Background & Aims
Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. The global HCC BRIDGE study was a multiregional, large‐scale, longitudinal cohort study ...undertaken to improve understanding of real‐life management of patients with HCC, from diagnosis to death.
Methods
Data were collected retrospectively from January 2005 to September 2012 by chart reviews of eligible patients newly diagnosed with HCC at participating institutions.
Results
Forty‐two sites in 14 countries contributed final data for 18 031 patients. Asia accounted for 67% of patients, Europe for 20% and North America for 13%. As expected, the most common risk factor was hepatitis C virus in North America, Europe and Japan, and hepatitis B virus in China, South Korea and Taiwan. The most common Barcelona Clinic Liver Cancer stage at diagnosis was C in North America, Europe, China and South Korea, and A in Taiwan and Japan. Across all stages, first HCC treatment was most frequently transarterial chemoembolization in North America, Europe, China and South Korea, percutaneous ethanol injection or radiofrequency ablation in Japan and resection in Taiwan. Survival from first HCC treatment varied significantly by region, with median overall survival not reached for Taiwan and 60, 33, 31, 24 and 23 months for Japan, North America, South Korea, Europe and China respectively (P < 0.0001).
Conclusions
Initial results from the BRIDGE study confirm previously reported regional trends in patient demographic characteristics and HCC risk factors, document the heterogeneity of treatment approaches across regions/countries and underscore the need for earlier HCC diagnosis worldwide.
Activation of the c-Met pathway occurs in a range of malignancies, including papillary renal cell carcinoma (RCC). Its activity in clear cell RCC is less clear. We investigated c-Met expression and ...inhibition in a large cohort of RCC tumors and cell lines.
c-Met protein expression was determined by automated quantitative analysis (AQUA) on a tissue microarray (TMA) constructed from 330 RCC tumors paired with adjacent normal renal tissue. c-Met expression and selective inhibition with SU11274 and ARQ 197 were studied in clear cell RCC cell lines.
Higher c-Met expression was detected in all RCC subtypes than in the adjacent normal renal tissue (P < 0.0001). Expression was highest in papillary and sarcomatoid subtypes, and high-grade and stage tumors. Higher c-Met expression correlated with worse disease-specific survival risk ratio = 1.36; 95% confidence interval (CI) 1.08–1.74; P = 0.0091 and was an independent predictor of survival, maintained in clear cell subset analyses. c-Met protein was activated in all cell lines, and proliferation (and colony formation) was blocked by SU11274 and ARQ 197.
c-Met is associated with poor pathologic features and prognosis in RCC. c-Met inhibition demonstrates in vitro activity against clear cell RCC. Further study of ARQ 197 with appropriate biomarker studies in RCC is warranted.
We use nonadiabatic mixed quantum/classical molecular dynamics to simulate recent time-resolved photoelectron spectroscopy (TRPES) experiments on the hydrated electron, and compare the results for ...both a cavity and a noncavity simulation model to experiment. We find that cavity-model hydrated electrons show an “adiabatic” relaxation mechanism, with ground-state cooling that is fast on the time scale of the internal conversion, a feature that is in contrast to the TRPES experiments. A noncavity hydrated electron model, however, displays a “nonadiabatic” relaxation mechanism, with rapid internal conversion followed by slower ground-state cooling, in good qualitative agreement with experiment. We also show that the experimentally observed early time red shift and loss of anisotropy of the excited-state TRPES peak are consistent with hydrated electron models with homogeneously broadened absorption spectra, but not with those with inhomogeneously broadened absorption spectra. Finally, we find that a decreasing photoionization cross section upon cooling causes the excited-state TRPES peak to decay faster than the underlying radiationless relaxation process, so that the experimentally observed 60–75 fs peak decay corresponds to an actual excited-state lifetime of the hydrated electron that is more likely ∼100 fs.
Mechanical forces are central to developmental, physiological and pathological processes. However, limited understanding of force transmission within sub-cellular structures is a major obstacle to ...unravelling molecular mechanisms. Here we describe the development of a calibrated biosensor that measures forces across specific proteins in cells with piconewton (pN) sensitivity, as demonstrated by single molecule fluorescence force spectroscopy. The method is applied to vinculin, a protein that connects integrins to actin filaments and whose recruitment to focal adhesions (FAs) is force-dependent. We show that tension across vinculin in stable FAs is ∼2.5 pN and that vinculin recruitment to FAs and force transmission across vinculin are regulated separately. Highest tension across vinculin is associated with adhesion assembly and enlargement. Conversely, vinculin is under low force in disassembling or sliding FAs at the trailing edge of migrating cells. Furthermore, vinculin is required for stabilizing adhesions under force. Together, these data reveal that FA stabilization under force requires both vinculin recruitment and force transmission, and that, surprisingly, these processes can be controlled independently.
In vivo animal experiments demonstrate neurotoxicity of exposures to particulate matter (PM) and ozone, but only one small epidemiological study had linked ambient air pollution with central nervous ...system (CNS) functions in children.
To examine the neurobehavioral effects associated with long-term exposure to ambient PM and ozone in adults.
We conducted a secondary analysis of the Neurobehavioral Evaluation System-2 (NES2) data (including a simple reaction time test SRTT measuring motor response speed to a visual stimulus; a symbol-digit substitution test SDST for coding ability; and a serial-digit learning test SDLT for attention and short-term memory) from 1764 adult participants (aged 37.5
±
10.9 years) of the Third National Health and Nutrition Examination Survey in 1988–1991. Based on ambient PM
10 (PM with aerodynamic diameter <10
μm) and ozone data from the EPA Aerometric Information Retrieval System database, estimated annual exposure prior to the examination were aggregated at the centroid of each census-block group of geocoded residences, using distance-weighted averages from all monitors in the residing and adjoining counties. Generalized linear models were constructed to examine the associations, adjusting for potential confounders.
In age- and sex-adjusted models, PM
10 predicted reduced CNS functions, but the association disappeared after adjustment for sociodemographic factors. There were consistent associations between ozone and reduced performance in NES2. In models adjusting for demographics, socioeconomic status, lifestyle, household and neighborhood characteristics, and cardiovascular risk factors, ozone predicted high scores in SDST and SDLT, but not in SRTT. Each 10-ppb increase in annual ozone was associated with increased SDST and SDLT scores by 0.16 (95%CI: 0.01, 0.23) and 0.56 (95%CI: 0.07, 1.05), equivalent to 3.5 and 5.3 years of aging-related decline in cognitive performance.
Our study provides the first epidemiological data supporting the adverse neurobehavioral effects of ambient air pollutants in adults.
Empirical spatial air pollution models have been applied extensively to assess exposure in epidemiological studies with increasingly sophisticated and complex statistical algorithms beyond ordinary ...linear regression. However, different algorithms have rarely been compared in terms of their predictive ability.
This study compared 16 algorithms to predict annual average fine particle (PM2.5) and nitrogen dioxide (NO2) concentrations across Europe. The evaluated algorithms included linear stepwise regression, regularization techniques and machine learning methods. Air pollution models were developed based on the 2010 routine monitoring data from the AIRBASE dataset maintained by the European Environmental Agency (543 sites for PM2.5 and 2399 sites for NO2), using satellite observations, dispersion model estimates and land use variables as predictors. We compared the models by performing five-fold cross-validation (CV) and by external validation (EV) using annual average concentrations measured at 416 (PM2.5) and 1396 sites (NO2) from the ESCAPE study. We further assessed the correlations between predictions by each pair of algorithms at the ESCAPE sites.
For PM2.5, the models performed similarly across algorithms with a mean CV R2 of 0.59 and a mean EV R2 of 0.53. Generalized boosted machine, random forest and bagging performed best (CV R2~0.63; EV R2 0.58–0.61), while backward stepwise linear regression, support vector regression and artificial neural network performed less well (CV R2 0.48–0.57; EV R2 0.39–0.46). Most of the PM2.5 model predictions at ESCAPE sites were highly correlated (R2 > 0.85, with the exception of predictions from the artificial neural network). For NO2, the models performed even more similarly across different algorithms, with CV R2s ranging from 0.57 to 0.62, and EV R2s ranging from 0.49 to 0.51. The predicted concentrations from all algorithms at ESCAPE sites were highly correlated (R2 > 0.9). For both pollutants, biases were low for all models except the artificial neural network. Dispersion model estimates and satellite observations were two of the most important predictors for PM2.5 models whilst dispersion model estimates and traffic variables were most important for NO2 models in all algorithms that allow assessment of the importance of variables.
Different statistical algorithms performed similarly when modelling spatial variation in annual average air pollution concentrations using a large number of training sites.
•Multiple statistical algorithms with very different assumptions were compared.•Despite the difference in modeling frameworks, predictions among the models exhibit generally good agreement.•The use of an external evaluation dataset strengthens evaluation by cross-validation.
We report observations from the Magnetospheric Multiscale (MMS) satellites of a large guide field magnetic reconnection event. The observations suggest that two of the four MMS spacecraft sampled the ...electron diffusion region, whereas the other two spacecraft detected the exhaust jet from the event. The guide magnetic field amplitude is approximately 4 times that of the reconnecting field. The event is accompanied by a significant parallel electric field (E(sub parallel lines) that is larger than predicted by simulations. The high-speed (approximately 300 km/s) crossing of the electron diffusion region limited the data set to one complete electron distribution inside of the electron diffusion region, which shows significant parallel heating. The data suggest that E(sub parallel lines) is balanced by a combination of electron inertia and a parallel gradient of the gyrotropic electron pressure.
The autonomic nervous system regulates all aspects of normal cardiac function, and is recognized to play a critical role in the pathophysiology of many cardiovascular diseases. As such, the value of ...neuroscience‐based cardiovascular therapeutics is increasingly evident. This White Paper reviews the current state of understanding of human cardiac neuroanatomy, neurophysiology, pathophysiology in specific disease conditions, autonomic testing, risk stratification, and neuromodulatory strategies to mitigate the progression of cardiovascular diseases.
To present pilot toxicity and survival outcomes for a prospective trial investigating adaptive radiotherapy (ART) for oropharyngeal squamous cell carcinoma.
A total of 24 patients were enrolled in an ...institutional review board-approved clinical trial; data for 22 of these patients were analyzed. Daily CT-guided setup and deformable image registration permitted serial mapping of clinical target volumes and avoidance structures for ART planning. Primary site was base of tongue in 15 patients, tonsil in 6 patient, and glossopharyngeal sulcus in 1 patient. Twenty patients (91%) had American Joint Committee on Cancer (AJCC) Stage IV disease. T stage distribution was 2 T1, 12 T2, 3 T3, 5 T4. N stage distribution was 1 N0, 2 N1, 5 N2a, 12 N2b, and 2 N2c. Of the patients, 21 (95%) received systemic therapy.
With a 31-month median follow-up (range, 13-45 months), there has been no primary site failure and 1 nodal relapse, yielding 100% local and 95% regional disease control at 2 years. Baseline tumor size correlated with absolute volumetric treatment response (p = 0.018). Parotid volumetric change correlated with duration of feeding tube placement (p = 0.025). Acute toxicity was comparable to that observed with conventional intensity-modulated radiotherapy (IMRT). Chronic toxicity and functional outcomes beyond 1 year were tabulated.
This is the first prospective evaluation of morbidity and survival outcomes in patients with locally advanced head-and-neck cancer treated with automated adaptive replanning. ART can provide dosimetric benefit with only one or two mid-treatment replanning events. Our preliminary clinical outcomes document functional recovery and preservation of disease control at 1-year follow-up and beyond.
There is an urgent need to create novel models using human disease-relevant cells to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) biology and to facilitate drug screening. Here, ...as SARS-CoV-2 primarily infects the respiratory tract, we developed a lung organoid model using human pluripotent stem cells (hPSC-LOs). The hPSC-LOs (particularly alveolar type-II-like cells) are permissive to SARS-CoV-2 infection, and showed robust induction of chemokines following SARS-CoV-2 infection, similar to what is seen in patients with COVID-19. Nearly 25% of these patients also have gastrointestinal manifestations, which are associated with worse COVID-19 outcomes
. We therefore also generated complementary hPSC-derived colonic organoids (hPSC-COs) to explore the response of colonic cells to SARS-CoV-2 infection. We found that multiple colonic cell types, especially enterocytes, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-LOs, we performed a high-throughput screen of drugs approved by the FDA (US Food and Drug Administration) and identified entry inhibitors of SARS-CoV-2, including imatinib, mycophenolic acid and quinacrine dihydrochloride. Treatment at physiologically relevant levels of these drugs significantly inhibited SARS-CoV-2 infection of both hPSC-LOs and hPSC-COs. Together, these data demonstrate that hPSC-LOs and hPSC-COs infected by SARS-CoV-2 can serve as disease models to study SARS-CoV-2 infection and provide a valuable resource for drug screening to identify candidate COVID-19 therapeutics.
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