tbuckley/cabot-search huggingface dataset:
Racial Differences in<i>BRAF</i>/<i>KRAS</i>Mutation Rates and Survival in Stage III Colon Cancer Patients
Authors: Harry H. Yoon, Qian Shi, Steven R. Alberts, Richard M. Goldberg, Stephen N. Thibodeau, Daniel J. Sargent, Frank A. Sinicrope
Journal: JNCI Journal of the National Cancer Institute (2015)

It is unknown if, after controlling for clinicopathologic variables and treatment, racial disparities in colon cancer outcomes persist. Molecular marker analysis in North American patients comparing Asians with other races has not been reported. BRAFV600E and KRAS mutations were analyzed in node-positive colon cancer patients (n = 3305) treated with FOLFOX-based chemotherapy in an adjuvant trial (Alliance N0147). Race categories included Asian, black, or white. Cox models were used to estimate disease-free survival (DFS) and time to recurrence (TTR). All statistical tests were two-sided. BRAF mutation frequency in tumors from whites (13.9%) was twice that of tumors from Asians or blacks. KRAS mutation rates were highest in tumors from blacks (44.1%). KRAS/BRAF wild-type tumors were most common among Asians (66.7%) (Poverall < .001). The prognostic impact of race differed by age and N stage (both Pinteraction < .02). Compared with whites, blacks had shorter DFS among patients younger than age 50 years (hazard ratio [HR] = 2.84, 95% confidence interval [CI] = 1.73 to 4.66) or with N1 disease (HR = 1.54, 95% CI = 1.04 to 2.29), independent of BRAF, KRAS, and other covariates. Findings were consistent using TTR as the outcome. Asians had longer DFS among N2 tumors that was partly mediated by less frequent BRAF mutation. Colon cancers from Asians have a lower rate of BRAF and KRAS mutations than blacks or whites. We report a novel interaction of race with age and N stage in node-positive disease, indicating that racial disparities in survival persist despite uniform stage and treatment in a phase III trial.
LSC 2013 abstract - Microbial communities in the respiratory tract of patients with interstitial lung disease
Authors: Markus Hilty, Christian Garzoni, Silvio Brugger, Kathrin Mühlemann, Christophe von Garnier
Journal: European Respiratory Journal (2013)

Background: Molecular methods based on 16S rRNA gene evolutionary differences/diversity are able to characterise the microbiota in the respiratory tract in health and disease.

Objectives: Our goals were 1) to characterize bacterial communities in the lower airways of patients with and without interstitial lung disease (ILD) 2) to explore if and how immunosuppression and viral or fungal infection influence the microbiota and 3) to analyse if there is a topographical continuity along the respiratory tract.

Methods: We examined the upper and lower respiratory tract of 30 patients with and without interstitial lung disease (15 and 15, respectively). Bronchoalveolar lavage (BAL) fluid and oropharyngeal swabs were collected simultaneously and characterisation of the microbiota was performed by ultra-deep 16S rRNA gene sequencing.

Results: The microbiota of the lower airways of the majority of patients (27 patients; 90%) primarily consisted of Prevotellaceae, Streptococcaceae and Acidaminococcaceae without significantly disordered microbial communities for ILD. In contrast, immunosuppression showed a trend towards reduced diversity (p=0.06) and viral or fungal infection significantly affected both, bacterial diversity and composition (beta diversity) (p=0.01). Comparing bacterial populations of the upper with the lower respiratory tract showed significant topographical discontinuities for 7/30 (23%) patients.

Conclusions: ILD is not associated with disordered lower airway microbiota. However, molecular analysis of the topographical microbiota continuity along the respiratory tract may provide additional information to assist management of patients presenting with clinical worsening of ILD.
Abnormal Left Ventricular Diastolic Filling in Chronic Thromboembolic Pulmonary Hypertension
Authors: Swaminatha V. Gurudevan, Philip J. Malouf, William R. Auger, Thomas J. Waltman, Michael Madani, Ajit B. Raisinghani, Anthony N. DeMaria, Daniel G. Blanchard
Journal: Journal of the American College of Cardiology (2007)
Dynamic changes in quadriceps strength and 6 minute walk distance during COPD exacerbations in the COPDMAP consortium
Authors: Bethan Barker, Umme Kolsum, Vandana Gupta, Karen Edwards, Maria Shelley, Joanne Finch, Dave Singh, Christopher Brightling, Michael Steiner
Journal: European Respiratory Journal (2014)

Background: The impact of exacerbations of chronic obstructive pulmonary disease (COPD) upon skeletal muscle dysfunction is unclear.

Aims: We sought to examine the effects of a COPD exacerbation upon quadriceps maximal voluntary contraction (QMVC) and the 6 minute walk distance (6MWD).

Methods: In subjects with COPD as part of the COPDMAP consortium spirometry, COPD assessment test (CAT) score, C reactive protein (CRP), QMVC and 6MWD were recorded at a stable visit, an exacerbation requiring oral corticosteroids and/or antibiotics (excluding 6MWD), and at two weeks post exacerbation.

Results: At exacerbation compared to stable state (n=72) there was a significant increase in the mean (SEM) CAT (20.2[0.8] vs. 25.1[0.7]; p<0.01) and the median (IQR) CRP (3[3-8] vs. 10[3-22]mg/L; p<0.01), and a reduction in the mean (SEM) FEV1% (54[2] vs. 48[2]%; p<0.01) and QMVC (27.7 [1.4] vs. 25.8[1.3]kg; p=0.02, n=52). There was no significant difference in FEV1%, CAT, QMVC or 6MWD between stable state and 2 week post exacerbation visits(n=54).

![Figure][1] 



Conclusions : COPD exacerbations are associated with impaired muscle strength. Two weeks post exacerbation QMVC and 6MWD are not significantly different to stable state, suggesting that skeletal muscle dysfunction does not persist following a moderate, community managed COPD exacerbation.

 [1]: pending:yes
The decline in lung function is related to both emphysema and fibrosis extent in patients with idiopathic pulmonary fibrosis (IPF)/ combined pulmonary fibrosis and emphysema (CPFE)
Authors: Vincent Cottin, David Hansell, Katerina Antoniou, Arjun Nair, Mark Atwood, Nicola Sverzellati, Gerry Oster, Derek Weycker, Harold R. Collard, Athol Wells
Journal: European Respiratory Journal (2014)

Background: Concurrent emphysema may be associated with spurious preservation of FVC in CPFE. Serial FVC measurement used to monitor progression in IPF might fail to capture disease progression in CPFE.  Aim: To evaluate the change in FVC% predicted over time in patients with IPF and CPFE in relation to the extent of emphysema and fibrosis on HRCT.  Methods: The extent of fibrosis and emphysema on baseline HRCT scans was quantified by visual estimation in 309 patients participating in a placebo-controlled clinical trial of interferon γ-1b with evaluable HRCT scans. The diagnosis of IPF was made using ATS/ERS 2000 criteria, with surgical lung biopsy in 58.3% of patients.  Results: The mean age was 66.0±8.1 years, including 225 males (72.8%) with 68.0% former and 5.2% current smokers. At baseline, FVC% predicted was 73.2±13.5% and DLco was 46.9±8.6%. Emphysema was present in 121 patients (39%). The extent of emphysema was negatively related with the extent of fibrosis (r = -0.277, p l 0.001 ; and test of linear trend, p=0.01). The 48-week decrease in FVC% predicted was correlated with the extent of fibrosis (r = 0.249; p l 0.001), and inversely correlated with the extent of emphysema (r= -0.115; p=0.044). Patients with less fibrosing disease and those with a higher extent of emphysema showed less decline of FVC% predicted, but no less decline in DLco and no greater increase in CPI score.  Conclusions: In patients with IPF and associated emphysema (CPFE), change in FVC may not be a sensitive measure of disease progression. These findings have implications for both patient management and clinical trial design.
Respiratory function during wakefulness and sleep among survivors of respiratory and non-respiratory poliomyelitis
Authors: TE Dolmage, MA Avendano, RS Goldstein
Journal: European Respiratory Journal (1992)

The purpose of this study was to determine whether there is a difference in respiratory mechanics and gas exchange between polio survivors and healthy, age-matched controls during wakefulness and sleep. Polio survivors were divided into four groups. The first group included those who had evidence of respiratory muscle involvement originally (PRM) and the second group included those who had bulbar muscle involvement originally (PBM). The third and fourth groups had only limb involvement originally but were separated by absence (PSL) or presence of a scoliosis (PSS) at the time of their evaluation. Each subject completed baseline and one year follow-up measurements of lung volumes, diffusion, flow rates, respiratory muscle strength, central and peripheral chemoreflexes and arterial blood gases. Sleep measurements included a full respiratory polysomnographic study. Fifty polio survivors and 13 controls completed the study. The PRM and PSS groups had an elevated arterial carbon dioxide tension (PaCO2) (mean +/- SE 6.0 +/- 0.4 and 6.0 +/- 0.3 kPa, respectively), reduced vital capacity (2.8 +/- 0.3 and 2.9 +/- 0.3 l, respectively), reduced maximal inspiratory pressure (-5.9 +/- 0.7 and -5.4 +/- 0.8 kPa, respectively) and reduced maximal expiratory pressure (9.8 +/- 1.1 and 9.1 +/- 1.2 kPa, respectively), when compared with non-polio controls. During sleep PRM and PSS groups experienced a higher PaCO2 (6.5 +/- 0.5 and 6.7 +/- 0.4 kPa, respectively) and a lower arterial oxygen saturation (SaO2) (89 +/- 4 and 86 +/- 3%, respectively). There were no differences among groups for diffusion, flow rates and chemoreflexes. All other polio survivors showed essentially normal respiratory function.(ABSTRACT TRUNCATED AT 250 WORDS)
Amelioration of Experimental Autoimmune Arthritis Through Targeting of Synovial Fibroblasts by Intraarticular Delivery of MicroRNAs 140‐3p and 140‐5p
Authors: Jia‐Shiou Peng, Shih‐Yao Chen, Chao‐Liang Wu, Hao‐Earn Chong, Yun‐Chiao Ding, Ai‐Li Shiau, Chrong‐Reen Wang
Journal: Arthritis & Rheumatology (2015)

Objective Synovial fibroblasts (SFs) with aberrant expression of microRNAs (miRNAs) are critical pathogenic regulators in rheumatoid arthritis (RA), and studies analyzing the effect of overexpressing or silencing miRNA expression in arthritis models can contribute to the development of miRNA‐based therapeutic strategies. This study was undertaken to examine the hypothesis that miRNAs 140‐3p and 140‐5p are involved in the pathogenesis of RA, and to determine whether targeting SFs through the intraarticular (IA) delivery of these molecules could ameliorate autoimmune arthritis in mice. Methods Synovial tissue samples were obtained from patients with RA. In addition, 2 experimental models in mice were used, collagen‐induced arthritis (CIA) and collagen antibody–induced arthritis (CAIA). Overexpression of miRNAs 140‐3p and 140‐5p in SFs and synovial tissue was induced using lentivirus (LV)–mediated transfer of pre‐miR‐140 precursor molecules. Results Lower expression levels of miR‐140‐3p and miR‐140‐5p were detected in synovial tissue and SFs from patients with RA and from mice in both arthritis models. In mice with CIA and mice with CAIA, the LV‐mediated IA transfer of miR‐140‐3p and miR‐140‐5p ameliorated arthritis, as determined by clinical examination and histopathologic evaluations showing a decrease in SF densities. Overexpression of miRNAs 140‐3p and 140‐5p caused a reduction in expression, with correlated kinetic patterns, of their corresponding target molecules sirtuin 1 and stromal cell–derived factor 1 in the SFs and joints of mice. Transfection of miR‐140‐3p and miR‐140‐5p into SFs increased cell apoptosis, reduced proliferation responses and migration abilities, and verified the concept that miR‐140 expression is regulated by proinflammatory cytokines. Conclusion These results demonstrate that targeting SFs by IA delivery of miRNAs 140‐3p and 140‐5p can ameliorate autoimmune arthritis. These findings might facilitate the pharmacologic development of molecular‐based therapies in RA.
The role of pre-receptor glucocorticoid metabolism in regulating the severity of ALI
Authors: Sian Lax, Micheal Wilson, Masao Takata, David Thickett
Journal: European Respiratory Journal (2012)

Acute lung injury (ALI) is a major cause of respiratory failure in the critically ill patient. With a mortality rate of 40-60%, 50% of survivors left with pulmonary impairment and no current licenced treatment there is a need for novel therapies. Our current research suggests that local steroid metabolism by alveolar macrophages is defective in ALI patients. As a major function of these cells is phagocytosis of apoptotic neutrophils during resolution of inflammation, we sought to investigate the effect of pre-receptor glucocorticoid metabolism in a murine model of ALI.

Using intra-tracheal instillations of LPS, we analysed the inflammatory response in wildtype mice compared to those deficient in 11β-hydroxysteroid dehydrogenase 1 (HSD1). These mice specifically lack the enzyme which converts inactive cortisone to active cortisol. Cell infiltrates and expression of several inflammatory markers within bronchial lavage fluid, as well as tissue permeability were examined to evaluate the immune response and lung damage.

Here we report that in HSD1-/- mice, lung permeability increases (6.1x10-3 ±0.9x10-3 v 10.7x10-3 ±2x10-3) 24hrs post-LPS. In addition, there was a build-up of apoptotic neutrophils (20.3x103 ±5.9x103 v 39.2x103 ±6.1x103), with a significant increase in CD11c+CD11b+ monocytes recruited into the lung (35.2x103 ±5.7x103 v 81.8x103 ±1.4x103) 72hrs post-LPS. Moreover, dys-regulation of IL6 was observed (1.5ng/ml ±0.62 versus 0.2ng/ml ±0.08) 72hrs post-LPS.

Our data indicate that insufficient alveolar glucocorticoid metabolism augments lung injury and suggests that therapies targetting defective macrophage HSD-1 expression may have value in ALI.
Familial Dysalbuminaemic Hyperthyroxinaemia and Other Causes of Euthyroid Hyperthyroxinaemia
Authors: C Farror, M L Wellby, C Beng
Journal: Journal of the Royal Society of Medicine (1987)

Clinical and biochemical studies on a family in which 3 members have familial dysalbuminaemic hyperthyroxinaemia (FDH) are presented. They were clinically euthyroid with elevated serum thyroxine (T4) and free T4 indices but normal free T4 by equilibrium dialysis and normal serum triiodothyronine (total and free). All thyroid function tests on the remaining family members were normal. The inheritance is consistent with autosomal dominance. Also presented are data on 4 unrelated patients with FDH and two patients with T4 autoantibodies. The methods for detecting FDH, T4 antibodies and other causes of euthyroid hyperthyroxinaemia are now freely available. Since these anomalies may be more common than previously supposed, clinical awareness of the conditions is necessary to protect patients from the consequences of incorrect diagnosis of thyrotoxicosis.
Antibacterial Activity of Honey against Strains of Staphylococcus Aureus from Infected Wounds
Authors: R A Cooper, P C Molan, K G Harding
Journal: Journal of the Royal Society of Medicine (1999)

The antibacterial action of honey in infected wounds does not depend wholly on its high osmolarity. We tested the sensitivity of 58 strains of coagulase-positive Staphylococcus aureus, isolated from infected wounds, to a pasture honey and a manuka honey. There was little variation between the isolates in their sensitivity to honey: minimum inhibitory concentrations were all between 2 and 3% (v/v) for the manuka honey and between 3 and 4% for the pasture honey. Thus, these honeys would prevent growth of S. aureus if diluted by body fluids a further seven-fold to fourteen-fold beyond the point where their osmolarity ceased to be completely inhibitory. The antibacterial action of the pasture honey relied on release of hydrogen peroxide, which in vivo might be reduced by catalase activity in tissues or blood. The action of manuka honey stems partly from a phytochemical component, so this type of honey might be more effective in vivo. Comparative clinical trials with standardized honeys are needed.
Unscheduled DNA Synthesis in Human Oral Mucosa Treated With Chemical Carcinogens in Short-Term Organ Culture<xref ref-type="fn" rid="fn2">2</xref>
Authors: F Ide, T Ishikawa, M Takagi, S Umemura, S Takayama
Journal: JNCI Journal of the National Cancer Institute (1982)

Unscheduled DNA synthesis (UDS) was investigated by autoradiography in human oral mucosa treated with 10 representative chemical carcinogens. Small sections of gingiva in short-term organ culture were exposed for 2 hours to chemical carcinogens plus [methyl-3H]thymidine. Significant numbers of silver grains, indicating UDS, were detected over the nuclei of both epithelial cells and fibroblasts. All ultimate or proximate carcinogens tested induced UDS. Of five procarcinogens tested, only benzo[a]pyrene (BP) did not induce UDS, but the more activated metabolite of BP, (+/-)-trans-7 beta-8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE I), was very effective in inducing UDS. Ultimate or proximate carcinogens induced higher levels of UDS than did procarcinogens. All the carcinogens that induced UDS showed clear dose-dependent effects. UDS levels were twofold to fivefold higher in the epithelial cells than in the fibroblasts, regardless of the type of carcinogen tested. Comparisons of the levels of UDS induced by 4-(hydroxyamino)quinoline 1-oxide, methyl methanesulfonate, or BPDE I did not reveal any significant differences. These findings indicate that human gingival epithelial UDS assay should be useful for short-term detection of environmental carcinogens that induce cancer in human oral mucosa.
High-Dose Intra-Arterial Cisplatin Boost With Hyperfractionated Radiation Therapy for Advanced Squamous Cell Carcinoma of the Head and Neck
Authors: William F. Regine, Joseph Valentino, Susanne M. Arnold, Richard C. Haydon, David Sloan, Daniel Kenady, James Strottmann, Calixto Pulmano, Mohammed Mohiuddin
Journal: Journal of Clinical Oncology (2001)

To evaluate the tolerance and efficacy of intra-arterial (IA) cisplatin boost with hyperfractionated radiation therapy (HFX-RT) in patients with advanced squamous cell carcinoma of the head and neck (SCCHN).Forty-two patients with locally advanced primary SCCHN were treated on consecutive phase I/II studies of HFX-RT (receiving a total of 76.8 to 81.6 Gy, given at 1.2 Gy bid) and IA cisplatin (150 mg/m(2) received at the start of and during RT boost treatment).Acute grade 3 to 4 toxicities were as follows: grade 4 and grade 3 mucosal toxicity occurred in three (7%) and 31 patients (69%), respectively, and grade 3 hematologic, infectious, and skin events occurred in one patient each. Eight of 24 patients (33%) were unable to receive a second planned dose of IA cisplatin because of general anxiety (n = 5), nausea and/or emesis (n = 2), or asymptomatic occlusion of an external carotid artery (n = 1). Thirty-seven patients (88%) experienced complete response (CR) at primary site. Twenty-nine (85%) of 34 patients presenting with nodal disease experienced CR. The actuarial 2-year rates of locoregional control and disease-specific and overall survival are 73%, 63%, and 57%, respectively, with a median active follow-up of 30 months.In this highly unfavorable subset of patients, these results seem superior to previously reported chemoradiation regimens in more favorable patients. Use of a second dose of IA cisplatin boost was associated with increased toxicity without obvious therapeutic gain. This novel strategy allows for an incremental increase in the treatment intensity of the HFX-RT regimen recently established as superior to once-a-day RT.
Dynamic pressure-volume loops as predictors of long-timescale derecruitment in the lung
Authors: Bradford Smith, Jason Bates
Journal: European Respiratory Journal (2013)

The tendency of the injured lung to derecruit with time is reflected in its increases in elastance during a few minutes of mechanical ventilation immediately following a recruitment maneuver. This procedure is inconvenient for clinical use, however, so we investigated whether the dynamic pressure-volume (PV) loop obtained during a single large breath can be used to estimate lung derecruitability.  Anesthetized, paralyzed, tracheostomized BALB/c mice were subjected, at zero end-expiratory pressure, to 16.5 min periods of over-ventilation (tidal volume, Vt = 1.0,1.1,1.2,1.3 ml) during which PV loops were recorded every 5.5 min. Lung derecruitability (Vt = 0.25ml) was assessed for 4.5 min between each over-ventilation epoch. The mice were exposed to alternating derecruitability tests and over-ventilation epochs for up to 4 hrs.  Each derecruitability test provided an initial value of lung elastance ( H  1 ) and a subsequent mean rate of change of elastance ( D Rate  ). Each dynamic PV loop provided a measure of lung elastance ( H  0.2  m   l  ) at the 0.2 ml point during inspiration. Both  H  1  (Fig. 1a) and  D Rate   (Fig. 1b) exhibited strongly correlated sigmoidal relationships with  H  0.2  m   l  . This suggests that the long timescale derecruitability of the lung, encapsulated in  H  1  and  D Rate  , is also reflected in the shape of the dynamic PV relationship, quantified by  H  0.20  m   l  . The latter may thus be a clinically useful measure of derecruitability.