Characterization of mutational load in patients with advanced urothelial cancer.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 460-460
Author(s):  
Sumanta K. Pal ◽  
Siraj Mahamed Ali ◽  
Riley Ennis ◽  
Julia Andrea Elvin ◽  
JoAnn Vergilio ◽  
...  
Keyword(s):  
Urothelial Cancer ◽  
Clinical Care ◽  
Mutational Load ◽  
Deleterious Mutations ◽  
Coverage Depth ◽  
Comprehensive Genomic Profiling ◽  
Advanced Urothelial Cancer ◽  
Very High ◽  
75Th Quartile

460 Background: The efficacy of novel immunotherapeutic agents (e.g., PD-1/PD-L1 and CTLA4 inhibitors) in advanced cancer is linked to tumor mutational load. We assessed mutational load via comprehensive genomic profiling (CGP) performed in the course of clinical care for patients with advanced urothelial cancer (UC). Methods: DNA was extracted from 40 microns of FFPE sections from 760 consecutive patients with relapsed/metastatic UC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 646X for at least 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Mutational load was characterized as the number of such SUBs or INDELs per megabase (Mb) after filtering to remove known somatic and deleterious mutations, given that these are selected for with hybrid capture. Results: The median age of the patients was 66 years old with a 3:1 male:female ratio. Mean mutations per megabase were assessed as a range of 0 to 79, and the 25th, median, and 75th quartile thresholds were 3.2, 5.5, and 8.8. MSH6 alterations in 0.8% cases had a median of 15.2 mutations per megabase. However, the ten most frequently altered genes in this series- TERT (64%), TP53 (54%), CDKN2A (35%), CDKN2B (28%), KDM6A (24%), ARID1A (23%), MLL2 (22%), PIK3CA (21%), RB1 (21%) and FGFR3 (19%) - were not associated with differences in mutational load. Conclusions: A highly variable mutational load was seen in patients with advanced UC. A subpopulation of MSH6-altered UC had very high mutational loads relative to other UCs. Further correlation to clinical outcomes will be investigated to assess the correlation between mutational load and response to immunotherapy.

Comprehensive genomic profiling (CGP) to assess mutational load in gastric and esophageal adenocarcinomas: Implications for immunotherapies.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 66-66
Author(s):  
Garrett Michael Frampton ◽  
Alexa Betzig Schrock ◽  
Zachary Rockow Chalmers ◽  
James Sun ◽  
Riley Ennis ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Clinical Care ◽  
Mutational Load ◽  
Mismatch Repair Genes ◽  
Histologic Subtype ◽  
Dna Mismatch ◽  
Significant Difference ◽  
Comprehensive Genomic Profiling ◽  
Repair Genes

66 Background: Gastroesophageal cancer (GEC) present a management challenge, particularly when ERBB2 is not amplified and cytotoxic therapy has failed. Tumor mutational load is linked to predicted benefit from immune checkpoint inhibitors in advanced cancers. Using CGP we assessed the relationship between mutational burden and clinically relevant genomic alterations in GEC samples in the course of routine clinical care. Methods: DNA was extracted from 40 microns of FFPE sections from patients with GEC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of greater than 500x for 236 or 315 cancer-related genes. Mutational load was characterized as the number of somatic base substitutions and short indels per megabase. Samples were stratified by histologic subtype, and presence or absence of therapeutically relevant receptor tyrosine kinase (RTK) alterations. The majority of samples were from patients with advanced disease. Results: The genomic profiles from a total of 736 gastric and 862 esophageal carcinomas were assessed. Median patient age was 57 for gastric and 60 for esophageal cases. There was no significant difference in mutational load between gastric and esophageal samples. 10th, 25th, median, 75th, and 90th percentiles of mutation load were 1.3, 2.7, 6.3, 11.3, and 20.0 for gastric cancers and 1.8, 3.6, 6.4, 11.3, and 17.5 for esophageal cancers. 27 (3.7%) gastric and 20 (2.3%) esophageal cases had alterations in mismatch repair genes MLH1, MSH2, MSH6 which was associated with ~2.5 fold increased mutational load. Mutational load was not significantly associated with the presence of RTK alterations, which occurred in 155 (21%) gastric and 355 (41%) esophageal cases. Conclusions: CGP in the course of clinical care can be used to assess mutational load in GEC. Alterations in RTKs were not exclusive of the high mutation subgroup, contrary to some previous reports. Mutations in DNA mismatch repair genes were associated with higher mutation burden as expected. Incorporation of CGP into ongoing prospective immunotherapy trials and clinical practice is needed to refine these relationships.

scholarly journals A Combination of Targeted Therapy with Chemotherapy Backbone Induces Response in a Treatment-Resistant Triple-Negative MCL1-Amplified Metastatic Breast Cancer Patient

2016 ◽  
Vol 9 (1) ◽  
pp. 112-118 ◽  
Author(s):  
Siraj M. Ali ◽  
Jessica Watson ◽  
Kai Wang ◽  
Jon H. Chung ◽  
Caitlin McMahon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Hospice Care ◽  
Treatment Initiation ◽  
Clinical Care ◽  
Metastatic Breast ◽  
Genomic Profiling ◽  
Treatment Resistant ◽  
Bcl2 Family ◽  
Comprehensive Genomic Profiling

After failure of anthracycline- and platinum-based therapy, no effective therapies exist for management of metastatic triple-negative breast cancer (TNBC). We report a case of metastatic TNBC harboring MCL1 amplification, as identified by comprehensive genomic profiling in the course of clinical care. MCL1 is an antiapoptotic gene in the BCL2 family, and MCL1 amplification is common in TNBC (at least 20%). A personalized dose-reduced regimen centered on a combination of sorafenib and vorinostat was implemented, based on preclinical evidence demonstrating treatment synergy in the setting of MCL1 amplification. Although hospice care was being considered before treatment initiation, the personalized regimen yielded 6 additional months of life for this patient. Further rigorous studies are needed to confirm that this regimen or derivatives thereof can benefit the MCL1-amplified subset of TNBC patients.

Ionized gas kinematics and luminosity profiles of Low-z Lyman Alpha Blobs

2019 ◽  
Vol 15 (S359) ◽  
pp. 413-414
Author(s):  
María P. Agüero ◽  
Rubén Díaz ◽  
Mischa Schirmer
Keyword(s):  
Emission Line ◽  
Galactic Nuclei ◽  
Host Galaxies ◽  
Ionized Gas ◽  
Lyman Alpha ◽  
Gas Kinematics ◽  
The Universe ◽  
Very High ◽  
The Continuum

AbstractThis work is focused on the characterization of the Seyfert-2 galaxies hosting very large, ultra-luminous narrow-line regions (NLRs) at redshifts z = 0.2−0.34. With a space density of 4.4 Gcp−3 at z ∼ 0.3, these “Low Redshift Lyman-α Blob” (LAB) host galaxies are amongst the rarest objects in the universe, and represent an exceptional and short-lived phenomenon in the life cycle of active galactic nuclei (AGNs). We present the study of GMOS spectra for 13 LAB galaxies covering the rest frame spectral range 3700–6700 Å. Predominantly, the [OIII]λ5007 emission line radial distribution is as widespread as that of the continuum one. The emission line profiles exhibit FWHM between 300–700 Km s−1. In 7 of 13 cases a broad kinematical component is detected with FWHM within the range 600–1100 Km s−1. The exceptionally high [OIII]λ5007 luminosity is responsible for very high equivalent width reaching 1500 Å at the nucleus.

scholarly journals On the Average Coefficient of Dominance of Deleterious Spontaneous Mutations

Genetics ◽  
2000 ◽  
Vol 155 (4) ◽  
pp. 1991-2001 ◽  
Author(s):  
A García-Dorado ◽  
A Caballero
Keyword(s):  
Deleterious Mutations ◽  
Spontaneous Mutations ◽  
Partial Dominance ◽  
High Viability ◽  
Significant Difference ◽  
Plausible Hypothesis ◽  
Average Coefficient ◽  
Series Of Experiments ◽  
Very High ◽  
Balancer Chromosome

Abstract T. Mukai and co-workers in the late 1960s and O. Ohnishi in the 1970s carried out a series of experiments to obtain direct estimates of the average coefficient of dominance (h¯) of minor viability mutations in Drosophila melanogaster. The results of these experiments, although inconsistent, have been interpreted as indicating slight recessivity of deleterious mutations, with h¯≈0.4. Mukai obtained conflicting results depending on the type of heterozygotes used, some estimates suggesting overdominance and others partial dominance. Ohnishi's estimates, based on the ratio of heterozygous to homozygous viability declines, were more consistent, pointing to the above value. However, we have reanalyzed Ohnishi's data, estimating h¯ by the regression method, and obtained a much smaller estimate of ~0.1. This significant difference can be due partly to the different weighting implicit in the estimates, but we suggest that this is not the only explanation. We propose as a plausible hypothesis that a putative nonmutational decline in viability occurring in the first half of Ohnishi's experiment (affecting both homozygotes and heterozygotes) has biased upward the estimates from the ratio, while it would not bias the regression estimates. This hypothesis also explains the very high h¯≈0.7 observed in Ohnishi's high-viability chromosomes. By constructing a model of spontaneous mutations using parameters in the literature, we investigate the above possibility. The results indicate that a model of few mutations with moderately large effects and h¯≈0.2 is able to explain the observed estimates and the distributions of homozygous and heterozygous viabilities. Accounting for an expression of mutations in genotypes with the balancer chromosome Cy does not alter the conclusions qualitatively.

Sequential therapies for advanced urothelial cancer: Hope meets new challenges

2021 ◽  
pp. 103248
Author(s):  
Daniel Herchenhorn ◽  
Vinicius Freire ◽  
Thamires Oliveira ◽  
Juliana Tarouquella
Keyword(s):  
Urothelial Cancer ◽  
New Challenges ◽  
Advanced Urothelial Cancer

scholarly journals Halogenated Volatile Organic Compounds in Water Samples and Inorganic Elements Levels in Ores for Characterizing a High Anthropogenic Polluted Area in the Northern Latium Region (Italy)

2021 ◽  
Vol 18 (4) ◽  
pp. 1628
Author(s):  
Mario Vincenzo Russo ◽  
Ivan Notardonato ◽  
Alberto Rosada ◽  
Giuseppe Ianiri ◽  
Pasquale Avino
Keyword(s):  
Organic Compounds ◽  
Mean Value ◽  
Greenhouse Crops ◽  
River Waters ◽  
Liquid Liquid Extraction ◽  
Volatile Organic ◽  
High Concentrations ◽  
Very High ◽  
Inorganic Fraction

This paper shows a characterization of the organic and inorganic fraction of river waters (Tiber and Marta) and ores/soil samples collected in the Northern Latium region of Italy for evaluating the anthropogenic/natural source contribution to the environmental pollution of this area. For organic compounds, organochloride volatile compounds in Tiber and Marta rivers were analyzed by two different clean-up methods (i.e., liquid–liquid extraction and static headspace) followed by gas chromatography–electron capture detector (GC-ECD) analysis. The results show very high concentrations of bromoform (up to 1.82 and 3.2 µg L−1 in Tiber and Marta rivers, respectively), due to the presence of greenhouse crops, and of chloroform and tetrachloroethene, due to the presence of handicrafts installations. For the qualitative and quantitative assessment of the inorganic fraction, it is highlighted the use of a nuclear analytical method, instrumental neutron activation analysis, which allows having more information as possible from the sample without performing any chemical-physical pretreatment. The results have evidenced high levels of mercury (mean value 88.6 µg g−1), antimony (77.7 µg g−1), strontium (12,039 µg g−1) and zinc (103 µg g−1), whereas rare earth elements show levels similar to the literature data. Particular consideration is drawn for arsenic (414 µg g−1): the levels found in this paper (ranging between 1 and 5100 µg g−1) explain the high content of such element (as arsenates) in the aquifer, a big issue in this area.

scholarly journals Characterization of Deleterious Mutations in Outcrossing Populations

Genetics ◽  
1998 ◽  
Vol 150 (2) ◽  
pp. 945-956 ◽  
Author(s):  
Hong-Wen Deng
Keyword(s):  
Genetic Variation ◽  
Genetic Variance ◽  
Estimation Bias ◽  
Deleterious Mutations ◽  
Environmental Variance ◽  
Higher Power ◽  
Sib Mating ◽  
The Mean ◽  
Simulation Results

Abstract Deng and Lynch recently proposed estimating the rate and effects of deleterious genomic mutations from changes in the mean and genetic variance of fitness upon selfing/outcrossing in outcrossing/highly selfing populations. The utility of our original estimation approach is limited in outcrossing populations, since selfing may not always be feasible. Here we extend the approach to any form of inbreeding in outcrossing populations. By simulations, the statistical properties of the estimation under a common form of inbreeding (sib mating) are investigated under a range of biologically plausible situations. The efficiencies of different degrees of inbreeding and two different experimental designs of estimation are also investigated. We found that estimation using the total genetic variation in the inbred generation is generally more efficient than employing the genetic variation among the mean of inbred families, and that higher degree of inbreeding employed in experiments yields higher power for estimation. The simulation results of the magnitude and direction of estimation bias under variable or epistatic mutation effects may provide a basis for accurate inferences of deleterious mutations. Simulations accounting for environmental variance of fitness suggest that, under full-sib mating, our extension can achieve reasonably well an estimation with sample sizes of only ∼2000-3000.

scholarly journals Expression and Characterization of the Flocculin Flo11/Muc1, a Saccharomyces cerevisiae Mannoprotein with Homotypic Properties of Adhesion

2007 ◽  
Vol 6 (12) ◽  
pp. 2214-2221 ◽  
Author(s):  
Lois M. Douglas ◽  
Li Li ◽  
Yang Yang ◽  
A. M. Dranginis
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Biofilm Formation ◽  
In Vitro System ◽  
Glycosylphosphatidylinositol Anchor ◽  
Fungal Adhesion ◽  
Very High ◽  
Molecular Weight Form

ABSTRACT The Flo11/Muc1 flocculin has diverse phenotypic effects. Saccharomyces cerevisiae cells of strain background Σ1278b require Flo11p to form pseudohyphae, invade agar, adhere to plastic, and develop biofilms, but they do not flocculate. We show that S. cerevisiae var. diastaticus strains, on the other hand, exhibit Flo11-dependent flocculation and biofilm formation but do not invade agar or form pseudohyphae. In order to study the nature of the Flo11p proteins produced by these two types of strains, we examined secreted Flo11p, encoded by a plasmid-borne gene, in which the glycosylphosphatidylinositol anchor sequences had been replaced by a histidine tag. A protein of approximately 196 kDa was secreted from both strains, which upon purification and concentration, aggregated into a form with a very high molecular mass. When secreted Flo11p was covalently attached to microscopic beads, it conferred the ability to specifically bind to S. cerevisiae var. diastaticus cells, which flocculate, but not to Σ1278b cells, which do not flocculate. This was true for the 196-kDa form as well as the high-molecular-weight form of Flo11p, regardless of the strain source. The coated beads bound to S. cerevisiae var. diastaticus cells expressing FLO11 and failed to bind to cells with a deletion of FLO11, demonstrating a homotypic adhesive mechanism. Flo11p was shown to be a mannoprotein. Bead-to-cell adhesion was inhibited by mannose, which also inhibits Flo11-dependent flocculation in vivo, further suggesting that this in vitro system is a useful model for the study of fungal adhesion.

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