More than 30% of patients with pleural infection either die or require surgery. Drainage of infected fluid is key to successful treatment, but intrapleural fibrinolytic therapy did not improve ...outcomes in an earlier, large, randomized trial.
We conducted a blinded, 2-by-2 factorial trial in which 210 patients with pleural infection were randomly assigned to receive one of four study treatments for 3 days: double placebo, intrapleural tissue plasminogen activator (t-PA) and DNase, t-PA and placebo, or DNase and placebo. The primary outcome was the change in pleural opacity, measured as the percentage of the hemithorax occupied by effusion, on chest radiography on day 7 as compared with day 1. Secondary outcomes included referral for surgery, duration of hospital stay, and adverse events.
The mean (±SD) change in pleural opacity was greater in the t-PA-DNase group than in the placebo group (-29.5±23.3% vs. -17.2±19.6%; difference, -7.9%; 95% confidence interval CI, -13.4 to -2.4; P=0.005); the change observed with t-PA alone and with DNase alone (-17.2±24.3 and -14.7±16.4%, respectively) was not significantly different from that observed with placebo. The frequency of surgical referral at 3 months was lower in the t-PA-DNase group than in the placebo group (2 of 48 patients 4% vs. 8 of 51 patients 16%; odds ratio for surgical referral, 0.17; 95% CI, 0.03 to 0.87; P=0.03) but was greater in the DNase group (18 of 46 patients 39%) than in the placebo group (odds ratio, 3.56; 95% CI, 1.30 to 9.75; P=0.01). Combined t-PA-DNase therapy was associated with a reduction in the hospital stay, as compared with placebo (difference, -6.7 days; 95% CI, -12.0 to -1.9; P=0.006); the hospital stay with either agent alone was not significantly different from that with placebo. The frequency of adverse events did not differ significantly among the groups.
Intrapleural t-PA-DNase therapy improved fluid drainage in patients with pleural infection and reduced the frequency of surgical referral and the duration of the hospital stay. Treatment with DNase alone or t-PA alone was ineffective. (Funded by an unrestricted educational grant to the University of Oxford from Roche UK and by others; Current Controlled Trials number, ISRCTN57454527.).
Long bones are composite materials possessing nonhomogeneous and anisotropic properties. They repair themselves (self-repairing) and adapt to changing mechanical demands by altering their shape and ...mechanical properties (self-adapting). Such exceptional features make long bones intriguing materials to comprehend properly. This also expands our knowledge of engineering materials and motivates researchers to employ novel techniques where conventional approaches may present limitations. This paper delves into the use of artificial neural network (ANN) expert systems to predict load-displacement curves of a long bone. Thirteen hydrated third metacarpal (MC3) bones from thoroughbred horses aged from twelve hours to three years were loaded in compression in an MTS machine. Strain readings from one three-gauge rosette and three distinct single-element gauges at different locations on the MC3 midshaft, displacement, load, load exposure time, horse age and bone side (left or right limb) were recorded for each bone. This information shaped ANNs input variables. Two in-series feedforward back-propagation ANNs were employed where the experimental recordings except for load were fed into the first ANN to predict load. Then, the predicted load along with the rest of experimental recordings were fed into the second ANN to predict displacement. Cyclic load-displacement and stiffness predicted by ANNs were plotted versus experimental counterparts. ANNs regression analyses showed R > 0.95 for training and testing datasets. To confirm their accuracy, ANNs were used to predict responses of specific bone samples that were not used in ANNs training. The ANNs trained using 17,718 experimental data points from twelve bones predicted the load (R = 0.997, RMSE = 2.44 kN), displacement (R = 0.948, RMSE = 0.321 mm), and stiffness (R = 0.982, RMSE = 1.197 kN/mm) of the thirteenth bone. The encouraging outcomes exhibit the exceptional ability of artificial neural networks in capturing the mechanical characteristics of complex structures.
Malignant pleural effusion causes disabling dyspnea in patients with a short life expectancy. Palliation is achieved by fluid drainage, but the most effective first-line method has not been ...determined.
To determine whether indwelling pleural catheters (IPCs) are more effective than chest tube and talc slurry pleurodesis (talc) at relieving dyspnea.
Unblinded randomized controlled trial (Second Therapeutic Intervention in Malignant Effusion Trial TIME2) comparing IPC and talc (1:1) for which 106 patients with malignant pleural effusion who had not previously undergone pleurodesis were recruited from 143 patients who were treated at 7 UK hospitals. Patients were screened from April 2007-February 2011 and were followed up for a year.
Indwelling pleural catheters were inserted on an outpatient basis, followed by initial large volume drainage, education, and subsequent home drainage. The talc group were admitted for chest tube insertion and talc for slurry pleurodesis.
Patients completed daily 100-mm line visual analog scale (VAS) of dyspnea over 42 days after undergoing the intervention (0 mm represents no dyspnea and 100 mm represents maximum dyspnea; 10 mm represents minimum clinically significant difference). Mean difference was analyzed using a mixed-effects linear regression model adjusted for minimization variables.
Dyspnea improved in both groups, with no significant difference in the first 42 days with a mean VAS dyspnea score of 24.7 in the IPC group (95% CI, 19.3-30.1 mm) and 24.4 mm (95% CI, 19.4-29.4 mm) in the talc group, with a difference of 0.16 mm (95% CI, −6.82 to 7.15; P = .96). There was a statistically significant improvement in dyspnea in the IPC group at 6 months, with a mean difference in VAS score between the IPC group and the talc group of −14.0 mm (95% CI, −25.2 to −2.8 mm; P = .01). Length of initial hospitalization was significantly shorter in the IPC group with a median of 0 days (interquartile range IQR, 0-1 day) and 4 days (IQR, 2-6 days) for the talc group, with a difference of −3.5 days (95% CI, −4.8 to −1.5 days; P < .001). There was no significant difference in quality of life. Twelve patients (22%) in the talc group required further pleural procedures compared with 3 (6%) in the IPC group (odds ratio OR, 0.21; 95% CI, 0.04-0.86; P = .03). Twenty-one of the 52 patients in the catheter group experienced adverse events vs 7 of 54 in the talc group (OR, 4.70; 95% CI, 1.75-12.60; P = .002).
Among patients with malignant pleural effusion and no previous pleurodesis, there was no significant difference between IPCs and talc pleurodesis at relieving patient-reported dyspnea.
isrctn.org Identifier: ISRCTN87514420.
Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, ...germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (∼1-5%) who could have selective therapeutic sensitivity to PARP inhibition.
Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We adapted methods from molecular evolution and applied ...them to 7,664 tumors across 29 cancer types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, <1 coding base substitution/tumor is lost through negative selection, with purifying selection almost absent outside homozygous loss of essential genes. This allows exome-wide enumeration of all driver coding mutations, including outside known cancer genes. On average, tumors carry ∼4 coding substitutions under positive selection, ranging from <1/tumor in thyroid and testicular cancers to >10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We systematically catalog cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.
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•Unlike the germline, somatic cells evolve predominantly by positive selection•Nearly all (∼99%) coding mutations are tolerated and escape negative selection•Exome-wide estimates of the total number of driver coding mutations per tumor•Half of the coding driver mutations occur outside of known cancer genes
Adapting an evolutionary genomics approach to cancer highlights a limited impact of negative selection on cancer genomes and significant variations in the proportion of coding driver mutations per tumor among different tumor types.
The development and use of experimental models using lymphatic cannulation techniques have been hampered by the lack of high-quality colour imaging of lymphatic vessels in situ. Most descriptions of ...lymphatic anatomy in sheep have historically depended on schematic diagrams due to limitations in the ability to publish colour images of the lymphatic vessels with decent resolution. The aim of this work was to encourage more widespread use of the ovine cannulation model by providing clear photographic images identifying the location and anatomical layout of some major lymphatic ducts and their in situ relationship to surrounding tissues.
The cadavers of the sheep were collected after they had been euthanized at the end of animal trials not associated with this study. The lymphatics were dissected and exposed to show their appearance in the surrounding tissues and their relationship to other organs. Patent Blue was used to locate lymphatic vessels in exploratory preparations. However, in order to present the natural appearance of the vessels, we used minimal dissection and dye was not used for the photographed examples. Instead, we have indicated the course of the vessels with lines where their position is less clear.
In this paper, we have used sheep specimens as examples to show characteristic images of lymphatic vessels. The images of in situ lymphatics and lymph nodes combined with schematic summaries provide a concise illustration of the lymphatic drainage scheme in sheep.
This paper reports on an investigation into the relationship between stiffness and applied force of an advanced biological composite structure using four techniques: experimental observation; finite ...element analysis (FEA); regression learner analysis; and, artificial neural networks (ANNs). The entire hydrated third metacarpal bones (MC3) from 16 thoroughbred horses were loaded in compression in an MTS machine. The stiffness was then determined from the applied force, MC3 displacement, and load exposure time. A variety of mathematical functions were fitted to the sample data points using MATLAB to demonstrate force-dependent stiffness. Two functions were found that exhibited a strong correlation between force and stiffness (R
2
= 0.75). Additionally, a power function was found that demonstrated a stronger correlation between the stiffness and force (R
2
= 0.81) if the exposure time was also incorporated. FEA considered the calculated force-dependent stiffness when assigning material properties. FEA results were compared with experimental data (for verification and validation), and a good agreement was found for the displacement (RMSE = 0.032 mm) and strain (RMSE = 61.85 με). Machine learning regression models were also employed to predict the stiffness of this complex structure. Applied force, exposure time, MC3 geometry (length and area of cross sections), and age were defined as the independent variables. The regression learner offered excellent reliability (R
2
= 0.98) for the prediction of stiffness. Also, feedforward back-propagation artificial neural networks were employed to improve and generalize the stiffness prediction ability to a wider population. ANN regression analysis showed R = 0.992 for training, R = 0.99 for testing, and R = 0.991 for the all datasets. To confirm its accuracy, the ANN was used to predict stiffness of specific samples that were not used in its training. This offered excellent reliability in predicting real-world data that ANNs have not seen before (R = 0.976).
The Life History of 21 Breast Cancers Nik-Zainal, Serena; Van Loo, Peter; Wedge, David C. ...
Cell,
05/2012, Letnik:
149, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Cancer evolves dynamically as clonal expansions supersede one another driven by shifting selective pressures, mutational processes, and disrupted cancer genes. These processes mark the genome, such ...that a cancer's life history is encrypted in the somatic mutations present. We developed algorithms to decipher this narrative and applied them to 21 breast cancers. Mutational processes evolve across a cancer's lifespan, with many emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, and most mutations are found in just a fraction of tumor cells. Every tumor has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent cell lineages capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer's development, triggering diagnosis.
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► Genome-wide analyses of mutations emerging through time in 21 breast cancers ► Minimal expansion of subclones occurs until thousands of mutations have accumulated ► Cancer-specific signatures of point mutations and genomic instability emerge late ► ERBB2 amplification begins early but continues to evolve over long molecular time
Newly developed algorithms allow the reconstruction of the genomic history of different breast cancers, tracing the temporal evolution of each tumor and the emergence of the dominant subclones that will eventually trigger diagnosis.
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