Anaplastic lymphoma kinase status in lung cancers: An immunohistochemistry and fluorescence in situ hybridization study from a tertiary cancer center in India.

BACKGROUND AND OBJECTIVES: Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) have shown good concordance for the detection of echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (ALK) rearrangement. Since studies reporting FISH/IHC concordance, clinicopathological features, and clinical outcomes of ALK-positive patients from India are lacking, this study was undertaken. MATERIALS AND METHODS: This is a retrospective, observational study of patients with adenocarcinoma of the lung on whom ALK test was performed between March 2013 and December 2015. ALK status was assessed in 341 patients by FISH using Vysis ALK Dual Color Break Apart Rearrangement Probe and IHC using ALK D5F3 clone. Clinicopathological features were noted. Patients were managed as per the standard guidelines. Clinical outcomes - response rate (RR) and progression-free survival (PFS) - were measured. RESULTS: ALK rearrangement was positive in 37 patients (10.9%). ALK positivity was observed more commonly in younger patients with no predilection for any gender or any specific histological subtype. ALK by IHC was highly sensitive (100%), compared to FISH with concordance rate of 94.4%. Thirty one of thirty seven (31 of 37) patients received therapy of which 3 patients received palliative chemotherapy and 28 patients received tyrosine kinase inhibitors (crizotinib/ceritinib). Overall RR observed was 77.4%, and median PFS had not been reached at a median follow-up of 12.5 months. INTERPRETATION AND CONCLUSIONS: We report higher frequency of ALK positivity (10.9%) in patients with adenocarcinoma of the lung. ALK by IHC is more sensitive than FISH for ALK detection with high concordance. These patients had good clinical outcome with TKIs targeting ALK fusion protein.

A Reduced Form Model for Ozone Based on Two Decades of CMAQ Simulations for the Continental United States.

A Reduced Form Model (RFM) is a mathematical relationship between the inputs and outputs of an air quality model, permitting estimation of additional modeling without costly new regional-scale simulations. A 21-year Community Multiscale Air Quality (CMAQ) simulation for the continental United States provided the basis for the RFM developed in this study. Predictors included the principal component scores (PCS) of emissions and meteorological variables, while the predictand was the monthly mean of daily maximum 8-hour CMAQ ozone for the ozone season at each model grid. The PCS form an orthogonal basis for RFM inputs. A few PCS incorporate most of the variability of emissions and meteorology, thereby reducing the dimensionality of the source-receptor problem. Stochastic kriging was used to estimate the model. The RFM was used to separate the effects of emissions and meteorology on ozone concentrations. by running the RFM with emissions constant (ozone dependent on meteorology), or constant meteorology (ozone dependent on emissions). Years with ozone-conducive meteorology were identified, and meteorological variables best explaining meteorology-dependent ozone were identified. Meteorology accounted for 19% to 55% of ozone variability in the eastern US, and 39% to 92% in the western US. Temporal trends estimated for original CMAQ ozone data and emission-dependent ozone were mostly negative, but the confidence intervals for emission-dependent ozone are much narrower. Emission-driven changes in monthly mean ozone levels for the period 2000-2010 ranged from 6.4 to 10.9 ppb for the eastern US and from 1.4 to 2.5 ppb for the western US.

Space-time analysis of the Air Quality Model Evaluation International Initiative (AQMEII) Phase 1 air quality simulations.

UNLABELLED: This study presents an evaluation of summertime ozone concentrations over North America (NA) and Europe (EU) using the database generated from Phase 1 of the Air Quality Model Evaluation International Initiative (AQMEII). The analysis focuses on identifying temporal and spatial features that can be used to stratify operational model evaluation metrics and to test the extent to which the various modeling systems can replicate the features seen in the observations. Using a synoptic map typing approach, it is demonstrated that model performance varies with meteorological conditions associated with specific synoptic-scale flow patterns over both eastern NA and EU. For example, the root mean square error of simulated daily maximum 8-hr ozone was twice as high when cloud fractions were high compared with when cloud fractions were low over eastern NA. Furthermore, results show that over both NA and EU the regional models participating in AQMEII were able to better reproduce the observed variance in ambient ozone levels than the global model used to specify chemical boundary conditions, although the variance simulated by almost all regional models is still less that the observed variance on all spatiotemporal scales. In addition, all modeling systems showed poor correlations with observed fluctuations on the intraday time scale over both NA and EU. Furthermore, a methodology is introduced to distinguish between locally influenced and regionally representative sites for the purpose of model evaluation. Results reveal that all models have worse model performance at locally influenced sites. Overall, the analyses presented in this paper show how observed temporal and spatial information can be used to stratify operational model performance statistics and to test the modeling systems' ability to replicate observed temporal and spatial features, especially at scales the modeling systems are designed to capture. IMPLICATIONS: The analyses presented in this paper demonstrate how observed temporal and spatial information can be used to stratify operational model performance and to test the modeling systems' ability to replicate observed temporal and spatial features. Decisions for the improvement of regional air quality models should be based on the information derived from only regionally representative sites.

Assessment of geochemical processes occurring in groundwaters in the coastal alluvial aquifer.

Groundwater samples are collected from 30 observation wells in the study area to analyze the hydrochemical quality for determining the seawater encroachment in the part of Central Godavari Delta, Bay of Bengal, India. In order to establish the baseline hydrochemical conditions and processes determining the groundwater quality, an integrated investigation coupled with multivariate statistical analysis and hydrochemical methods are used to identify and interpret the groundwater chemistry of the aquifer system. The major land use is irrigated agriculture and aquaculture in the study area. The ground waters affected by the seawater intrusion featured high levels of sodium (Na(+)), chloride (Ca(+)), and TDS, which are the simplest common indicators for seawater influence. The elevated levels of NO3-N at some monitoring wells indicate nitrate pollution of groundwater due to anthropogenic origin such as septic effluents or chemical fertilizers. Besides the major chemical compositions, it was also demonstrated that ionic ratios would be useful to delineate seawater intrusion and they include Na(+)/Ca(2+), Mg(2+)/Ca(2+), SO4 (2-)/Ca(2+), Na(+)/(Na(+) + Cl(-)), and Ca(-)/sum of anions. This paper demonstrates the variations in hydrochemical quality of groundwater and its evolution processes in two different seasons in the coastal aquifer alluvial settings.

Recurrent alpha-fetoprotein secreting Sertoli-Leydig cell tumor of ovary with an unusual presentation.

Alpha-fetoprotein secreting (AFP) Sertoli-Leydig cell tumors of ovary (SLCT) are now identified as a distinct entity among the uncommon group of sex cord tumors of ovary. We report an unusual case of recurrent AFP secreting ovarian tumors and as ileocecal mesenteric cyst in a 25-year-old patient resulting in difficulty in initial diagnosis of AFP producing SLCT. Although six recurrent cases were described out of the 25 reported cases of AFP secreting SLCTs, this patient with an unusual presentation of recurrence is the second case in the literature to the best of our knowledge.

Anesthetic consideration in downs syndrome--a review.

Downs syndrome constitutes to be the most common chromosomal disorder. Patients with Downs's syndrome are posted for several surgeries including dental procedures and even for facial reconstruction. They are associated with several congenital anomalies in different organ system. There is also increased incidence of atlanto axial instability and risk of spinal cord injury. These children are susceptible to infection and they are also considered to be hypersensitive to the effect or atropine. These all factors modify the anesthetic implication and also anesthetic management in these cases. We have highlighted all these factors and reviewed the anesthetic implication of these child posted for several procedures under anesthesia.

Assessing the effects of transboundary ozone pollution between Ontario, Canada and New York, USA.

We investigated the effects of transboundary pollution between Ontario and New York using both observations and modeling results. Analysis of the spatial scales associated with ozone pollution revealed the regional and international character of this pollutant. A back-trajectory-clustering methodology was used to evaluate the potential for transboundary pollution trading and to identify potential pollution source regions for two sites: CN tower in Toronto and the World Trade Center in New York City. Transboundary pollution transport was evident at both locations. The major pollution source areas for the period examined were the Ohio River Valley and Midwest. Finally, we examined the transboundary impact of emission reductions through photochemical models. We found that emissions from both New York and Ontario were transported across the border and that reductions in predicted O3 levels can be substantial when emissions on both sides of the border are reduced.

Spatial and temporal variations in the trace elemental data over the northeastern United States.

Time series of trace elemental concentrations (14 species) of atmospheric fine particles measured in the northeastern United States between 1988 and 1998 are analyzed for spatial and temporal variations. The influence of synoptic-scale systems to the transport and accumulation of pollutants can be investigated successfully if the short-term fluctuations (i.e. weather-induced variations) embedded in the time series of pollutant concentrations are separated from the original time series. The spatial short-term correlation coefficients for Al, Br, Fe, Se, and Zn permit good predictions of pollutant concentrations up to distances of about 350 km from a given monitor. The species correlation matrices for individual sites reveal that As, Br, Se, and Zn are highly correlated in New York State, while Fe, Mn, and V show also strong correlations, suggesting the commonality of source regions for these industrial and urban pollutants impacting New York.

An evaluation of the UAM-V predicted concentrations of carbon monoxide and reactive nitrogen compounds over the eastern United States during summer 1995.

While there is a clear need to evaluate a photochemical model's ability in predicting not only the concentrations of O3, but also precursors and other trace species, many previous studies have focused only on the assessment of During the 1995 summer season, in addition to the routine monitoring of criteria pollutants, several research-oriented monitoring campaigns were conducted over the eastern United States, providing an extensive database of reactive nitrogen compounds, CO, and speciated hydrocarbon data. In this study, we examine the ability of a photochemical modeling system, RAMS/ UAM-V, to reproduce the measured concentrations of CO, NO2, and NOy over the region during the summer of 1995. The results demonstrate that there is agreement between modeled and measured seasonal average concentrations of NO2, both at the routine and research monitors. The same is true for NOy, but to a lesser degree. However, the model is found to significantly underpredict CO for the routine monitors in comparison to the research monitors.

Do we understand trends in atmospheric sulfur species?

Anomalies appear to exist in our understanding of atmospheric sulfur compounds, specifically as evidenced in the time trends of the different chemical forms of these compounds. Trends determined at a number of locations by several different groups seem to indicate that, responding to emission reductions across North America, the concentration of SO2 in the atmosphere is declining more rapidly than that of aerosol SO4(2-). A number of possible reasons for this discrepancy are examined, but it is not possible to provide a definitive answer at this stage. The intent is to stimulate debate, because shortcomings in our understanding of the processes involved could have profound implications for the credibility of abatement strategies and policies for both acid deposition and fine particulate matter (PM).

A comparison of measured and simulated ozone concentrations in the rural areas of the eastern United States during summer 1995.

The recent regulatory actions toward a longer-term (i.e., 8-hr) average ozone standard have brought forth the potential for many rural areas in the eastern United States to be in noncompliance. However, since a majority of these rural areas have generally few sources of anthropogenic emissions, the measured ozone levels primarily reflect the effects of the transport of ozone and its precursor pollutants and natural emissions. While photochemical grid models have been applied to urban areas to develop ozone mitigation measures, these efforts have been limited to high ozone episode events only and do not adequately cover rural regions. In this study, we applied a photochemical modeling system, RAMS/UAM-V, to the eastern United States from June 1-August 31, 1995. The purpose of the study is to examine the predictive ability of the modeling system at rural monitoring stations that are part of the Clean Air Status Trends Network (CASTNet) and the Gaseous Pollutant Monitoring Program (GPMP). The results show that the measured daily 1-hr ozone maxima and the seasonal average of the daily 1-hr ozone maxima are in better agreement with the predictions of the modeling system than those for the daily 8-hr ozone maxima. Also, the response of the modeling system in reproducing the measured range of ozone levels over the diurnal cycle is poor, suggesting the need for improvement in the treatment of the physical and chemical processes of the modeling system during the nighttime and morning hours if it is to be used to address the 8-hr ozone standard.

Ozone air quality over North America: part I--a review of reported trends.

Ozone and precursor trends can be used to measure the effectiveness of regulatory programs that have been implemented. In this paper, we review trends in the concentrations of O3 NOx, and HCs over North America that have been reported in the literature. Although most existing trend studies are confounded by meteorological variability, both the raw data trends and the trends adjusted for meteorology collectively indicate a general decreasing trend in O3 concentrations in most areas of the United States during 1985-1996. In Canada, mean daily maximum 1-hr O3 concentrations at urban sites show mixed trends with a majority of sites showing an increase from 1980 to 1993. Mean daily maximum 1-hr O3 at most regionally representative Canadian sites appears to decrease from 1985 to 1993 or shows no significant change. There are far fewer data and analyses of NOx and HC trends. Available studies covering various ranges of years indicate decreases in ambient NO and HC concentrations in Los Angeles, CA, decreases in HC concentrations in northeastern U.S. cities, and decreases in NOx concentrations in Canadian cities. Two key needs are long-term HC and NOx measurements, particularly at rural sites, and a systematic comparison of trend detection techniques on a reference data set.

Ozone air quality over north america: part II--an analysis of trend detection and attribution techniques.

Assessment of regulatory programs aimed at improving ambient O3 air quality is of considerable interest to the scientific community and to policymakers. Trend detection, the identification of statistically significant long-term changes, and attribution, linking change to specific climatological and anthropogenic forcings, are instrumental to this assessment. Detection and attribution are difficult because changes in pollutant concentrations of interest to policymakers may be much smaller than natural variations due to weather and climate. In addition, there are considerable differences in reported trends seemingly based on similar statistical methods and databases. Differences arise from the variety of techniques used to reduce nontrend variation in time series, including mitigating the effects of meteorology and the variety of metrics used to track changes. In this paper, we review the trend assessment techniques being used in the air pollution field and discuss their strengths and limitations in discerning and attributing changes in O3 to emission control policies.

Demonstrating attainment of the air quality standards: integration of observations and model predictions into the probabilistic framework.

This paper introduces an integrated observational-modeling approach to transform the deterministic nature of attainment demonstrations of the National Ambient Air Quality Standard (NAAQS) into the probabilistic framework. While the methods presented here can be used to address any air quality standard that is based on extreme values, this paper focuses on the application to the 1-hr and 8-hr NAAQS for ozone. Extreme value statistics and resampling techniques are applied to estimate the probability of exceeding the NAAQS for both 1-hr and 8-hr ozone concentrations. Within the integrated observation-modeling analysis approach, we show that the model-to-model differences in the predicted responses to emission reductions are smaller than the model-to-model differences in predicted absolute ozone concentrations. We illustrate that the emission reductions stemming from a real-world emission control strategy would substantially reduce the probability of exceeding the NAAQS over a large portion of the eastern United States, especially for the 8-hr average ozone concentrations.

A novel end-to-end binding of two netropsins to the DNA decamers d(CCCCCIIIII)2, d(CCCBr5CCIIIII)2and d(CBr5CCCCIIIII)2.

Netropsin is bound to the DNA decamer d(CCCCCIIIII)2, the C-4 bromo derivative d(CCCBr5CCIIIII)2and the C-2 bromo derivative d(CBr5CCCCIIIII)2in a novel 2:1 mode. Complexes of the native decamer and the C-4 bromo derivative are isomorphous, space group P1, unit cell dimensions a = 32.56 A (32.66), b = 32.59 A (32.77), c = 37.64 A (37.71), alpha = 86.30 degrees (86.01 degrees), beta = 84.50 degrees (84.37 degrees), gamma = 68.58 degrees (68.90 degrees) with two independent molecules (A and B) in the asymmetric unit (values in parentheses are for the derivative). The C-2 bromo derivative is hexagonal P61, unit cell dimensions a = b = 32.13 A, c = 143.92, gamma = 120 degrees with one molecule in the asymmetric unit. The structures were solved by the molecular replacement method. The novelty of the structures is that there are two netropsins bound end-to-end in the minor groove of each B-DNA decamer which has nearly a complete turn. The netropsins are held by hydrogen bonding interactions to the base atoms and by sandwiching van der Waal's interactions from the sugar-phosphate backbones of the double helix similar to every other drug.DNA complex. Each netropsin molecule spans approximately 5 bp. The netropsins refined with their guanidinium heads facing each other at the center, although an orientational disorder for the netropsins cannot be excluded. The amidinium ends stretch out toward the junctions and bind to the adjacent duplexes in the columns of stacked symmetry-related complexes. Both cationic ends of netropsin are bridged by water molecules in one of the independent molecules (molecule A) of the triclinic structures and also the hexagonal structure to form pseudo-continuous drug.decamer helices.

X-ray structures of Mn, Cd and Tb metal complexes of troponin C.

The crystal structures of three metal complexes of troponin C (TnC) have been determined and refined where the two occupied structural Ca(2+) sites in the C domain have been substituted by Mn(2+), Cd(2+) and Tb(3+). The X-ray intensity data were collected to 2.1, 1.8 and 1.8 A resolution, respectively, on the three metal complexes, which are isomorphous with Ca-TnC. The three complexes have r.m.s. deviations of 0.27, 0.25 and 0.35 A, respectively, for all protein atoms, from Ca-TnC. Irrespective of the charge on the metal (+2 or +3), the occupied sites 3 and 4 exhibit a distorted pentagonal bipyramidal coordination, like Ca-TnC, with seven ligands, six from the 12-residue binding loop and the seventh from a water molecule. Mn(2+) at site 4 seems to display a longer distance to one of the carboxyl bidentate ligands representing an intermediate coordination simulating the six-coordinate Mg(2+). The carboxyl O atoms of the bidentate Glu12 are displaced on the side of the equatorial plane passing through the remaining three ligands with one O atom closer to the plane (Delta of 0.11 to 0.76 A) than the other (Delta of 0.93 to 1.38 A). The two axial ligands are an aspartic carboxyl O atom and a water molecule. The metal is displaced (0.18 to 0.56 A) towards the water facing the water channel.

Crystal structure of the B-DNA hexamer d(CTCGAG): model for an A-to-B transition.

The crystal structure of the B-DNA hexamer d(CTCGAG) has been solved at 1.9 A resolution by iterative single isomorphous replacement, using the brominated derivative d(CG5BrCGAG), and refined to an R-factor of 18.6% for 120 nonhydrogen nucleic acid atoms and 32 water molecules. Although the central four base pairs form a typical B-form helix, several parameters suggest a transition to an A-like conformation at the termini. Based on this observation, a B-to-A transition was modeled, maintaining efficient base stacking across the junction. The wide minor groove (approximately 6.9 A) is reminiscent of that in the side-by-side double drug-DNA complexes and hosts a double spine of hydration. The global helix axes of the pseudo-continuous helices are at an acute angle of 60 degrees. The pseudocontinuous stacking is reinforced by the minor groove water structure extending between the two duplexes. The crossover point of two pairs of stacked duplexes is at the stacking junction, unlike that observed in the B-DNA decamers and dodecamers. This arrangement may have implications for the structure of a four-way DNA junction. The duplexes are arranged around a large (approximately 20 A diameter) channel centered on a 6(2) screw axis.

The structure of r(UUCGCG) has a 5'-UU-overhang exhibiting Hoogsteen-like trans U.U base pairs.

The crystal structure of the RNA fragment, 5'-r(UUCGCG)-3', has been determined at 1.4 A resolution by a combination of single isomorphous replacement and molecular search methods. The 3'-terminal CGCG portion of the hexamer engages in Watson-Crick hydrogen bonding while the 5'-terminal UU-overhang forms novel Hoogsteen-like U.U self-base pairs with the overhang of an adjacent duplex. The U.U pairs display a single conventional hydrogen bond between O4 (U1) and N3 (U8) and a CH-O hydrogen bond between C5-H (U1) and O4 (U8), through the Hoogsteen face of the pyrimidine base U1. This unusual arrangement of one of the bases results in a trans U.U pair on antiparallel strands in contrast to the usual cis base pairs. The structure emphasizes the pronounced polymorphism of U.U pairs and has implications for folding of RNA molecules.

Studies of monoclinic hen egg-white lysozyme. IV. X-ray refinement at 1.8 A resolution and a comparison of the variable regions in the polymorphic forms.

Monoclinic crystals of hen egg-white lysozyme (E.C. 3.2.1.17, HEL) grown at low pH in the presence of NaNO(3) belong to space group P2(1) with unit-cell dimensions, a = 28.0, b = 62.5, c = 60.9 A and beta= 90.8 degrees with two molecules in the asymmetric unit. 1.8 A resolution intensity data, collected on a CAD-4 diffractometer, contained 17 524 reflections with F > 3sigma (93% complete). Our earlier preliminary 1.8 A model was refitted and refined using X-PLOR to an R value of 0.189. The deviations in the model from ideal geometry are 0.013 A in bond lengths and 2.8 degrees in bond angles. The r.m.s. deviation in the backbone atoms between the two molecules is 0.42 A. A comparison of HEL in different polymorphic crystal forms reveals that the prominent structural variability among them resides in two exposed regions 45-50 and 65-73 which are also regions of lattice contacts.

X-ray structures of the B-DNA dodecamer d(CGCGTTAACGCG) with an inverted central tetranucleotide and its netropsin complex.

The crystal structures of the B-DNA dodecamer d(CGCGTTAACGCG) duplex (T2A2), with the inverted tetranucleotide core from the duplex d(CGCGAATTCGCG) [A2T2, Dickerson & Drew (1981). J. Mol. Biol. 149, 761-768], and its netropsin complex (T2A2-N) have been determined at 2.3 A resolution. The crystals are orthorhombic, space group P2(1)2(1)2(1), unit-cell dimensions of a = 25.7, b = 40.5 and c = 67.0 A, for T2A2 and a = 25.49, b = 40.87, c = 67.02 A for T2A2-N and are isomorphous with A2T2. The native T2A2 structure, with 70 water molecules had a final R value of 0.15 for 1522 reflections (F > 2sigma), while for the netropsin complex, with 87 water molecules, the R value was 0.16 for 2420 reflections. In T2A2, a discontinuous string of zig-zagging water molecules hydrate the narrow A.T minor groove. In T2A2-N, netropsin binds in one orientation in the minor groove, covering the TTAA central region, by displacing the string of waters, forming the majority of hydrogen bonds with DNA atoms in one strand, and causing very little perturbation of the native structure. The helical twist angle in T2A2 is largest at the duplex center, corresponding to the cleavage site by the restriction enzymes HpaI and HincII. The sequence inversion AATT-->TTAA of the tetranucleotide at the center of the molecule results in a different path for the local helix axis in T2A2 and A2T2 but the overall bending is similar in both cases.