Single nucleotide variants in nuclear pore complex disassembly pathway associated with poor survival in osteosarcoma.

Introduction: The bone tumor, osteosarcoma, remains challenging to treat in children and young adults, especially when patients present with metastatic disease. Developing new therapies based on genomic data from sequencing projects has proven difficult given the lack of recurrent genetic lesions across tumors. MYC overexpression has been associated with poor outcomes in osteosarcoma. However, other genomic markers of disease severity are lacking. Materials and Methods: We utilized whole genome sequencing of 106 tumors and matched normal controls in order to define genomic characteristics that correlate with overall survival. Single nucleotide variants were overlaid onto annotated molecular pathways in order to define aberrant pathway signatures specific to aggressive osteosarcoma. Additionally, we calculated differential gene expression in a subsample of 71 tumors. Differentially expressed genes were then queried for known MYC-responsive genes. Results: Molecular pathways specific to nuclear pore complex disassembly (NPCD) show significant correlation with poor overall survival in osteosarcoma when mutations were present. Genes involved in immune response and immune regulation are enriched in the differential expression analysis of samples with and without NPCD pathway aberrations. Furthermore, neither MYC nor MYC-responsive genes show differential expression between NPCD-aberrant and non-aberrant groups. The NPCD pathway mutations are dominated by regulatory region variants rather than protein-altering mutations, suggesting that dysregulation of genetic regulatory networks may be the underlying mechanism for their relation to osteosarcoma phenotype. Discussion: Overall survival is significantly worse in patients whose tumors show aberrations in the NPCD pathway. Moreover, this difference in survival is not driven by MYC-overexpression, suggesting a novel mechanism for some aggressive osteosarcomas. These findings add light to the evolving understanding of the drivers of osteosarcoma and may aid in the search for new treatments based on patient-specific genetic data.

Integrated approach for the evaluation of groundwater quality through hydro geochemistry and human health risk from Shivganga river basin, Pune, Maharashtra, India.

The present study is focused on seasonal variation in groundwater quality, hydrochemistry, and associated human health risk in the Shivganga river basin, Western Maharashtra, India, to promote sustainable development of groundwater resources of this semi-arid region. The qualitative geochemical analysis, contamination levels, and human health risk assessment (HHRA) of groundwater are integral steps in groundwater management in the Deccan Plateau basalt flow region of India. Representative groundwater samples (n = 68) collected from the Shivganga River basin area of Pune district, Maharashtra, during pre-monsoon (PRM) and post-monsoon (POM) seasons in 2015 were analyzed for major cations and anions. According to the World Health Organization (WHO, 2017) drinking standards, EC, total dissolved solids, hardness, bicarbonate, calcium, and magnesium surpassed the desirable limit. Boron and fluoride content exceeded the prescribed desirable limit of the WHO. The pollution and drinking suitability were assessed by computing pollution index of groundwater (PIG), groundwater quality index (GWQI), and HHRA particularly for boron and fluoride toxicity. PIG values inferred that about 6% of groundwater samples has moderate, 24% has low, and 70% has insignificant pollution in the PRM season, while only 1 sample (3%) showed high pollution, 6% showed low, and 91% showed insignificant pollution in the POM season. GWQI classification demonstrated that 27% and 15% samples are within the poor category, and only 15% and 18% of the samples fall into excellent water category in the PRM and the POM seasons, respectively. Total hazard index (THI) revealed that 88% of children, 59% of adults, and about 38% of infants are exposed to non-carcinogenic risk, as THI values (>1) were noted for the PRM season, while 62% of children, 47% of adults, and 24% of infants are vulnerable to non-carcinogenic health hazard during the POM period.

Seasonal variation in groundwater quality and beneficial use for drinking, irrigation, and industrial purposes from Deccan Basaltic Region, Western India.

Sustainable management of groundwater resources requires detailed basin-wide water assessments. Semi-urbanized areas surrounding metropolitan cities in the western part of India were assessed for their suitability for domestic, irrigation, and industrial purposes. These study areas reflect rapid urban growth with residential complexes, combined with agricultural, horticultural, and industrial uses. Therefore, 68 representative groundwater samples were collected during the pre-monsoon (PRM) and post-monsoon (POM) seasons of 2015 and analyzed for major ions. According to the World Health Organization (WHO) drinking standards, parameters like EC, TDS, TH, HCO3, Ca, and Mg were found to exceed the desirable maximum limits, and the B and F content exceeded the permissible limits. The drinking suitability was studied using the modified water quality index (MWQI). The irrigation suitability was assessed using indices such as sodium adsorption ratio (SAR), percent sodium (%Na), and permeability index (PI). The industrial suitability was evaluated based on Langelier saturation index (LSI), saturation index (SI), Ryznar stability index (RSI), etc. MWQI results corroborate that 52.94 and 70% samples fall in no pollution category, and 47% and 30% samples were identified to be in the moderate category of pollution in the PRM season and POM season, respectively. The spatial variation maps of LSI, SI, RSI, Puckorius scaling index (PSI) and Larson-Skold index (LaI) show that the majority of the samples in the PRM season have low to insignificant scaling and corrosive potentials as compared to POM samples. The study results provide reliable information for water reserve managers to prepare the sustainable and more accurate basin management plans.

Functional genomic analysis identifies drug targetable pathways in invasive and metastatic cutaneous squamous cell carcinoma.

Although cutaneous squamous cell carcinoma (cSCC) is treatable in the majority of cases, deadly invasive and metastatic cases do occur. To date there are neither reliable predictive biomarkers of disease progression nor FDA-approved targeted therapies as standard of care. To address these issues, we screened patient-derived primary cultured cells from invasive/metastatic cSCC with 107 small-molecule inhibitors. In-house bioinformatics tools were used to cross-analyze drug responses and DNA mutations in tumors detected by whole-exome sequencing (WES). Aberrations in molecular pathways with evidence of potential drug targets were identified, including the Eph-ephrin and neutrophil degranulation signaling pathways. Using a screening panel of siRNAs, we identified EPHA6 and EPHA7 as targets within the Eph-ephrin pathway responsible for mitigating decreased cell viability. These studies form a plausible foundation for detecting biomarkers of high-risk progressive disease applicable in dermatopathology and for patient-specific therapeutic options for invasive/metastatic cSCC.

Illuminating biological pathways for drug targeting in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) remains a morbid disease with poor prognosis and treatment that typically leaves patients with permanent damage to critical functions such as eating and talking. Currently only three targeted therapies are FDA approved for use in HNSCC, two of which are recently approved immunotherapies. In this work, we identify biological pathways involved with this disease that could potentially be targeted by current FDA approved cancer drugs and thereby expand the pool of potential therapies for use in HNSCC treatment. We analyzed 508 HNSCC patients with sequencing information from the Genomic Data Commons (GDC) database and assessed which biological pathways were significantly enriched for somatic mutations or copy number alterations. We then further classified pathways as either "light" or "dark" to the current reach of FDA-approved cancer drugs using the Cancer Targetome, a compendium of drug-target information. Light pathways are statistically enriched with somatic mutations (or copy number alterations) and contain one or more targets of current FDA-approved cancer drugs, while dark pathways are enriched with somatic mutations (or copy number alterations) but not currently targeted by FDA-approved cancer drugs. Our analyses indicated that approximately 35-38% of disease-specific pathways are in scope for repurposing of current cancer drugs. We further assess light and dark pathways for subgroups of patient tumor samples according to HPV status. The framework of light and dark pathways for HNSCC-enriched biological pathways allows us to better prioritize targeted therapies for further research in HNSCC based on the HNSCC genetic landscape and FDA-approved cancer drug information. We also highlight the importance in the identification of sub-pathways where targeting and cross targeting of other pathways may be most beneficial to predict positive or negative synergy with potential clinical significance. This framework is ideal for precision drug panel development, as well as identification of highly aberrant, untargeted candidates for future drug development.

Network-Based Predictors of Progression in Head and Neck Squamous Cell Carcinoma.

The heterogeneity in head and neck squamous cell carcinoma (HNSCC) has made reliable stratification extremely challenging. Behavioral risk factors such as smoking and alcohol consumption contribute to this heterogeneity. To help elucidate potential mechanisms of progression in HNSCC, we focused on elucidating patterns of gene interactions associated with tumor progression. We performed de-novo gene co-expression network inference utilizing 229 patient samples from The Cancer Genome Atlas (TCGA) previously annotated by Bornstein et al. (2016). Differential network analysis allowed us to contrast progressor and non-progressor cohorts. Beyond standard differential expression (DE) analysis, this approach evaluates changes in gene expression variance (differential variability DV) and changes in covariance, which we denote as differential wiring (DW). The set of affected genes was overlaid onto the co-expression network, identifying 12 modules significantly enriched in DE, DV, and/or DW genes. Additionally, we identified modules correlated with behavioral measures such as alcohol consumption and smoking status. In the module enriched for differentially wired genes, we identified network hubs including IL10RA, DOK2, APBB1IP, UBASH3A, SASH3, CELF2, TRAF3IP3, GIMAP6, MYO1F, NCKAP1L, WAS, FERMT3, SLA, SELPLG, TNFRSF1B, WIPF1, AMICA1, PTPN22; the network centrality and progression specificity of these genes suggest a potential role in tumor evolution mechanisms related to inflammation and microenvironment. The identification of this network-based gene signature could be further developed to guide progression stratification, highlighting how network approaches may help improve clinical research end points and ultimately aid in clinical utility.

Occurrence of chlorinated volatile organic compounds (VOCs) in a sanitary sewer system: Implications for assessing vapor intrusion alternative pathways.

Sewer systems have been recently recognized as potentially important exposure pathways to consider during vapor intrusion assessments; however, this pathway has not been well-characterized and there is need for additional information about the occurrence of volatile organic compounds (VOCs) in sewer systems. This paper reports the results of sewer gas sampling conducted in a sanitary sewer over the years of 2014-2017. Sewer gas samples were collected and analyzed using several different techniques, including TO-15 (grab), TO-17 (passive), Radiello® (passive) and a novel continuous monitoring technique, the Autonomous Rugged Optical Multigas Analyzer (AROMA). The applicability of each of the different approaches used in this study is discussed in the context of investigating sanitary sewers as a vapor intrusion alternative pathway. The data confirmed that trichloroethylene (TCE) concentrations in sewer gas were detected adjacent to and extending hundreds of feet away from a previously defined vapor intrusion area, where TCE was a primary contaminant. TCE concentrations detected in sewer gas ranged from non-detect to 1600µg/m3. Temporal variability was observed in TCE concentrations over timescales that ranged from minutes to months to years at discrete sampling locations. Spatial variability in sewer gas concentrations was also observed throughout the study area. Temporal and spatial variability may be caused by groundwater contamination sources in the study area, as well as sewer gas transport mechanisms.

Deficiency of MIWI2 (Piwil4) induces mouse erythroleukemia cell differentiation, but has no effect on hematopoiesis in vivo.

Piwi proteins and their small non-coding RNA partners are involved in the maintenance of stem cell character and genome integrity in the male germ cells of mammals. MIWI2, one of the mouse Piwi-like proteins, is expressed in the prepachytene phase of spermatogenesis during the period of de novo methylation. Absence of this protein leads to meiotic defects and a progressive loss of germ cells. There is an accumulation of evidence that Piwi proteins may be active in hematopoietic tissues. Thus, MIWI2 may have a role in hematopoietic stem and/or progenitor cell self-renewal and differentiation, and defects in MIWI2 may lead to abnormal hematopoiesis. MIWI2 mRNA can be detected in a mouse erythroblast cell line by RNA-seq, and shRNA-mediated knockdown of this mRNA causes the cells to take on characteristics of differentiated erythroid precursors. However, there are no detectable hematopoietic abnormalities in a MIWI2-deficient mouse model. While subtle, non-statistically significant changes were noted in the hematopoietic function of mice without a functional MIWI2 gene when compared to wild type mice, our results show that MIWI2 is not solely necessary for hematopoiesis within the normal life span of a mouse.

Long-term population dynamics of seeded plants in invaded grasslands.

In recent decades, dozens of studies have involved attempts to introduce native and desirable nonnative plant species into grasslands dominated by invasive weeds. The newly introduced plants have proved capable of establishing, but because they are rarely monitored for more than four years, it is unknown if they have a high likelihood of persisting and suppressing invaders for the long-term. Beyond invaded grasslands, this lack of long-term monitoring is a general problem plaguing efforts to reintroduce a range of taxa into a range of ecosystems. We introduced species from seed and then periodically measured plant abundances for nine years at one site and 15 years at a second site. To our knowledge, our 15-year data are the longest to date from a seeding experiment in invaded, never-cultivated grassland. At one site, three seeded grasses maintained high densities for three or more years, but then all or nearly all individuals died. At the second site, one grass performed similarly, but two other grasses proliferated and at least one greatly suppressed the dominant invader (Centaurea maculosa). In one study, our point estimate suggests that the seeded grass Thinopyrum intermedium reduced C. maculosa biomass by 93% 15 years after seeding. In some cases, data from three and fewer years after seeding falsely suggested that seeded species were capable of persisting within the invaded grassland. In other cases, data from as late as nine years after seeding falsely suggested seeded populations would not become large enough to suppress the invader. These results show that seeded species sometimes persist and suppress invaders for long periods, but short-term data cannot predict if, when, or where this will occur. Because short-term data are not predictive of long-term seeded species performances, additional long-term data are needed to identify effective practices, traits, and species for revegetating invaded grasslands.

Experimental validation of an extended Jones matrix calculus model to study the 3D structural orientation of the collagen fibers in articular cartilage using polarization-sensitive optical coherence tomography.

We report results to verify a theoretical framework to analyze the 3D depth-wise structural organization of collagen fibers in articular cartilage using polarization-sensitive optical coherence tomography. Apparent birefringence data obtained from multi-angle measurements using a time domain polarization-sensitive optical coherence tomography system has been compared with simulated data based on the extended Jones matrix calculus. Experimental data has been shown to agree with the lamellar model previously proposed for the cartilage microstructure based on scanning electron microscopy data. This tool could have potential application in mapping the collagen structural orientation information of cartilage non-invasively during arthroscopy.

Engineering assessment of the longitudinal compression behaviour of contemporary coronary stents.

AIMS: There have been recently reported clinical observations of significant longitudinal compression or "stent shortening" in certain contemporary drug-eluting stents (DES), when re-crossed with other devices such as post-dilatation balloons, stent delivery systems or intravascular ultrasound (IVUS) catheters. The aim of this study was to understand the effect of stent design on longitudinal compression for coronary stents, when subjected to certain forces in vitro. This goal was achieved by experimentally evaluating the longitudinal strength of 14 contemporary stent designs under a clinically relevant compression force using a bench test method developed for this purpose. The results from the study are intended to provide an indication whether there is a quantifiable difference in the ability of the different stent platform designs to resist longitudinal compression in a deployed configuration. METHODS AND RESULTS: A test method was developed to evaluate the longitudinal compression behaviour of coronary stents. The test method was used to compare the longitudinal compression of four stent design families including a total of 14 commercialised stent platforms under a clinically relevant longitudinal compression force. The nominal expansion diameter of stents used in this study was 3.0 mm with stent lengths ranging from 28-30 mm. A test method was also developed to estimate a value of the clinically relevant longitudinal compression force to which a deployed stent may be subjected in a situation when a catheter tip is caught while trying to cross a freshly deployed stent. That force was determined to be 50 gram force (gf) (0.49 N). Based on the results of the testing it was noted that three of the four design families (13 of the 14 stents tested) demonstrated a longitudinal compression in the range of 1.25-5.30 mm (longitudinal compression of 4.46%-18.93% compared to the nominal expanded stent length), with the exception of the offset peak-to-peak stent platform having results clearly outside of this grouping. The stent in the offset peak-to-peak design category (Element stent platform) had an average longitudinal compression of 13.20 mm (longitudinal compression of 47.07%), thus demonstrating a markedly lower resistance to longitudinal compression. CONCLUSIONS: Stent design is a primary driver determining the longitudinal compression behaviour of coronary stent platforms. The results of this study comparing the longitudinal compression performance of four different commercial stent design families indicate that the tendency of a deployed stent to undergo longitudinal compression is associated with the stent design concept. It was determined that the particular 2-link offset peak-to-peak design evaluated in this study had the lowest compression resistance compared to the other stent design families.

Novel influenza A (H1N1) viral infection in pediatric patients with sickle-cell disease.

BACKGROUND: The 2009 novel influenza A (H1N1) pandemic has had profound public health implications all over the world. The majority of patients infected with the novel strain have recovered uneventfully. However, certain populations have been defined who appear to be at increased risk of complications due to H1N1 infections. This review summarizes the clinical course of five patients with sickle cell, four of whom had confirmed H1N1 infection, and one whom had a presumed H1N1 infection. PROCEDURE: The clinical presentation, hospital course, and treatment of five pediatric patients with sickle-cell disease and H1N1 infection were reviewed retrospectively. RESULTS: In this case series, our patients experienced complications such as the acute chest syndrome, acute marrow suppression of red cell production, pain crisis, and hematuria. CONCLUSIONS: In this population, who are at increased risk for bacterial superinfection as well as complications from the influenza virus itself, vigilance toward diagnosis and aggressive treatment will continue to be important as long as the novel virus is in circulation.

Isolated extramedullary relapse in childhood acute lymphocytic leukemia.

Although the vast majority of children with acute lymphocytic leukemia attain remission with modern therapies, an unacceptably high number will suffer a disease relapse. Both the duration of remission and the site of relapse are important prognostic factors. This review focuses on leukemic relapse isolated to sites outside the bone marrow (extramedullary sites). Data from cooperative study groups as well as large single institutions are reviewed with respect to the incidence of isolated extramedullary relapse as well as the outcome following relapse. The unique anatomic and physiologic properties of the testes and the central nervous system-the two most common sites of isolated extramedullary relapse-are discussed. Finally, the evolution of leukemia therapy is reviewed, bringing into focus the goals and challenges of future therapeutic endeavors.

Proteomic comparison of needles from blister rust-resistant and susceptible Pinus strobus seedlings reveals upregulation of putative disease resistance proteins.

In order to characterize a hypersensitive-like reaction in selected Pinus strobus seedlings to Cronartium ribicola, a proteomic comparison of needles from resistant and susceptible seedlings was undertaken using two-dimensional gel electrophoresis (2-DE). The results revealed 19 polypeptides specific to resistant seedlings and seven of these specific to infected resistant seedlings. There were 13 polypeptides up-regulated (> or = 3-fold increase) in resistant family P327 in comparison to needle tissue from susceptible and mock-inoculated seedlings. Electrospray ionization liquid chromatography and tandem mass spectrometry was used to sequence 11 proteins from the 2-DE gels. Sequences obtained from electrospray ionization liquid chromatography and tandem mass spectrometry were used for MS-BLAST and Pro-ID database searches allowing identification with a 95 to 99% confidence level. Six proteins were determined to be homologs of proteins with known roles in disease resistance, five were determined to be homologs of members of the leucine-rich repeat (LRR) superfamily, and one was a homolog of heat shock protein 90, a protein that serves as a cofactor for certain LRR proteins. This is the first report of members of the LRR family with functional homologs in Pinus strobus and of a molecular basis for white pine blister rust resistance in Pinus strobus.

The taxonomy of Psilocybe fagicola-complex.

Psilocybe fagicola comprises a complex of more than eight species, six of them in Mexico, and all of them possessing a long pseudorhiza, a characteristic not listed by Heim and Cailleux in 1959 in the original description of the type species, but described by Guzmán in 1978 and 1983. The description of Psilocybe fagicola s.s. is here emended to include the length of the cheilocystidia of (6-) 12-20 (-30) microm, as well as the absence or scarcity of pleurocystidia. Psilocybe xalapensis and P. wassoniorum are considered to be synonymous with P. fagicola s.s. However, Psilocybe banderillensis and P. herrerae from Mexico, P. columbiana from Colombia, and P. keralensis from India are considered to be valid species within this complex. Moreover, P. novoxalapensis and P. teofilae, both from Mexico, are described as new species. Length of spores, presence or absence of pleurocystidia and their variations, and type of cheilocystidia constitute the principal defining characteristics of the species. Setaceous hyphae at the base of the stipe, as well as caulocystidia, lack taxonomic value, as do other morphological characteristics, including pileipellis and subpileipellis. A key to the eight considered species is also presented within the paper.