexity of mtDNA, we designed shorter versions of the mitoTALEN specific for the MERRF m.8344A>G mutation. These shorter mitoTALENs also eliminated the mutant mtDNA. These reductions in size will improve our ability to package these large sequences into viral vectors, bringing the use of these genetic tools closer to clinical trials.
Effect of BIPAP on diaphragm paralysis after single lung transplantation
Authors: Shadi Shafaghi, Parisa Adimi, Atefeh Fakharian, Amir Hassan Nassiri, Fariba Ghorbani, Seyed Shahabedin Mohammad Makki, Hamid Reza Khoddami Vishteh, Katayoun Najafizadeh
Journal: European Respiratory Journal (2011)

Diaphragm is a chief muscle of inspiration and its unilateral or bilateral paralysis can lead to dyspnea and affect ventilator function. Here, we are reporting management of an emphysematous patient who is undergone single lung transplant and was suffering from diaphragmatic paralysis.  A 53 year old male emphysematous patient was transplanted in 2009 and had no significant complication after transplantation. He was admitted 3 months and 9 months after transplantation due to acute rejection and received corticosteroid pulse therapy which the results were acceptable. 14 months after transplantation an elevated hemi diaphragm on chest x-ray was suggestive of diaphragmatic paralysis which was confirmed by paradoxical upward movement of right hemi diaphragm during fluoroscopic imaging. He had dyspnea with minimal exercise, reduced pulmonary function test (FVC from 63% to 38%) and oxygen saturation fall to 75% in rest without any oxygen supplement. Considering hypoxia and Co2 retention, polysomnography was performed to look for sleep apnea. Patient apnea hypopnea index (AHI) was 17 with 5 hypopnea, 5 central and 7 obstructive sleep events. After titration test, bi-level positive airway pressure apparatus (BIPAP) (PI=15, PE=11, st back up=14) was administered by oronasal mask. Althogh the authors worried about over expansion of high compliance emphysematous native lung with using BIPAP, pulmonary function test result improved significantly (FVC from 38% to 58%) and oxygen saturation during exercise increased to greater than 88% dramatically without expanding the native lung. We claim that BIPAP could be recommended for management of these patients without any considrable side effects.
Characterization and identification of novel serum miRNAs in sepsis patients with different outcomes
Authors: Huijuan Wang, Pengjun Zhang, Weijun Chen, Dan Feng, Yanhong Jia, Lixin Xie
Journal: European Respiratory Journal (2013)

Circulating microRNAs (miRNAs) are an emerging biomarker for sepsis patients. The purpose of this study was to identify novel miRNAs in the sera of sepsis patients and determine their prognostic value. Ninety-four serum samples were collected from sepsis patients within 24 hours of intensive care unit admission. Solexa sequencing followed by bioinformatics analysis was used to predict novel miRNAs in survivors (n=9) and non-survivors (n=9). A total of 650 novel miRNAs were predicted by bioinformatics analysis after Solexa sequencing, and 41 novel miRNAs were validated in 10 survivors, 10 non-survivors, and 10 healthy controls by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Among these 41 miRNAs, 18 were present in both survivors and non-survivors, and 9 were differentially expressed between the 2 groups. The expression levels of the 9 miRNAs were determined by qRT-PCR in 32 non-survivors and 24 survivors, and 6 were differentially expressed. Conjoin analysis of the 6 miRNAs showed that the area under the receiver operating characteristic curve (AUC) for the predictive value of the 6 miRNAs was 0.913 (95% CI 0.841-0.985). When the cutoff point was set at 0.372, the 6 miRNAs provided a sensitivity of 87.5% and a specificity of 87.5%. In conclusion, 41 novel miRNAs were detectable in the sera of sepsis patients, and 6 of them might be related to sepsis outcome.
Prognostic significance of EGFR FISH and IHC in non small-cell lung cancer patients treated with chemotherapy alone
Authors: R. Dziadziuszko, B. Holm, B. G. Skov, K. Osterlind, W. A. Franklin, M. Varella-Garcia, P. A. Bunn, F. R. Hirsch
Journal: Journal of Clinical Oncology (2006)

7193 Background: High EGFR gene copy number by fluorescence in situ hybridization (FISH) predicts response and survival benefit in non small-cell lung cancer (NSCLC) patients (pts) treated with EGFR tyrosine-kinase inhibitors, but its prognostic value remains debated. We aimed to evaluate the association of EGFR FISH, EGFR immunohistochemistry (IHC) and prognosis in NSCLC pts treated with chemotherapy alone. Methods: 85 pts treated with platinum-containing chemotherapy (median follow up of 15 months [range: 2–29 months]) were included in the study. There were 47% females, 35% of pts with performance status (PS) 0, 53% PS = 1 and 12% PS = 2, 6% of never-smokers. Median age was 62 years (range: 41–80 years). Stage I-IIIA was diagnosed in 7%, stage IIIB - 44% and stage IV - 48% pts. Adenocarcinoma was the most common histology (51% pts). EGFR FISH was performed using LSI EGFR SpectrumOrange/CEP 7 SpectrumGreen probe and IHC using DAKO PharmDx kit. Results: FISH results were available in 79 pts (93%), and EGFR FISH-positive tumors (high polysomy or gene amplification) were found in 28 pts (35%). IHC results were available in 81 pts (95%) and 25 pts (31%) were scored as positive (staining index ≥200). Distribution of clinical characteristics did not differ according to either FISH or IHC result. FISH-positive pts had higher EGFR IHC staining indices as compared with FISH-negative pts (median 160 vs. 60, p = 0.005, Mann-Whitney U test). Median survival of FISH-positive pts was 12.6 months vs. 8.1 months in FISH-negative pts (log-rank p = 0.68; HR = 0.88 [95% CI: 0.49–1.59]) and the respective figures for progression-free survival (PFS) were 7.5 vs. 4.9 months, log-rank p = 0.72; HR = 0.91 [95% CI: 0.55–1.51]. Median survival in IHC-positive vs. IHC-negative pts was 6.6 months vs. 9.2 months (log-rank p = 0.44; HR = 1.27 [95% CI: 0.69–2.36]). There was no significant difference in PFS (median of 4.8 vs. 5.3 months, respectively; log-rank p = 0.71; HR = 1.11 [95% CI: 0.64–1.92]). FISH and IHC remained insignificant in a Cox regression survival analysis. Conclusion: In this cohort of NSCLC patients treated with chemotherapy alone, EGFR FISH was associated with EGFR IHC and both features had no statistically significant influence on prognosis. [Table: see text]
Late diagnosis of high tracheoesophageal fistula
Authors: Thorsten Eichler, Frank Ahrens, Konrad Reinshagen, Frank Riedel
Journal: European Respiratory Journal (2013)

In a term newborn a resistance at inserting a nasogastric tube was noted. On chest x-ray the tip of the tube projected at the jugulum with airless abdomen. An oesophageal atresie type II was diagnosed and a gastrostomy performed. Anastomosis was finally completed at 5 months of age.  The postoperative course was complicated by repeated atelactasis in the right lung and persistent need of oxygen support. Flexible bronchoscopy showed a malacia of the distal trachea and a protrusion in the pars membranacea in the proximal trachea. Dyed milk given in the oesophagus appeared in the trachea in the area of the protrusion. Aspiration via the larynx could not be ruled out completely. Esophagoscopy was unremarkable except for a stenosis of the anastomosis. An esophagogram did not reveal a fistula.  Because of persisting desaturations at sleep and aspiration pneumonias rigid bronchoscopy was performed and a pit was seen in the subglottic protrusion. An uretral catheter with an angled tip could be inserted in the protrusion and emerged in the esophagus. Therefore an esophageal atresie type IIIa was diagnosed, the rarest typ (less than 1%). The fistula was closed by surgery. Soon after operation no supportiv oxygen was needed aspiration pneumonias ceased.  A high fistula is often hard to recognize in flexible bronchoscopy at spontaneous breathing. Using rigid bronchoscopy under artificial ventilation can be decisive for the diagnosis of high tracheoesophageal fistulas.
Influence of ADRB2 gene polymorphism on cold airway hyperresponsiveness and asthma control depending on inhaled glucocorticoids use
Authors: Denis E. Naumov, Julius M. Perelman, Viktor P. Kolosov, Vladimir N. Maksimov, Mikhail I. Voevoda, Xiangdong Zhou, Qi Li
Journal: European Respiratory Journal (2012)

Previously published data suggest an association between c.46A>G SNP of ADRB2 gene, functional activity of β2-adrenergic receptors (β2-AR) and cold airway hyperresponsiveness (CAH) in patients with bronchial asthma (BA).

Objective: We aimed to investigate the impact of inhaled glucocorticosteroids (ICS) on the clinical state and CAH in BA patients depending on the c.46A>G (rs1042713) variants of ADRB2 gene.

Methods: 136 mild to moderate Caucasian asthmatics with mean age 37±10 were recruited. All the patients were assessed for asthma control, previous ISC use and underwent 3-min isocapnic cold air hyperventilation (ICAH) challenge. Genotyping of the SNP was performed by PCR-RFLP analysis.

Results: ICS users number and daily dosage were comparable among distinct genotypes. AA homozygotes who did not receive therapy proved to have lower ACT score (14 (11; 14) vs. 18 (16; 19), p<0.001) and excessive FEV1 fall after the ICAH (-22 (-51; -15) vs. -2,2 (-6.8; 1.08), p<0.001) in comparison with GG homozygotes. On the contrary, ICS users did not show such associations. Relations of their CAH level and disease control to genotype were not statistically significant. CAH prevalence was greater among AA homozygotes and decreased substantially if they received ICS treatment (p=0.01) while therapeutic effect on CAH in GG patients was not so noticeable.

Conclusions: The obtained results indicate diminished activity of β2-AR in the examined AA carriers as they more frequently exhibited CAH and had poorer asthma control. ICS therapy can reverse depressed β2-AR function in spite of the genetically induced defect and therefore provides particular benefit in AA patients.
Somatic Mutations of the Protein Kinase Gene Family in Human Lung Cancer
Authors: Helen Davies, Chris Hunter, Raffaella Smith, Philip Stephens, Chris Greenman, Graham Bignell, Jon Teague, Adam Butler, Sarah Edkins, Claire Stevens, Adrian Parker, Sarah O'Meara, Tim Avis, Syd Barthorpe, Lisa Brackenbury, Gemma Buck, Jody Clements, Jennifer Cole, Ed Dicks, Ken Edwards, Simon Forbes, Matthew Gorton, Kristian Gray, Kelly Halliday, Rachel Harrison, Katy Hills, Jonathon Hinton, David Jones, Vivienne Kosmidou, Ross Laman, Richard Lugg, Andrew Menzies, Janet Perry, Robert Petty, Keiran Raine, Rebecca Shepherd, Alexandra Small, Helen Solomon, Yvonne Stephens, Calli Tofts, Jennifer Varian, Anthony Webb, Sofie West, Sara Widaa, Andrew Yates, Francis Brasseur, Colin S. Cooper, Adrienne M. Flanagan, Anthony Green, Maggie Knowles, Suet Y. Leung, Leendert H.J. Looijenga, Bruce Malkowicz, Marco A. Pierotti, Bin T. Teh, Siu T. Yuen, Sunil R. Lakhani, Douglas F. Easton, Barbara L. Weber, Peter Goldstraw, Andrew G. Nicholson, Richard Wooster, Michael R. Stratton, P. Andrew Futreal
Journal: Cancer Research (2005)

Abstract Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. We screened the coding sequences of 518 protein kinases (∼1.3 Mb of DNA per sample) for somatic mutations in 26 primary lung neoplasms and seven lung cancer cell lines. One hundred eighty-eight somatic mutations were detected in 141 genes. Of these, 35 were synonymous (silent) changes. This result indicates that most of the 188 mutations were “passenger” mutations that are not causally implicated in oncogenesis. However, an excess of ∼40 nonsynonymous substitutions compared with that expected by chance (P = 0.07) suggests that some nonsynonymous mutations have been selected and are contributing to oncogenesis. There was considerable variation between individual lung cancers in the number of mutations observed and no mutations were found in lung carcinoids. The mutational spectra of most lung cancers were characterized by a high proportion of C:G &amp;gt; A:T transversions, compatible with the mutagenic effects of tobacco carcinogens. However, one neuroendocrine cancer cell line had a distinctive mutational spectrum reminiscent of UV-induced DNA damage. The results suggest that several mutated protein kinases may be contributing to lung cancer development, but that mutations in each one are infrequent.
Use and Duration of Chemotherapy in Patients With Metastatic Breast Cancer According to Tumor Subtype and Line of Therapy
Authors: Davinia S.E. Seah, Ines Vaz Luis, Erin Macrae, Jessica Sohl, Georgia Litsas, Eric P. Winer, Nancy U. Lin, Harold J. Burstein
Journal: Journal of the National Comprehensive Cancer Network (2014)

Benefits of chemotherapy vary in patients with metastatic breast cancer (MBC). This article describes the impact of tumor subtype and the line of therapy on the duration of chemotherapy. Clinicopathologic characteristics were extracted from the medical records of 199 consecutive patients with MBC at Dana-Farber Cancer Institute and analyzed according to subtype. Tumor subtypes were classified as hormone receptor (HR)-positive, triple-negative (TNBC), or HER2-amplified breast cancer. Duration of chemotherapy of each line was defined as the start of a chemotherapy regimen to the start of the next line of therapy as a result of progression or toxicity. There were 96, 44, and 59 patients with HR+, TNBC, and HER2-amplified breast cancer, respectively. Median age at MBC diagnosis was 53 years. Median overall survivals were 32 and 54 months for HER2-amplified disease, 36 months for HR+ breast cancer, and 17 months for TNBC (P<.0001). Patients with HER2-amplified disease received the most lines (median, 4; P=.032) and the longest duration of chemotherapy for every line. The median duration of chemotherapy in HER2-amplified patients remained at more than 4 months even out to sixth-line therapy. Patients with TNBC tended to receive the shortest duration of chemotherapy for every line of therapy. Tumor subtypes influence the number of lines, duration of chemotherapy, and survival. Among patients with HR+ and HER2-amplified disease who undergo chemotherapy beyond the third line, substantial rates of prolonged therapies suggest clinical benefit. The role of advanced (greater than third) chemotherapy lines in improving survival of all patients with MBC warrants further study.